Open Collections

UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

The role of the response contingency in the development and dissipation of tolerance to ethanol's anticonvulsant… Mana, Michael Joseph 1986

Your browser doesn't seem to have a PDF viewer, please download the PDF to view this item.

Item Metadata

Download

Media
831-UBC_1986_A8 M34_2.pdf [ 4.08MB ]
Metadata
JSON: 831-1.0097021.json
JSON-LD: 831-1.0097021-ld.json
RDF/XML (Pretty): 831-1.0097021-rdf.xml
RDF/JSON: 831-1.0097021-rdf.json
Turtle: 831-1.0097021-turtle.txt
N-Triples: 831-1.0097021-rdf-ntriples.txt
Original Record: 831-1.0097021-source.json
Full Text
831-1.0097021-fulltext.txt
Citation
831-1.0097021.ris

Full Text

THE ROLE OF THE RESPONSE CONTINGENCY IN THE DEVELOPMENT AND DISSIPATION OF TOLERANCE TO ETHANOL'S ANTICONVULSANT EFFECT B . S c , Washington S t a t e U n i v e r s i t y , 1982. A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF ARTS i n THE FACULTY OF GRADUATE STUDIES DEPARTMENT OF PSYCHOLOGY We a c c e p t t h i s t h e s i s as conforming to the requir-ed s t a n d a r d THE UNIVERSITY OF BRITISH COLUMBIA October 1986 ( c j M i c h a e l Joseph Mana By MICHAEL JOSEPH MANA In presenting t h i s thesis i n p a r t i a l f u l f i l m e n t of the requirements for an advanced degree at the University of B r i t i s h Columbia, I agree that the Libr a r y s h a l l make i t f r e e l y a v a i l a b l e for reference and study. I further agree that permission for extensive copying of t h i s thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. I t i s understood that copying or publi c a t i o n of t h i s thesis for f i n a n c i a l gain s h a l l not be allowed without my written permission. x . c. PSYCHOLOGY Department of The University of B r i t i s h Columbia 1956 Main Mall Vancouver, Canada V6T 1Y3 Date October 11, 1986 ABSTRACT Ethanol blocks the seizures normally e l i c i t e d i n kindled rats by convulsive stimulation. Tolerance to t h i s anticonvulsant e f f e c t r a p i d l y develops following a series of ethanol injections delivered at 48-hr in t e r v a l s only when convulsive stimulation i s administered during the periods of int o x i c a t i o n . Subjects receiving ethanol 1 hr before convulsive stimulation demonstrate tolerance a f t e r just f i v e tolerance-development t r i a l s , whereas there i s l i t t l e tolerance in subjects that receive ethanol 1 hr afte r each stimulation. Such tolerance i s termed contingent tolerance because i t s development is contingent upon the occurrence of the c r i t e r i o n response ( i . e . , convulsive a c t i v i t y ) during the periods of ethanol exposure. The purpose of thi s thesis was to c l a r i f y the nature of contingent tolerance to ethanol's anticonvulsant e f f e c t . The f i r s t three experiments were designed to determine whether any tolerance at a l l develops in rats that do not receive stimulation during periods of in t o x i c a t i o n . The fourth experiment was designed to determine whether the d i s s i p a t i o n of tolerance to ethanol's anticonvulsant e f f e c t i s influenced by the response contingency. Experiment 1 tested the hypothesis that the development of tolerance in the ethanol-after condition might be i i i detectable i f a smaller treatment dose than that previously studied was used. The subjects that were Intubated with ethanol (either 2 g/kg or 5 g/kg) before stimulation on the f i v e tolerance-development t r i a l s demonstrated substantial tolerance development, whereas there was l i t t l e evidence of tolerance in the ethanol-after subjects. The purpose of Experiment 2 was to determine whether the ethanol-after subjects would develop tolerance i f more than the customary number of treatment t r i a l s were administered. Rats that received ethanol (2 g/kg, intubated) before each stimulation demonstrated s i g n i f i c a n t tolerance a f t e r just 5 tolerance-development t r i a l s , whereas there was l i t t l e evidence of tolerance in the ethanol-after condition even after 20 t r i a l s . In Experiment 3, a s e n s i t i v e m u l t i p l e - t r i a l test permitted the detection of tolerance to ethanol's anticonvulsant e f f e c t in the ethanol-after group. In the test phase, rats that had received 20 tolerance-development t r i a l s in which ethanol (1.5 g/kg, IP) was administered a f t e r each stimulation developed tolerance more quickly than rats that had received saline i n j e c t i o n s . However, even the results of Experiment 3 i l l u s t r a t e the importance of the response contingency i n the development of tolerance to ethanol's anticonvulsant e f f e c t . The tolerance that developed in the ethanol-after rats was not apparent on the f i r s t test t r i a l , and was detectable only as an acceleration in the development of tolerance when ethanol was administered before stimulation in a series of test t r i a l s . In contrast, s i g n i f i c a n t tolerance i s t y p i c a l l y detectable in the ethanol-before condition after only 5 t r i a l s . In Experiment 4, the response contingency was shown to play a c r i t i c a l role in the d i s s i p a t i o n of tolerance to ethanol's anticonvulsant e f f e c t . Tolerant rats that received no ethanol over a 14-day retention i n t e r v a l did not lose their tolerance i f they were not stimulated during t h i s period, whereas tolerant rats that continued to receive ethanol on the same b i d a i l y schedule associated with tolerance development demonstrated a complete loss of tolerance i f they were stimulated before, rather than during, the periods of i n t o x i c a t i o n . Accordingly, ethanol withdrawal was neither necessary nor s u f f i c i e n t for the d i s s i p a t i o n of tolerance; the c r i t i c a l factor was the e l i c i t a t i o n of seizures in the absence of ethanol. Together, the r e s u l t s of these experiments provide unequivocal evidence of the important role that the response contingency plays in both the development and d i s s i p a t i o n of tolerance to ethanol's anticonvulsant e f f e c t , and they c l e a r l y i l l u s t r a t e the inadequacy of two t r a d i t i o n a l assumptions about drug tolerance: 1) that the development of tolerance to a drug's e f f e c t s i s a sole function of the pattern of drug administration, and 2) that i t s d i s s i p a t i o n is a sole function of drug withdrawal. V TABLE OP CONTENTS Abstract i i Table of Contents v L i s t of Figures v i i i Acknowledgement ix I. General Introduction 1 1. Drug Tolerance 2 Context-Specific Tolerance 6 2. Contingent Drug Tolerance 10 The Concept 10 The Generality of Contingent Tolerance 14 i . Psychostimulants 14 i i . Morphine 16 i i i . Pentobarbital 17 iv . Delta-9-THC 17 v. Ethanol 18 3. Contingent Tolerance to Ethanol's Anticonvulsant E f f e c t 20 4. General Rationale 26 5. General Purpose 28 II. General Background for Experiments 1, 2, and 3 30 I I I . General Methodology 38 Subjects 38 Surgical Procedure 38 K indl ing ..38 Baseline 39 Treatment 40 Test 41 Histology 42 S t a t i s t i c a l Analysis ...42 v l IV. Experiment 1 43 Method 44 Tolerance-Development Phase 44 Test 45 Analysis 4 5 Results 45 Discussion 50 V. Experiment 2 51 Method 51 Tolerance-Development Phase 51 Test 52 Analysis 52 Results 52 Discussion 57 VI. Experiment 3 58 Method 58 Treatment 59 Test 59 Analysis 59 Results 61 Discussion 61 VII. Experiment 4 62 Subjects 63 Surgery 63 Kindling and Baseline Phase 63 Tolerance Development 63 Tolerance D i s s i p a t i o n 64 Test 65 Histology 65 S t a t i s t i c a l Analysis 65 Results 65 Discussion 66 VIII. General Discussion 72 1. General Discussion of Experiments 1, 2, and 3...73 2. General Discussion of Experiment 4 75 3. Theoretical Accounts of Contingent Tolerance 77 i . Reinforcement-Density Model 78 i i . State-Dependency Model 80 i i i . Homeostatic-Conditioning Model 81 4. Conclusions and Future Directions 86 References 91 v i i LIST OF FIGURES Figure 1....Contingent Tolerance to Ethanol's Anticonvulsant Ef f e c t (Pinel 1983) 23-24 Figure 2....Experiment 1. E f f e c t of Dose on the Detection of Tolerance in the Ethanol-After Group 47-48 Figure 3 .... Histology From Experiment 1 49 Figure 4....Experiment 2. E f f e c t of Increasing the Number of Tolerance-Development T r i a l s on the Detection of Tolerance in the Ethanol-After Group 54-55 Figure 5....Histology From Experiment 2 56 Figure 6.... Histology From Experiment 3 60 Figure 7....Experiment 4. The E f f e c t of the Response Contingency on the Dissipation of Tolerance to Ethanol's Anticonvulsant E f f e c t 67-68 Figure 8 ....Histology From Experiment 4 69 v i i i ACKNOWLEDGEMENTS I thank Dr. John P. J. Pinel for his support and his confidence/ and for his contributions in word and thought to th i s t h e s i s . I thank Dr. W. J. Jacobs for his comments, and J. A. Ward, G. Renfrey, and C. K. Kim for t h e i r assistance and insights during the conduct of these experiments. I thank Dr. E. Eich and Dr. A. G. P h i l l i p s for the i r contributions to the f i n a l copy. And I thank Janet for making things easier. 1 I. GENERAL INTRODUCTION P i n e l , Colbourne, Sigalet, and Renfrey (1983) recently demonstrated that tolerance develops to ethanol's anticonvulsant e f f e c t on motor seizures e l i c i t e d in kindled r a t s . The most inter e s t i n g feature of t h e i r demonstration was that the tolerance developed only i f convulsive stimulation was administered during the periods of ethanol exposure. Rats that were not stimulated during the tolerance-development phase of the experiment or that were stimulated prior to, rather than a f t e r , each of the f i v e ethanol intubations c o n s t i t u t i n g the tolerance-development phase demonstrated no tolerance whatsoever to the anticonvulsant e f f e c t of ethanol. In contrast, rats that received convulsive stimulation during each period of ethanol exposure demonstrated almost complete tolerance. Such tolerance, which i s not the inevitable product of drug exposure but i s contingent upon the repeated occurrence of the c r i t e r i o n response—convulsive a c t i v i t y , in t h i s c a s e — during the periods of drug exposure, has been termed contingent tolerance (Carlton & Wolgin, 1971). The general purpose of the present experiments was to c l a r i f y the nature of contingent tolerance to ethanol's anticonvulsant e f f e c t . Accordingly, the f i r s t three sections of t h i s General Introduction deal with: 1) drug tolerance in general, 2) contingent tolerance in general, and 3) 2 contingent tolerance to ethanol's anticonvulsant e f f e c t . The Introduction concludes with statements of: 4) the general rationale and 5) the general purposes of the t h e s i s . 1. Drug Tolerance Because i t i s an interesting example of b i o l o g i c a l adaptation (Cappell & LeBlanc, 1979) and because of i t s hypothetical r e l a t i o n to the phenomena of drug dependence, withdrawal, and abuse (Cappell & LeBlanc, 1979; Melmon, Gilman, & Mayer, 1980; Siegel & MacRae, 1984); tolerance i s one of the most widely studied drug-related phenomena. Yet our understanding of tolerance remains at an elementary l e v e l . Drug tolerance i s a decrease in an e f f e c t of a drug that occurs as the r e s u l t of previous exposure to i t . There are two ways of measuring drug tolerance, either as a decrease i n the e f f e c t e l i c i t e d by a given drug dose or as an increase in the dose required to e l i c i t a p a r t i c u l a r e f f e c t (Schuster, 1978). Although tolerance develops to the e f f e c t s of many drugs, i t does not develop to the e f f e c t s of a l l drugs. And i t does not necessarily develop to a l l of the e f f e c t s of a p a r t i c u l a r drug; exposure to a p a r t i c u l a r drug may lead to the development of tolerance to some of i t s e f f e c t s , while others may be unchanged or even increased i n magnitude (e.g., Woolverton, Kandel, & Schuster, 1978). Although the basic mechanisms responsible for the 3 development of drug tolerance are poorly understood, there are two general types of b i o l o g i c a l change to which tolerance is usually a t t r i b u t e d : d i s p o s i t i o n a l change or functional change. D i s p o s i t i o n a l change refers to any a l t e r a t i o n in the absorption, d i s t r i b u t i o n , breakdown, or clearance of a drug; whereas, functional change refers to any a l t e r a t i o n in the s e n s i t i v i t y of the physiological systems affected by the drug (Jaffe, 1980; Kalant et a l . , 1971). Although a t t r i b u t i n g each instance of tolerance to eithe r a d i s p o s i t i o n a l or a functional mechanism appears to be a reasonable step in the analysis of a pa r t i c u l a r instance of tolerance, t h i s approach has not proven to be p a r t i c u l a r l y f r u i t f u l . In my view, there are two major reasons for t h i s . F i r s t , each instance of drug tolerance i s not necessarily either d i s p o s i t i o n a l or functional; both types of change can contribute to a pa r t i c u l a r instance of tolerance ( c f . J a f f e , 1980; Kalant, LeBlanc, & Gibbins, 1971; Krasnegor, 1978). Second, instances of functional tolerance are often i d e n t i f i e d only by the f a i l u r e to i d e n t i f y an underlying d i s p o s i t i o n a l change (cf. Dews, 1978; L i s t e r , F i l e , & Greenblatt, 1983; Mycek & Breznof, 1976). The reason for t h i s reliance on "negative" evidence i s that so many d i f f e r e n t types of physiological a l t e r a t i o n s are subsumed under the rubric of functional  change that i t i s d i f f i c u l t to a t t r i b u t e a given instance of tolerance to any one of them. For example, functional change can refer to changes in the s e n s i t i v i t y or number of 4 neurotransmitter receptors (Rebec & Lee, 1983; Seeman, 1980); changes in the levels of neurotransmitters (Melchior & Tabakoff, 1981), neuromodulators ( V o l l i c e r & Ullman, 1985), or hormones (Wood, 1977; Tabakoff & Yanai, 1979); changes in c e l l membrane composition (Goldstein, 1983); changes in the a c t i v i t y of secondary messengers necessary for many neurotransmitters to have a postsynaptic e f f e c t (e.g., Siggins, 1979); or changes i n ion conductance (Ross, Garrett, & Cardenas, 1979 ) . Another reason why researchers have had d i f f i c u l t y determining the mechanisms responsible for a given instance of tolerance—and the one most pertinent to the present experiments—is the fact that they have l a r g e l y ignored the important role of the subject in the development of tolerance. Implicit in most discussions of tolerance i s the assumption that the pattern of drug exposure i s the preeminent factor in the development of tolerance, and the majority of the research in the area of tolerance r e f l e c t s t h i s assumption; most studies of tolerance have focused on the drug dose and on the route and schedule of drug administration. In a sense, the organism receiving the drug has been i m p l i c i t l y regarded as nothing more than a passive recipient of the drug, and the influence of the experiences of the subject during periods of drug exposure on the development of tolerance have thus been la r g e l y ignored. In the l a s t decade, however, i t has become obvious that 5 any account of tolerance that does not acknowledge the importance of the subject's drug-related experiences i s grossly inadequate. One of the most e x c i t i n g recent advances in behavioral pharmacology has been the accumulation of incontrovertible evidence that the development and d i s s i p a t i o n of many types of tolerance are often as dependent upon environmental and behavioral variables a f f e c t i n g the organism during periods of drug exposure as they are upon the t r a d i t i o n a l variables associated with the drug's administration (cf. Balster, 1984). It i s t h i s recent recognition of the role of drug-related experiences in drug tolerance that provided the general background and i n s p i r a t i o n for the present t h e s i s . The e f f e c t of environmental and behavioral variables on tolerance has been demonstrated repeatedly by two types of research: by studies of context-specific drug tolerance (Baker & Tiffany, 1985; Eikelboom & Stewart, 1982; Siegel, 1975; 1977; Siegel & MacRae, 1984; Solomon, 1977; Wikler, 1948; 1973) and by studies of a phenomenon often referred to as contingent drug tolerance (Demellweek & Goudie, 1983b; Goudie & G r i f f i t h , 1985). The present thesis i s concerned with contingent drug tolerance; however, a b r i e f introduction to context-specific tolerance precedes a more extensive review of the contingent tolerance phenomenon. 6 Context-Specific Drug Tolerance The manifestation of many types of drug tolerance has been shown to be dependent upon the drug's being administered in the context in which the subjects had previously experienced the drug's e f f e c t s (e.g., Oafters & Anderson, 1982; Siegel, 1978). If subjects receive the t e s t dose of a drug in the same context in which i t had been previously administered, they d i s p l a y considerable tolerance to i t s e f f e c t s ; whereas, i f the drug i s administered on the test t r i a l in a context with no drug-related history, the subjects display l i t t l e or no tolerance. Such context-specific tolerance has been demonstrated to the e f f e c t s of: 1) morphine (Siegel, 1975, 1977), 2) ethanol (Mansfield & Cunningham, 1980), 3) pentobarbital (Hinson, Poulos, & Cappell, 1982), 4) scopolamine (Poulos, Wilkinson, & Cappell, 1981), 5) caffeine (Rozin, Reff, Mark, & S c h e l l , 1984), and 6) amphetamine (Poulos & Hinson, 1984). According to Siegel (1975; 1977; 1984), the context s p e c i f i c i t y of t h i s tolerance is the consequence of Pavlovian conditioning. I t i s Siegel's view that the context in which a subject repeatedly experiences the drug's e f f e c t s can be a conditional stimulus (CS) that becomes associated with the unconditional e f f e c t s of the drug (the unconditional s t i m u l i or UCS's). Siegel argues that as t h i s association i s strengthened, the context begins to e l i c i t a conditional compensatory response (CCR), 7 which opposes the unconditional e f f e c t s of the drug and increases in magnitude as the association between the context and the drug's effects strengthens. Because the CCR i s manifested only when the drug i s administered in the usual context, the manifestation of tolerance is con t e x t - s p e c i f i c . Several l i n e s of evidence support Siegel's Pavlovian explanation of context-specific tolerance. F i r s t , the development of context-specific tolerance i s se n s i t i v e to preexposure to the CS; i f subjects are repeatedly presented with the context that is to become the CS prior to the regimen of drug exposure, the development of tolerance when the context and the drug's e f f e c t s are subsequently paired i s much slower than i t i s i f subjects have had no prior experience with the context (Siegel, 1977). Second, instances of context-specific tolerance have been found to be sensit i v e to extinction procedures. When a tolerant subject is repeatedly placed in the context that has become a CS for a p a r t i c u l a r drug e f f e c t , but the drug i s not administered, there i s a gradual decline in the tolerance that has developed (Siegel, 1975; Greeley, Le, Poulos, & Cappell, 1984) . The t h i r d , and most d i r e c t , l i n e of evidence supporting Siegel's Pavlovian theory of context-specific tolerance has been provided by studies of the conditional compensatory response, the hypothetical construct on which Siegel's theory i s based. The administration of a placebo to tolerant 8 subjects in the drug-predictive environment has frequently been reported to e l i c i t a CCR, that i s a response opposite to the i n i t i a l e f f e c t of the drug. For example, placebo injections in the drug-predictive environment have been shown to e l i c i t hyperalgesia in rats that have developed context-s p e c i f i c tolerance to the analgesic e f f e c t of morphine (Krank, Hinson, & Siegel, 1981), hypothermia in rats tolerant to morphine's hyperthermic e f f e c t (Siegel, 1978), or hyperactivity in rats tolerant to ethanol's hypoactive e f f e c t (Mansfield & Cunningham, 1980). Unfortunately, many attempts to demonstrate a conditional compensatory response have been unsuccessful, and Siegel's Pavlovian model of context-s p e c i f i c tolerance has been c r i t i c i z e d by a number of researchers on t h i s basis (e.g., Baker & T i f f a n y , 1985; Goudie & G r i f f i t h s , 1985; Shapiro, Dudek, & R o s e l l i n i , 1983; Tiffany, Baker, P e t r i e , & Dahl, 1983). In what i s arguably the most well-developed alt e r n a t i v e to Siegel's Pavlovian theory of context-specific tolerance, Baker and his colleagues (Baker & Tiffany, 1985; Kesner & Baker, 1981; Kesner & Cook, 1983) have argued that such tolerance can be attributed to a cued habituation to the drug's e f f e c t s (see also Solomon, 1977; Wagner, 1978; 1981, for e a r l i e r versions of t h i s idea). According to t h i s theory of context-specific tolerance, repeated administration of a drug i n a p a r t i c u l a r environment leads to the development of an association between the contextual cues and the drug's e f f e c t s . As a 9 re s u l t of t h i s association, subsequent presentation of the contextual cues leads to the r e t r i e v a l from long-term memory of a representation of the drug's e f f e c t s . This " a s s o c i a t i v e l y generated priming r e s u l t [ s ] in decreased neural processing of the drug stimulus. Such decreased processing of drug stimulus information r e s u l t s in [sic] attenuated behavioral e f f e c t and constitutes tolerance." (Baker & Ti f f a n y , 1985, p. 83). The fact that reasonable a l t e r n a t i v e s to Siegel's Pavlovian theory of context-dependent tolerance e x i s t i l l u s t r a t e s the inapproprlateness of using the terms Pavlovian tolerance or conditional tolerance to refer to tolerance that i s affected by the context present during periods of drug exposure. Because these terms refer to a possible explanation of context-specific tolerance, their use as labels for the tolerance i t s e l f i s c i r c u l a r , and places the i n d i v i d u a l using such terms in the pos i t i o n of debating whether Pavlovian (conditional) tolerance i s in fact c ontrolled by Pavlovian (conditioning) mechanisms. Because i t i s always important to maintain a conceptual d i s t i n c t i o n between the phenomenon i t s e l f and the explanations of i t , the less common, but more neutral, term context-specific  tolerance i s used here to refer to the phenomenon. Regardless of the s p e c i f i c mechanisms underlying context-specific tolerance, the wide recognition the phenomenon i t s e l f has received represents a major advance in 10 the study of drug tolerance. In studies of context-specific tolerance, various groups of subjects with i d e n t i c a l drug h i s t o r i e s display markedly d i f f e r e n t l e v e l s of tolerance depending on the contextual cues present during periods of drug exposure. This finding has, more than any other, been responsible for focusing the attention of researchers on the importance of subject-related variables in drug tolerance. 2. Contingent Drug Tolerance The Concept Studies of contingent drug tolerance have also provided evidence that subject-related variables play an important role i n the development of drug tolerance. Contingent tolerance i s tolerance that develops p r e f e r e n t i a l l y to a drug's e f f e c t s on those responses that occur during the periods of drug exposure. It i s usually demonstrated in terms of the difference i n tolerance observed between the two groups of subjects in what has been termed the before-and- after design (Kumar & Stolerman, 1977). In t h i s design, the subjects in one group (the drug-before group) receive the drug before engaging in a p a r t i c u l a r response (the c r i t e r i o n response) on each tolerance-development t r i a l , so that the response i s performed while the subject i s under the influence of the drug. The subjects i n the second group (the drug-after group) receive the drug a f t e r engaging in the c r i t e r i o n response. On the te s t t r i a l , a l l subjects receive the drug before the performance of the c r i t e r i o n response so that the drug's e f f e c t s on i t can be assessed. Any evidence of greater tolerance in the drug-before subjects is attributed to the response contingency because the subjects in the two groups do not d i f f e r in either t h e i r exposure to the drug or in th e i r opportunity to perform the c r i t e r i o n response. Chen (1968) was the f i r s t to demonstrate the importance of the response contingency in a study of the development of tolerance to ethanol's disruptive e f f e c t s on maze running. He trained rats to perform a maze task and then assigned them to one of two groups. The rats in one group received ethanol before running the maze on each tolerance development t r i a l ; whereas, the rats in the other group ran the maze before receiving ethanol. Chen found that only those subjects that had the opportunity to practice the maze while under the influence of ethanol subsequently demonstrated tolerance to i t s d i sruptive e f f e c t s . The rats in the ethanol-after group demonstrated no tolerance to ethanol's e f f e c t on maze performance even though they had received the same number of ethanol i n j e c t i o n s and had the same amount of exposure to the maze. The key to understanding the concept of contingent drug tolerance l i e s in the idea that tolerance develops not to the systemic presence of a drug but to i t s e f f e c t s (cf. Demellweek & Goudie, 1983b; Okamoto, Boisse, Rosenberg, & Rosen, 1978). Many drug e f f e c t s are, under normal circumstances, an inevitable consequence of drug exposure (e.g., the hypothermic e f f e c t of ethanol). In such cases, the role of the response contingency i n the development of tolerance i s not r e a d i l y apparent because the systemic presence of the drug and i t s eff e c t s are i n e x t r i c a b l y related. However, there are other drug e f f e c t s that occur only i f the drug i s administered when the re c i p i e n t i s engaged in a p a r t i c u l a r response (the c r i t e r i o n response). In such cases, i t i s possible to show that the drug e f f e c t , rather than exposure to the drug per se, i s the c r i t i c a l factor i n the development of tolerance. For example, in Chen's experiment ethanol's disruptive e f f e c t on maze performance could manifest i t s e l f only when the rats were exposed to the maze while intoxicated, and i t was only in t h i s condition that tolerance developed. Poulos and his colleagues (Poulos & Hinson, 1984; Poulos et a l . , 1981) have i l l u s t r a t e d the importance of the c r i t e r i o n response to the development of contingent tolerance with an i n t e r e s t i n g analogy to a well-known perceptual phenomenon. According to these authors, to expect tolerance to develop i n the absence of the c r i t e r i o n response i s " l i k e expecting adaptation to the e f f e c t s of l a t e r a l l y d i s p l a c i n g prisms to develop in an organism maintained i n the dark. Without an adequate i n s t i g a t i n g stimulus to provide the basis for perceptual adaptation, none can occur" (Poulos et a l . , 1981, p. 745). Although their a l l u s i o n to the "displaced v i s i o n " phenomenon i s i n s i g h t f u l , i t requires a s l i g h t but s i g n i f i c a n t modification. It i s not l i g h t per se, but the subject's v i s u a l perception of "self-produced movement... with i t s contingent reafferentation [ s i c ] stimulation [that] is the c r i t i c a l factor in compensating for displaced v i s u a l images" (Held, 1972, p. 375; see also Rock & Harris, 1972). That i s , adaptation to the d i s r u p t i v e e f f e c t s of v i s u a l displacement on visuomotor responding does not occur unless such responding occurs under the influence of the displaced v i s i o n . In the same way, tolerance to a drug's e f f e c t s does not develop unless the e f f e c t s are manifested. In instances of contingent tolerance, performance of the c r i t e r i o n response i s necessary for the manifestation of the drug e f f e c t of interest, and thus for tolerance to develop to that e f f e c t . The term behavioral tolerance has also been used to refer to what I have la b e l l e d contingent tolerance (e.g., Chen, 1972; Dews, 1978; Hayes & Mayer, 1978). However, the term behavioral tolerance is also commonly used to refer to any tolerance that develops to the e f f e c t s of a drug on behavior (e.g., Kumar & Stolerman, 1977), and when used in t h i s fashion, i t has no implications whatsoever for the conditions underlying the development of the tolerance. Therefore, the term contingent tolerance i s used throughout the present thesis to avoid t h i s ambiguity. 14 The Generality of Contingent Tolerance Response contingencies have been shown to be an important, i f not c r u c i a l , factor in the development of tolerance to a wide v a r i e t y of drug e f f e c t s . This subsection b r i e f l y reviews reports of contingent drug tolerance to: i) the e f f e c t s of amphetamine and several other psychostimulants; i i ) the e f f e c t s of morphine; i i i ) the e f f e c t s of delta-9-THC; iv) the e f f e c t s of pentobarbital; and v) the e f f e c t s of ethanol. The focus of the present t h e s i s , that i s contingent tolerance to ethanol's anticonvulsant e f f e c t , i s introduced i n more d e t a i l in the next s e c t i o n . i . Contingent Tolerance to the E f f e c t s of Psychostimulants The term contingent tolerance was f i r s t used by Carlton and Volgin (1971) to describe t h e i r observation that the development of tolerance to the anorexigenic e f f e c t of d-amphetamine in rats i s contingent upon providing the subjects with an opportunity to eat during each period of drug exposure. Using a before-and-after design, Carlton and Wolgin found that rats allowed to drink a sweet milk s o l u t i o n while they were under the influence of d-amphetamine developed tolerance to the drug's anorexigenic e f f e c t s within just a few treatment sessions. In contrast, rats receiving each of t h e i r amphetamine inje c t i o n s a f t e r they had consumed the milk solution demonstrated no tolerance when they subsequently received the drug prior to the milk. Furthermore, the rats i n the drug-after condition developed tolerance to amphetamine's anorexlgenic e f f e c t no faster than drug-naive control rats when they subsequently received a serie s of amphetamine injections before milk consumption. The re s u l t s of Carlton and Wolgin's o r i g i n a l study have been replicated by a number of researchers (e.g., Demellweek & Goudie, 1982; 1983a; Emmett-Oglesby, Spencer, Wood, & L a i , 1984; Poulos et a l . , 1981). Contingent tolerance has also been demonstrated to the anorexlgenic e f f e c t s of psychostimulants other than amphetamine: cocaine (Woolverton et a l . , 1978), cathinone ( F o l t i n & Schuster, 1982), roethylphenidate (Emmett-Oglesby & Taylor, 1981), and guipazine (Rowland & Carlton, 1983). Furthermore, the tolerance that develops to the e f f e c t s of psychostimulant drugs on a v a r i e t y of operant tasks has also been shown to be influenced by a response contingency (e.g., Campbell & Seiden, 1973; Emmett-Oglesby et a l . , 1984). For instance, Emmett-Oglesby et a l . (1984) found that rats in a differential-reinforcement-for-low-rates-of-responding (DRL) paradigm developed tolerance to the acceleration of bar-press responding caused by amphetamine only when they had the opportunity to engage In the DRL task during periods of amphetamine exposure. This study i s p a r t i c u l a r l y i n t e r e s t i n g because Emmett-Oglesby and his colleagues found that the rats that had developed tolerance to amphetamine's e f f e c t on DRL 16 responding showed no loss of s e n s i t i v i t y to the drug's anorexigenic e f f e c t , and conversely that contingent tolerance developed to amphetamine's anorexigenic e f f e c t without a f f e c t i n g the drug's e f f e c t on the DRL response rate. In each condition, tolerance developed only to the e f f e c t of the drug that was allowed to manifest i t s e l f . 11. Contingent Tolerance to the E f f e c t s of Morphine The response contingency has also been reported to play a role i n the development of tolerance to morphine's analgesic e f f e c t . In several studies, rats that were placed on a functioning hotplate during periods of morphine exposure demonstrated greater tolerance to i t s analgesic e f f e c t than did rats that were not (e.g., Kayan & M i t c h e l l , 1969; Kayan, Woods, & M i t c h e l l , 1969; Moore, 1983). A s i m i l a r e f f e c t has been demonstrated in human subjects (Ferguson & M i t c h e l l , 1969), using a tourniquet rather than a hotplate to provide the painful stimulation . Because none of these studies of tolerance to morphine's analgesic e f f e c t used the before-and-after design, they do not provide unambiguous evidence that the response contingency i s an important factor in the development of such tolerance. However, the before-and-afte r design has been used to show that the response contingency plays an important role in the development of tolerance to the disruptive e f f e c t s of morphine on operant responding in the rat (Smith, 1979). 17 111. Contingent Tolerance to the Eff e c t s of Pentobarbital The response contingency has been implicated in the development of tolerance to the disruptive e f f e c t s of pentobarbital on operant behavior (Branch, 1983) and rotorod performance (Commissaris & Rech, 1981). The demonstration by Branch (1983) is unique in that a within-subject design was used. He f i r s t trained monkeys to perform a bar-press response for a food reward. Once a stable baseline was established, Branch administered pentobarbital to the monkeys immediately a f t e r they completed a test session on each of 20 consecutive days. On the twenty-first day, Branch administered pentobarbital to the monkeys before they performed the task, and found no evidence of tolerance to the drug's rate-increasing e f f e c t s . This administration schedule was maintained for the next 20 consecutive days, and Branch found that tolerance to the drug's e f f e c t on the operant response r a p i d l y developed. Branch concluded that drugged performance of the operant response was a c r i t i c a l factor i n the development of tolerance to pentobarbital's e f f e c t s on the task. Unfortunately, because Branch neglected to include the necessary controls (e.g., counterbalancing), his experiment does not provide incontrovertible evidence of contingent tolerance. Iv. Contingent Tolerance to the E f f e c t s of Delta-9-THC Contingent tolerance to the disruptive e f f e c t s of delta-9-THC on bar-press behavior In the monkey (Carder & 18 Olson, 1973; Elsmore, 1972), and on bar-press and avoidance behavior i n the rat (Manning, 1976a,b) have been demonstrated. In Manning's experiments, the development of contingent tolerance to delta-9-THC's e f f e c t on operant responding was not influenced by prior drug history; rats that had previously received the drug a f t e r performing the c r i t e r i o n a c t i v i t y developed tolerance no faster than naive controls when both groups of rats received the drug before performing the response. v. Contingent Tolerance to the Ef f e c t s of Ethanol As described e a r l i e r in t h i s section, Chen (1968) provided the f i r s t report of contingent tolerance to ethanol's e f f e c t s . Since Chen's seminal demonstration, contingent tolerance has been demonstrated to a v a r i e t y of ethanol's e f f e c t s . For example, contingent tolerance has been demonstrated to the e f f e c t of ethanol on treadmill running (LeBlanc, Gibbins, & Kalant, 1973; 1975; Wenger, Tiffany, Bombardier, Ni c h o l l s , & Woods, 1981), to ethanol's e f f e c t on operant responding (Chen, 1979; Wiggell & Overstreet, 1984), and to the ethanol-induced acceleration in the decay of postsynaptic potentiation in the abdominal ganglia of the marine mollusc Aplvsia (Traynor, Schlapfer, & Barondes, 1980). Contingent tolerance has also been demonstrated to ethanol's analgesic e f f e c t , using the t a i l -f l i c k test of analgesia (Jorgenson & Hole, 1984; Jorgenson, Berge, & Hole, 1985; Jorgenson, Farmer, & Hole, 1986). The 19 study by Jorgenson et a l . (1985) ls p a r t i c u l a r l y Interesting, because they demonstrated that contingent tolerance to ethanol's e f f e c t on the t a l l - f l i c k r e f l e x develops even when rats have been s p i n a l l y transected at the l e v e l of the ninth thoracic vertebrae. The response contingency has also been implicated in the development of tolerance to ethanol's hypothermic e f f e c t ; Alkana, Finn, and Malcolm (1982) found that tolerance does not develop If subjects are maintained at a constant body temperature during periods of ethanol exposure. This study ls p a r t i c u l a r l y interesting because of the methods used by Alkana et a l . to manipulate alcohol's hypothermic e f f e c t . Contingent tolerance i s usually studied to drug e f f e c t s that can occur only in a p a r t i c u l a r test s i t u a t i o n s (e.g., mazes, Skinner boxes, e t c . ) , and the experimenters control the performance of the c r i t e r i o n response by c o n t r o l l i n g the subjects' exposure to the test environments. In contrast, ethanol-induced hypothermia requires no s p e c i a l test s i t u a t i o n to manifest i t s e l f ; under normal conditions, hypothermia i s an inevitable consequence of ethanol exposure. To overcome t h i s problem, Alkana and his colleagues assigned mice to two groups. The mice in one group received a t o t a l of s i x d a i l y ethanol in j e c t i o n s . Immediately aft e r each i n j e c t i o n , the mice in t h i s group were placed i n a heated chamber so that the hypothermic e f f e c t of the ethanol was o f f s e t by the hyperthermic conditions present in the chamber. The subjects in the second group received the same number of ethanol i n j e c t i o n s , but were placed i n a chamber maintained at room temperature so that the hypothermic e f f e c t of each ethanol i n j e c t i o n could be manifested. On the test day, when a l l of the mice received an ethanol i n j e c t i o n and were placed in a chamber maintained at room temperature, Alkana and his colleagues found that only the mice in the group that had experienced ethanol's hypothermic e f f e c t demonstrated tolerance on the test day. 3. Contingent Tolerance to Ethanol's Anticonvulsant E f f e c t Pinel and his colleagues (1983; 1985) have demonstrated that contingent tolerance develops to ethanol's anticonvulsant e f f e c t . I t i s t h i s p a r t i c u l a r manifestation of contingent tolerance that i s the focus of the present t h e s i s . The three experiments in Pinel's o r i g i n a l (1983) report are noteworthy for two reasons. F i r s t , they provided the f i r s t unambiguous evidence that tolerance could develop to ethanol's anticonvulsant e f f e c t . Although Allan and Swinyard (1949) had reported tolerance to ethanol's anticonvulsant e f f e c t s on maximal electroshock seizures, subsequent attempts to confirm t h i s finding had f a i l e d (e.g., Chen, 1972; McQuarrie & F i n g l , 1972). The second important feature of Pinel et a l . ' s o r i g i n a l report of tolerance to ethanol's anticonvulsant e f f e c t , and the one more germane to the present t h e s i s , was that t h e i r rats developed tolerance to ethanol's anticonvulsant e f f e c t only i f they received convulsive amygdaloid stimulation during each period of ethanol exposure. In the f i r s t experiment of t h e i r o r i g i n a l (1983) report, Pinel and his colleagues found that kindled rats stimulated once every 24 hr for 5 days r a p i d l y developed tolerance to the anticonvulsant e f f e c t of ethanol (1.5 g/kg, IP) injected twice each day, once 12.5 hr before each d a i l y stimulation and again 0.5 hr before. In the second experiment, P i n e l et a l . found that there was no evidence of tolerance i n a group of rats that received the same schedule of ethanol injections that was administered to the ethanol subjects in Experiment 1, but no convulsive stimulation. This suggested that the development of tolerance to ethanol's anticonvulsant e f f e c t was contingent upon convulsive stimulation occurring during periods of ethanol exposure. In the t h i r d experiment, P i n e l and his colleagues used a before-and-after design to test the hypothesis suggested by the comparison of t h e i r f i r s t two experiments; that i s , that the response contingency was a c r u c i a l factor In the development of tolerance to ethanol's anticonvulsant e f f e c t . The rats in one group received an ethanol intubation (4.5 g/kg, i n a 30% v/v solution) 1.5 hr before each of f i v e b i d a i l y convulsive stimulations; t h i s dose of ethanol completely suppressed convulsive a c t i v i t y on the f i r s t treatment t r i a l . The rats in the second group received an i d e n t i c a l number of ethanol intubations, administered 1.5 hr after the stimulations. On the t e s t day, a l l of the rats received an ethanol i n j e c t i o n (1.5 g/kg, IP, in a 25% v/v solution) 1.5 hr before the stimulation was administered. As is evident in Figure 1, Pinel and his colleagues found that the rats in the group that had previously received convulsive stimulation while they were exposed to ethanol (the ethanol-before subjects) displayed substantial tolerance to ethanol's anticonvulsant e f f e c t . In contrast, there was no evidence of tolerance i n any of the subjects from the ethanol-after group. A subsequent analysis of the levels of ethanol in blood samples taken from the t a i l of each rat immediately after t e s t i n g revealed no s i g n i f i c a n t difference between the two groups. Pinel and Puttaswamaiah (1985) tested the p o s s i b i l i t y that contingent tolerance to ethanol's anticonvulsant e f f e c t was under Pavlovian c o n t r o l . Recall that i n instances of context-specific drug tolerance, the development and manifestation of tolerance to a drug's e f f e c t s are greatly influenced by the h i s t o r y of the contextual cues present during periods of drug exposure. Several authors have proposed that instances of contingent tolerance could be attributed to the same Pavlovian conditioning mechanism used to account for context-specific tolerance (e.g., Hinson & Seigel, 1980; Wenger et a l . , 1981). In the before-and-after 23 FIGURE 1. The e f f e c t of the response contingency on the development of tolerance to ethanol's anticonvulsant e f f e c t . During the treatment phase, ethanol (4.5 g/kg) was intubated at 48-hr i n t e r v a l s , either before or a f t e r convulsive stimulation. On the test t r i a l , the group that had received ethanol before stimulation on the treatment days (the prestimulation group) demonstrated substantial tolerance to the anticonvulsant e f f e c t of the t e s t dose of ethanol (1.5 g/kg, IP), whereas there was l i t t l e evidence of tolerance in the rats that had received ethanol af t e r each convulsive stimulation on the treatment days (the poststimulation group). (From Pinel et a l . , 1983; used with permission of Ankho International). MEAN DURATION OF FORELIMB CLONUS (sec) _ k I O W 4 » O O O O ——i—1—i—•—I—• r design, a l l of the subjects receive the drug before engaging in the c r i t e r i o n response on the test t r i a l . Thus, the t e s t t r i a l i s i d e n t i c a l to the tolerance-development sessions for the subjects in the before group, but not for the subjects from the aft e r group. According to the Pavlovian explanation of contingent tolerance, the absence of the c r i t e r i o n response prior to drug administration on the test day for the subjects in the after group changes the predrug context enough that the conditional compensatory response necessary for tolerance to occur does not f u l l y manifest i t s e l f . As a r e s u l t , the subjects from the after group do not appear tolerant on the t e s t t r i a l . P inel and Puttawamaiah (1985) attacked t h i s view by showing that the manipulation of contextual s t i m u l i associated with the administration of ethanol had no e f f e c t on contingent tolerance to ethanol's anticonvulsant e f f e c t . Pinel and Puttaswamaiah showed that tolerance to ethanol's anticonvulsant e f f e c t was not context-specific; there was no evidence of a conditional compensatory response; and preexposure to the contextual cues associated with ethanol administration had no e f f e c t on tolerance development. On the basis of these r e s u l t s , Pinel and Puttaswamaiah (1985) concluded that "tolerance to ethanol's anticonvulsant e f f e c t i s not amenable to Pavlovian conditioning" (p. 963) and thus that Pavlovian conditioning cannot account for demonstrations of contingent tolerance to ethanol's anticonvulsant e f f e c t . 26 This conclusion i s reinforced by Pinel et a l . ' s e a r l i e r (1983) observation that the manifestation of contingent tolerance to ethanol's anticonvulsant e f f e c t was unaffected by a change in the route of adminstration; subjects that had developed tolerance to ethanol's anticonvulsant e f f e c t when the drug was intubated displayed substantial tolerance when the ethanol was injected i n t r a p e r i t o n e a l l y on the test t r i a l . 4. G e n e r a l R a t i o n a l e There were three general reasons for my i n i t i a l i n t e r e s t in contingent tolerance to ethanol's anticonvulsant e f f e c t , as opposed to some other form of contingent tolerance. The f i r s t reason has to do with the fact that, although seizures are among the most c l i n i c a l l y s i g n i f i c a n t and most frequently studied symptoms of alcohol withdrawal, l i t t l e attention had been paid to the tolerance that most current theories predict to underlie them. The same physiological adaptations that are presumed to oppose alcohol's unconditional e f f e c t s , and therefore produce tolerance, are assumed to trigger withdrawal e f f e c t s opposite to the unconditional e f f e c t s of the ethanol once i t has been eliminated from a subject's body (Cicero, 1980; Goldstein, 1979). Thus, the existence of ethanol withdrawal seizures implies that tolerance develops to ethanol's we11-documented anticonvulsant e f f e c t . However, u n t i l P i n e l et a l . ' s o r i g i n a l (1983) report of contingent tolerance to ethanol's anticonvulsant e f f e c t , attempts to 27 demonstrate any kind o£ tolerance had been equivocal. Accordingly, roy i n i t i a l i n t e r e s t in contingent tolerance to ethanol's anticonvulsant e f f e c t was p a r t i a l l y stimulated by a general i n t e r e s t i n the r e l a t i o n between ethanol tolerance and dependence, and by what was an obvious gap in the knowledge concerning a phenomenon of major t h e o r e t i c a l and c l i n i c a l s i g n i f i c a n c e . The second reason for my interest i n contingent tolerance to ethanol's anticonvulsant e f f e c t was that i t is a p a r t i c u l a r l y robust example of the contingent tolerance. Pinel and his colleagues had used a variety of conditions to demonstrate contingent tolerance to ethanol's anticonvulsant e f f e c t , yet in each case the e f f e c t of the response contingency was impressively c l e a r . In each of Pinel's experiments, rats in the ethanol-before condition developed almost complete tolerance af t e r just a few treatment sessions; whereas, those in the ethanol-after condition displayed no tolerance whatsoever. Thus, the paradigm used by Pinel and his colleagues seemed p a r t i c u l a r l y suited to study the role of the response contingency i n drug tolerance. The t h i r d reason for my i n i t i a l i nterest in contingent tolerance to ethanol's anticonvulsant e f f e c t was the apparent lack of influence that Pavlovian manipulations have on i t (e.g., P i n e l & Puttaswamaiah, 1985). Poulos and his colleagues have reported several instances of contingent tolerance that also appear to be p a r t i a l l y under Pavlovian 28 c o n t r o l . For example, Poulos et a l . (1981) reported that contingent tolerance to amphetamine's anorectic e f f e c t manifested i t s e l f only when the drug was administered in the context i n which the drug was previously administered; i f subjects received the drug in a novel context, there was no evidence of tolerance whatsoever. S i m i l a r l y , Poulos and Hinson (1984) showed that the response contingency had no e f f e c t on the manifestation of tolerance to scopolamine's adipsic e f f e c t unless the drug was administered in the usual context on the t e s t day. It seemed advisable, therefore, to study the influence of the response contingency on the development and d i s s i p a t i o n of tolerance i n a paradigm uncontaminated by the complicating e f f e c t s of Pavlovian conditioning. 5. General Purposes The experiments in the present thesis had two general purposes, which were to a large degree independent of one another. The f i r s t was to determine whether or not any tolerance at a l l can develop in the absence of the opportunity to perform the c r i t e r i o n response during periods of ethanol exposure. The second was to determine whether the response contingency plays a s i g n i f i c a n t role in the d i s s i p a t i o n of tolerance to ethanol's anticonvulsant e f f e c t . The f i r s t three experiments dealt with the f i r s t issue; whereas, the fourth and f i n a l experiment dealt with the 29 second. Accordingly, the next section reviews the controversy surrounding the question "Can ethanol tolerance develop in the absence of the response contingency?", whereas the l i t e r a t u r e relevant to the r o l e of the response contingency in the d i s s i p a t i o n of tolerance i s reviewed prior to Experiment 4. 30 I I . GENERAL BACKGROUND FOR EXPERIMENTS 1.2. AND 3 Without doubt, the most heated debate generated by the many demonstrations of contingent tolerance to ethanol's e f f e c t s has been whether any tolerance at a l l develops in the subjects that do not engage i n the c r i t e r i o n response during periods of ethanol exposure. At an empirical l e v e l , the question i s deceptively simple; "Is there any difference on the test t r i a l in ethanol's e f f e c t on the performance of the c r i t e r i o n response between subjects i n an ethanol-after group and a group of rats receiving the drug for the f i r s t time?". Nevertheless, there has yet to be a s a t i s f a c t o r y r e s o l u t i o n to the question. In Chen's o r i g i n a l demonstration of contingent tolerance (Chen, 1968), afte r four tolerance-development t r i a l s there was no s i g n i f i c a n t difference between the maze performance of the rats in the ethanol-after group on the test t r i a l a f t e r four tolerance-development t r i a l s , and the maze performance of rats with prior exposure to ethanol. In a subsequent study, Chen (1972) found no s i g n i f i c a n t tolerance development in the ethanol-after rats a f t e r s i x d a i l y treatment t r i a l s . On the basis of these studies, Chen concluded that ethanol per se i s not a s u f f i c i e n t stimulus for the development of tolerance to i t s disruptive e f f e c t s on maze running. This conclusion was soon challenged by LeBlanc, Gibbins, and Kalant (1973), who pointed out an obvious flaw i n Chen's experiments. They argued that Chen did not administer ethanol often enough (only four t r i a l s in the 1968 study and six t r i a l s in the 1972 study) to conclude that tolerance to ethanol's effects could not develop in the absence of intoxicated practice in the maze. LeBlanc et a l . argued that tolerance would develop in the absence of any opportunity for intoxicated practice of the maze i f enough in j e c t i o n s were administered. To support t h e i r claim, LeBlanc et a l . (1973) trained three groups of rats in a maze si m i l a r to that used by Chen. After the rats had learned to negotiate the maze, they were assigned to one of three groups. The rats in one group received a d a i l y ethanol i n j e c t i o n before running i n the maze; the rats in the second group received an ethanol in j e c t i o n after running the maze; and those i n the t h i r d group received d a i l y saline injections before running the maze. Every 4th day was a te s t t r i a l on which a l l of the rats received an ethanol i n j e c t i o n before performing the maze task so that the development of tolerance could be assessed. LeBlanc et a l . found that the rats in the ethanol-before group developed asymptotic tolerance by the 8th day of treatment ( i . e . , the second test session); that the rats in the ethanol-after group reached the same asymptotic l e v e l of tolerance by the 24th day ( i . e . , by the s i x t h t e s t session); and that there was no evidence of tolerance i n the rats i n the saline group despite the fact that these animals had 32 received 11 ethanol i n j e c t i o n s , one every 4th day over the course of the experiment. On the basis of these r e s u l t s , LeBlanc et a l . (1973) concluded that performance of the c r i t e r i o n response while under the influence of alcohol s u b s t a n t i a l l y accelerates the development of tolerance but i s not e s s e n t i a l for i t s development. LeBlanc, Gibbins, and Kalant (1975) provided further support for t h e i r view that the response contingency was not necessary for the development of tolerance by demonstrating that the tolerance that rats developed to ethanol's e f f e c t s on the performance of Chen's maze would generalize to ethanol's e f f e c t s on the performance of a treadmill task. In t h i s treadmill task, each r at was required to walk on a moving treadmill in order to avoid footshock administered by an e l e c t r i f i e d g r i d that surrounded the t r e a d m i l l . Because there was no evidence of a transfer of learning between the tasks in undrugged subjects, LeBlanc and his colleagues argued that the fact that tolerance to ethanol's e f f e c t s on one task would generalize to i t s e f f e c t s on the other, which had never been performed under the influence of ethanol, meant that the performance of the c r i t e r i o n response was not necessary for the development of tolerance to ethanol's e f f e c t s on i t . Unfortunately, both l i n e s of evidence offered by LeBlanc and his colleagues to support t h e i r view have been d i s c r e d i t e d . F i r s t , Wenger and his colleagues (Wenger, B e r l i n , & woods, 1980; Wenger et a l . , 1981) have provided evidence in two separate studies that the gradual development of tolerance reported by LeBlanc's group in the rats In the ethanol-after condition was the r e s u l t of the tests that a l l of the subjects received every 4 days during the tolerance-development phase—you w i l l r e c a l l that on each te s t t r i a l a l l of the rats performed the c r i t e r i o n response (either the maze or the treadmill task) while they were intoxicated. Wenger et a l . (1980) found that rats from the ethanol-after group that received eight tolerance-development t r i a l s , but not the periodic testing, f a i l e d to develop any s i g n i f i c a n t tolerance to ethanol's e f f e c t s on LeBlanc's treadmill task. Wenger et a l . (1981) extended these re s u l t s by demonstrating that rats in the ethanol-after treatment condition did not develop tolerance to ethanol's e f f e c t s on the treadmill task even after 23 tolerance-development sessions unless they were tested p e r i o d i c a l l y during the tolerance-development phase of the study. Wenger et a l . (1981) concluded that: "the tolerance reported [by LeBlanc and his colleagues] to be a consequence of mere exposure to ethanol i s a c t u a l l y due to the practice given the animals every 4 days while they were being tested for the development of tolerance. A l l of the tolerance established over 23 days appears to be att r i b u t a b l e to [the response contingency] (p. 576)." Unfortunately, careful examination of the experimental bases for Wenger et a l . ' s c r i t i c i s m of LeBlanc et a l . ' s conclusions reveals that they are not without t h e i r own serious problems. In both papers, there i s cle a r evidence of tolerance development in the subjects from the ethanol-afte r condition, which was discounted by Wenger and his colleagues because i t did not quite reach s t a t i s t i c a l s i g n i f i c a n c e in either case. Thus, i f a few more subjects had been tested, i f a few more tolerance-development t r i a l s had been included in the design of the experiments, i f a d i f f e r e n t dose of ethanol had been administered to the rats during the tolerance-development phase, or i f the data from the two studies had been analyzed together; Wenger and his associates would l i k e l y have been forced to reach a conclusion completely opposite to the one that they published. The demonstration of an e f f e c t that just f a i l s to reach s t a t i s t i c a l s i gnificance in two Independent studies is an extremely tenuous basis for concluding that the e f f e c t does not e x i s t . Pinel and Mana (1986) attacked the second l i n e of research used by LeBlanc's group to support the position that tolerance to ethanol's e f f e c t s on a response can develop in the absence of any opportunity to perform the response while intoxicated. They questioned LeBlanc et a l . ' s interpretation of their 1975 finding that tolerance to the e f f e c t s of ethanol on the treadmill task transferred to 35 a maze task, even though the subjects had never been exposed to the maze while they were intoxicated. Pinel and Mana pointed out that the maze and treadmill tasks share a number of common behavioral elements, such as walking, visuomotor coordination, balancing, etc., which would l i k e l y be disrupted by ethanol. As a r e s u l t , the tolerance that developed to ethanol's effects on these common elements when rats performed the treadmill task while they were intoxicated could also express i t s e l f when they were tested on the maze task, even though the rats had never performed the maze task while intoxicated. Even though the aforementioned studies of Chen, LeBlanc, Wenger, and their respective colleagues f a i l e d to determine whether tolerance can develop to ethanol's e f f e c t s on responses that are not performed during periods of i n t o x i c a t i o n , each of them provided evidence of the major role of the response contingency in the development of ethanol tolerance. In other words, although they did not accomplish t h e i r goal, they each emphasized the importance of the question that they had attempted to answer. Cl e a r l y , the response contingency i s an important factor in the development of tolerance to ethanol's e f f e c t s , and u n t i l i t can be determined whether i t plays a permissive or a c r i t i c a l r o l e , our understanding of the phenomenon of drug tolerance, and the mechanisms underlying i t , w i l l be incomplete. Accordingly, the f i r s t three experiments of t h i s thesis addressed this issue with a number of innovative approaches. Perhaps the major innovation was the use of Pinel's model of contingent tolerance to ethanol's anticonvulsant e f f e c t to determine whether or not tolerance can develop i n the absence of the response contingency. The introduction of a new paradigm seemed obligatory i f only to broaden the generality of the data base relevant to the issue; other attempts to assess the necessity of the response contingency had used only the treadmill or maze task. More importantly, Pinel's paradigm has an c r u c i a l advantage over the treadmill and maze tasks; in Pinel's paradigm, the experimenter has much greater control of the c r i t e r i o n response than i s possible in either the treadmill task or the maze task. It i s d i f f i c u l t to control the performance of c r i t e r i o n responses l i k e maze running or treadmill performance, because i t i s possible for subjects to practice various components of these tasks (e.g., walking, vlsuomotor coordination) at w i l l . This lack of control makes i t impossible to unequivocally demonstrate that tolerance can develop to ethanol's e f f e c t on responses that do not occur during periods of intoxication, because i t is not possible to be c e r t a i n that such tolerance did not r e s u l t from the subjects in the ethanol-after condition performing components of the c r i t e r i o n response (e.g., walking) i n th e i r home cages after the ethanol was administered. This 37 problem does not e x i s t In Pinel's paradigm, in which seizures occur only when they are e l i c i t e d by e l e c t r i c a l stimulation delivered by the experimenter. C l e a r l y , the a b i l i t y to maintain s t r i c t control over the c r i t e r i o n response i s important i n any attempt to assess the importance of the response contingency to the development of drug tolerance. Although there was no evidence of tolerance i n the rats from the ethanol-after condition in Pinel et a l . ' s (1983) o r i g i n a l studies of contingent tolerance to ethanol's anticonvulsant e f f e c t , no e f f o r t was made to include conditions in these studies that would be p a r t i c u l a r l y s e n s i t i v e to the development of tolerance in t h i s condition; t h e i r goal was simply to demonstrate that the response contingency influenced tolerance development, not that i t was necessary for i t . Accordingly, each of the f i r s t three experiments in th i s thesis varied some aspect of the procedure used by Pi n e l et a l . (1983) i n order to f a c i l i t a t e the detection of tolerance in the rats from the ethanol-after treatment condition. In Experiment 1, the ef f e c t s of d i f f e r e n t treatment doses were assessed; in Experiment 2, the number of tolerance-development t r i a l s was increased; and in Experiment 3, a more s e n s i t i v e , multiple-t r i a l t e s t procedure was employed. 38 I I I . GENERAL METHODOLOGY This section of the paper describes the methods common to the f i r s t three experiments. Any s p e c i f i c additions to th i s general methodology are described in the methods section of each experiment. Subjects. The subjects in a l l of the experiments were male hooded rats (Charles River, Canada), weighing 350 to 400 g at the time of surgery. The rats were i n d i v i d u a l l y housed in wire mesh cages with continuous access to food and water. Each experiment was conducted during the l i g h t phase of the 12/12 hr light/dark cycle. Surgical Procedure. A single bipolar electrode ( P l a s t i c Products MS-303-2) was implanted in the amygdaloid nucleus of each r a t , 1.2 mm posterior to bregma, 5 mm l a t e r a l and 10 mm ventral to the s k u l l surface at bregma, with the inci s o r bar set at 0.0. Tetracycline was sprinkled on the i n c i s i o n before suturing, and i t was added to the drinking water for 7 days after surgery. Kindling. The kindling phase of each study began at least 7 days a f t e r surgery. During the kindling phase, each rat was stimulated (1 sec, 60 Hz, 400 A) three times per day, 5 days per week, for 3 weeks. There was at least 2 hr between consecutive stimulations. Prior to each stimulation, the stimulation lead was connected, and the subject was then 39 placed in a 58 X 58 X 25 cm opaque p l a s t i c chamber containing a layer of San-i-cel bedding material. The stimulation was delivered immediately, and the rat was returned to i t s home cage once the signs of convulsive a c t i v i t y ceased. As i s usual (Pinel & Rovner, 1978; P i n e l & Van Oot, 1975; Racine, 1978), the r a t s ' behavior was unaffected by the i n i t i a l stimulations in the s e r i e s , but by the end of the kindling phase, each stimulation e l i c i t e d a c l o n i c seizure characterized in sequence by f a c i a l clonus, forelimb clonus, rearing, and a loss of equilibrium. Baseline. In each study, the baseline phase began 48 hr aft e r the completion of the k i n d l i n g phase. During the baseline phase, each rat received f i v e amygdaloid stimulations, one every 48 hr. This b i d a i l y stimulation schedule was maintained for the remainder of each experiment. The duration of forelimb clonus e l i c i t e d by each stimulation was the dependent measure. On the fourth baseline t r i a l , each rat received an IP i n j e c t i o n of isotonic saline (room temperature, 7.6 ml/kg, volume matched to that for the subsequent t e s t dose of ethanol) 1 hr before stimulation. This was done to determine the e f f e c t s of the i n j e c t i o n procedure on the duration of forelimb clonus e l i c i t e d by the stimulation; subjects not displaying at least 20 s of clonus on t h i s baseline t r i a l were dropped from the study at t h i s point. On the f i f t h and l a s t baseline day, every subject received an IP i n j e c t i o n of ethanol (1.5 g/kg in a 25% v/v solution) 1 hr before convulsive stimulation. This was done to determine each subject's i n i t i a l s e n s i t i v i t y to ethanol's anticonvulsant e f f e c t before they were assigned to treatment groups. Subjects not displaying at least an 80% reduction in the duration of forelimb clonus from the fourth to the f i f t h baseline stimulation were dropped from the study at t h i s point. The r e j e c t i o n c r i t e r i a were enforced i n each study because the anticonvulsant e f f e c t of ethanol and the subsequent development of tolerance to i t cannot be r e a d i l y studied in subjects that do not co n s i s t e n t l y d i s p l a y substantial convulsive a c t i v i t y i n the absence of ethanol and a large i n i t i a l s e n s i t i v i t y to ethanol's anticonvulsant e f f e c t . It should also be pointed out that approximately 15% of the subjects meeting the c r i t e r i a and beginning the treatment phase of each of the studies did not complete them, usually because t h e i r electrode caps became dislodged or because of complications caused by the repeated ethanol administrations. Treatment. In each experiment, the rats were assigned to treatment groups i n such a way that the average duration of forelimb clonus e l i c i t e d by the fourth baseline stimulation was approximately equal for each group. The treatment t r i a l s began 48 hr af t e r the f i f t h baseline t r i a l , and occurred at about the same time every second day (+/- 2 hr) for the entire treatment phase. During each b i d a i l y 41 treatment t r i a l , each subject was removed from i t s home cage, weighed, and the appropriate dose of ethanol or isotonic saline was administered either 1 hr before or 1 hr aft e r convulsive stimulation. The number of treatment sessions varied from study to study. In Experiments 1 and 2, the treatment dose of ethanol was administered by intubation to reduce the r i s k of the i n f e c t i o n and subject a t t r i t i o n sometimes associated with IP inje c t i o n s . However, the r e s u l t s of a separate s e r i e s of studies suggested that t h i s was not a problem. Therefore, in Experiment 3 a l l of the injections of ethanol were administered i n t r a p e r i t o n e a l l y . Test. The test t r i a l always occurred 48 hr af t e r the l a s t treatment t r i a l . On the t e s t t r i a l , every rat i n the experiment received an IP ethanol i n j e c t i o n 1 hr before convulsive stimulation. In Experiments 1 and 2, the development of tolerance was assessed by comparing the duration of forelimb clonus e l i c i t e d in a subject on the test t r i a l to that e l i c i t e d on the f i f t h baseline day in the same subject. In addition, i n Experiment 1 a s a l i n e - c o n t r o l group permitted the assessment of tolerance by comparing the duration of clonus e l i c i t e d on the t e s t t r i a l in the subjects in the two ethanol groups with that e l i c i t e d in the saline control subjects on the same day. In Experiment 3, a more sensitive measure of tolerance development was used, the s p e c i f i c d e t a i l s of which are provided in the 42 methodology section of Experiment 3. Histology. At the end of each experiment, a l l the subjects were s a c r i f i c e d i n a C02 chamber according to Canada Council on Animal Care guidelines, and the i r brains were removed and sectioned to permit h i s t o l o g i c a l v e r i f i c a t i o n of electrode s i t e s using the blue-dot technique (Skinner, 1971) and Paxinos and Watson's atl a s of the rat brain (1982). S t a t i s t i c a l Analyses. Nonparametric s t a t i s t i c s (Siegel, 1956) were used to analyze the clonus-duration data in the f i r s t two experiments. Nonparametric s t a t i s t i c s were used to analyze these data in order to avoid s e r i o u s l y v i o l a t i n g the assumption of homogeneity of variance, which i s the basis for more conventional parametric analyses; the duration of forelimb clonus on the f i f t h baseline t r i a l , when ethanol was administered for the f i r s t time, was zero for almost every r a t , whereas there was substantial v a r i a b i l i t y i n some of the conditions on the t e s t t r i a l . The d i f f e r e n t measure of tolerance used in Experiment 3 permitted the use of parametric s t a t i s t i c a l procedures. 43 IV. EXPERIMENT 1 In Pi n e l et a l . ' s o r i g i n a l (1983) demonstration of contingent tolerance to ethanol's anticonvulsant e f f e c t , there was no s i g n i f i c a n t evidence of tolerance in the ethanol-after group even though a r e l a t i v e l y high treatment dose of ethanol (4.5 g/kg, intubated) was administered on the f i v e tolerance-development t r i a l s . Although there i s a large body of l i t e r a t u r e indicating that tolerance to a drug's e f f e c t s develops more ra p i d l y when a high treatment dose l s administered (e.g., Kalant et a l . , 1971; LeBlanc, Kalant, Gibbins, & Berman, 1969; Jorgenson, Fasmer, & Hole, 1986), i t has also been suggested that the detection of tolerance can be more d i f f i c u l t in animals that have received a high treatment dose of a drug, because of an accumulation of the drug in a subject or because the high dose resulted in some non-specific change i n the subject that interferes with the assessment of tolerance (Kalant et a l . , 1971). Thus, i t i s possible to argue that no tolerance was detected In the ethanol-after condition of Pinel et a l . ' s study because the treatment dose of ethanol was too high. Accordingly, in Experiment 1 contingent tolerance to ethanol's anticonvulsant e f f e c t was studied at two treatment doses that approached the lower and upper l i m i t s of the paradigm. P i l o t studies had indicated that 44 intubated doses of ethanol less than 2 g/kg would not r e l i a b l y block the kindled convulsions, and that doses greater than 5 g/kg would lead to subject a t t r i t i o n . METHOD Of the 80 rats completing the baseline phase of Experiment 1, 2 rats were rejected because the duration of forelimb clonus e l i c i t e d on the fourth baseline day did not meet the c r i t e r i o n for inclu s i o n , and 1 rat was rejected because i t did not respond adequately to ethanol's anticonvulsant e f f e c t on the f i f t h baseline day. Of the remaining 77 subjects, 67 completed the study. The data of only these 67 were analyzed. Tolerance-Development Phase. There were two tolerance-development conditions in Experiment 1: a before condition in which subjects were intubated with either ethanol or isotonic saline 1 hr before each b i d a i l y stimulation and were given a pseudointubation 1 hr afte r each stimulation, and an afte r condition in which the subjects received the same treatments but in the reverse order. Nothing was injected during the pseudointubations; the tubes were simply inserted into the stomach for a few seconds and then removed. After the f i f t h baseline stimulation, the subjects were assigned to one of s i x treatment groups. The rats in the three before groups were intubated with 2 g/kg of ethanol (n=ll; ethanol in a 12% v/v s o l u t i o n ) , 5 g/kg of ethanol (n=12; ethanol in a 30% v/v s o l u t i o n ) , or an isotonic saline solution (n=ll; 21.1 ml/kg). The intubation volume of the solutions was equal for a l l of the groups. The rats i n the three a f t e r groups were intubated with 2 g/kg of ethanol (n=ll), 5 g/kg of ethanol (n=ll), or an isotonic saline solution (n=ll) 1 hr a f t e r each stimulation. Test• The test for tolerance development occurred 48 hr afte r the l a s t tolerance-development t r i a l . Bach rat received a 1.5 g/kg IP ethanol i n j e c t i o n 1 hr before convulsive stimulation. Immediately a f t e r the cessation of the convulsion, a 200 1 sample of blood was drawn from the t a i l of each rat into a heparinized tube, and blood ethanol levels were subsequently determined using a modification of the head-space gas chromatographic method (Wilkinson, Wagner, & Sedman, 1975). Analysis. Wilcoxon's Matched-Pairs Ranked-Signs Test's were used to assess the si g n i f i c a n c e of the within-group differences in clonus duration between the f i f t h baseline t r i a l and the t e s t t r i a l . Mann-Whitney U Tests were used to assess the s i g n i f i c a n c e of the between-group differences in clonus duration on the f i f t h baseline t r i a l . The difference in blood ethanol concentrations between the d i f f e r e n t treatment groups was assessed with a simple 1-way ANOVA. Results. Figure 2 i l l u s t r a t e s the r e s u l t s of Experiment 1. Regardless of the dose, those subjects intubated with ethanol before each of the five tolerance-development stimulations displayed s i g n i f i c a n t l e v e l s of tolerance on the test t r i a l , whereas those intubated with ethanol a f t e r each stimulation did not. Thus, the forelimb clonus displayed by the subjects in the two ethanol-before groups was s i g n i f i c a n t l y longer on the test t r i a l than on the f i f t h baseline t r i a l (both Wilcoxon p_'s <.01). In contrast, the duration of forelimb clonus on the test t r i a l for the rats in the two alcohol-after groups and the two saline groups was not s i g n i f i c a n t l y longer than that e l i c i t e d on the f i f t h baseline t r i a l ( a l l Wilcoxon p_'s >.10). Moreover, the rats in the two ethanol-before groups displayed s i g n i f i c a n t l y longer forelimb clonus on the test t r i a l than did the rats from any of the other four groups ( a l l Mann-Whitney p_'s <.01). There were no s i g n i f i c a n t differences in the duration of the clonus e l i c i t e d on the tes t t r i a l between the two alcohol-before groups or between the ethanol-after and s a l i n e groups ( a l l Mann-Whitney p/s >.10). There were no s i g n i f i c a n t differences in the blood ethanol le v e l s of the s i x groups of subjects following the test stimulation, F (2,6) =0.02, p_>.10. The ov e r a l l mean blood alcohol l e v e l was 1.36 g/1. Examination of the h i s t o l o g i c a l data revealed that a l l of the electrode t i p s were in the amygdaloid complex, with most terminating in or near the baso-lateral amygdaloid nuclei (see Figure 3). 47 FIGURE 2. The e f f e c t of treatment dose on the development of tolerance to ethanol's anticonvulsant e f f e c t . During the treatment phase, kindled rats were intubated with ethanol (2 g/kg or 5 g/kg) either 1 hr before or 1 hr af t e r convulsive stimulation. On the tes t t r i a l , a l l subjects received ethanol (1.5 g/kg) 1 hr before stimulation. The rats in the two ethanol-before groups demonstrated substantial tolerance; i n contrast, there was l i t t l e evidence of tolerance development in the ethanol-after or the s a l i n e - c o n t r o l groups. 48 40 O £Q20r z ! < -j ai in O u-10 all subjects saline ethanol 2g/kg ethanol 5g/ kg tu2 DAY 4 DAY 5 A F T E R GROUP BEFORE GROUP BASELINE TEST 49 FIGURE 3. Histology from Experiment 1. 50 Discussion. The results of Experiment 1 provide further evidence of the importance of the response contingency in the development of tolerance to ethanol's anticonvulsant e f f e c t . Although a substantial degree of tolerance was evident a f t e r the fiv e tolerance-development t r i a l s in the rats that received an ethanol i n j e c t i o n before each b i d a i l y stimulation during the tolerance-development phase, there was no s i g n i f i c a n t evidence of tolerance i n the ethanol-af ter groups, at either treatment dose. It should be noted that there was an i n d i c a t i o n , a l b e i t an i n s i g n i f i c a n t one, of tolerance in the ethanol-after rats in the 2g/kg group (see Figure 2). This raises the p o s s i b i l i t y that a s i g n i f i c a n t degree of tolerance would have developed in t h i s group i f a greater number of tolerance-development t r i a l s had been administered. This p o s s i b i l i t y was tested in Experiment 2. 51 V. EXPERIMENT 2 It is possible that previous attempts to demonstrate tolerance to ethanol's anticonvulsant e f f e c t i n rats that receive ethanol aft e r convulsive stimulation during the tolerance-development phase have f a i l e d because these studies have been c u r t a i l e d prematurely. Although the development of tolerance to ethanol's e f f e c t s can be observed following a single i n j e c t i o n (e.g., Mellanby, 1919; T u l l i s , Sargent, Simpson, & Beard, 1977), i n most cases a larger number of tolerance-development t r i a l s are required for i t s development (cf., Hug, 1972; LeBlanc, et a l . , 1975). The purpose of Experiment 2 was to determine whether tolerance to ethanol's anticonvulsant e f f e c t would develop in the ethanol-after condition in rats exposed to 5, 10, or 20 tolerance-development t r i a l s . METHOD Of the 102 rats completing the baseline phase of Experiment 2, 6 did not display s u f f i c i e n t l y long clonus on the fourth baseline day, and 5 more did not dis p l a y the required reduction in clonus duration required on the f i f t h baseline day. The remaining 91 r a t s , only 71 completed the study. Tolerance-Development Phase. There were two general conditions in the tolerance-development phase: 1) an 52 ethanol-before condition in which subjects were intubated with ethanol (2 g/kg, in a 25% v/v solution) 1 hr before each b i d a i l y convulsive amygdaloid stimulation; and 2) an ethanol-after condition in which the rats were intubated with the same dose of ethanol 1 hr a f t e r each stimulation. The rats in each of these two general conditions were assigned to one of three treatment groups, which received either 5 (before n=ll, after n=10), 10 (before n=ll, a f t e r n=12), or 20 (before n=15, aft e r n=12) b i d a i l y intubations during the tolerance-development phase of the experiment. Test. On the test t r i a l , which occurred 48 hr aft e r the l a s t tolerance-development t r i a l , every rat received a single test i n j e c t i o n of ethanol (IP, 1.5 g/kg) 1 hr before amygdaloid stimulation. Immediately a f t e r the seizure subsided, a 200 1 sample of blood was taken from the animal's t a i l , and the blood l e v e l of ethanol was determined with a modified head-space gas chromatographic technique (Wilkinson et a l . , 1975). Analysis. Wilcoxon's Matched-Pairs Ranked-Signs Test's were used to assess the significance of the tolerance within each treatment group. Mann-Whitney U Tests were used to assess the s i g n i f i c a n c e of the differences i n clonus duration between groups. The s i g n i f i c a n c e of the differences in blood alcohol concentrations between the d i f f e r e n t treatment groups was assessed with a simple 1-way ANOVA. Results. It i s clear in Figure 4 that the rats receiving 53 ethanol before stimulation developed a substantial degree of tolerance to ethanol's anticonvulsant e f f e c t , but that there was l i t t l e evidence of tolerance in the rats from the ethanol-after groups. Thus, the rats in a l l three ethanol-before groups displayed s i g n i f i c a n t l y more forelimb clonus on the t e s t day than they had on the f i f t h ethanol baseline t r i a l ( a l l Wilcoxon p_'s <.01); whereas, those in the ethanol-after groups did not ( a l l Wilcoxon p_'s >.10). Moreover, there was a s i g n i f i c a n t difference in the duration of the forelimb clonus displayed by subjects in the respective ethanol-before and ethanol-after groups in the 5 intubations (Mann-Whitney p_ <.05), 10 Intubations (Mann-Whitney p_ <.01), and 20 intubations (Mann-Whitney p_<.025) conditions. Equipment f a i l u r e resulted in the loss of most of the blood samples taken in Experiment 2. Analysis of the 22 samples that were not l o s t revealed a difference in the blood alcohol concentrations between the rats in the 5-day before condition and the 20-day a f t e r condition (F (2,16)=3.98, p_<.05; Neuman Keuls p<.05), but there were no s i g n i f i c a n t differences between any of the other groups ( a l l Neuman Keuls p_>.05). However, given the unsystematic nature of the difference and the fact that i t has not been re p l i c a t e d , i t should be viewed with caution. 54 FIGURE 4. Tolerance to the anticonvulsant e f f e c t s of ethanol (2 g/kg) following 5, 10, or 20 intubations administered either before or af t e r b i d a i l y convulsive stimulation. There was substantial tolerance development in a l l three of the ethanol-before groups, whereas there was l i t t l e evidence of tolerance in any of the ethanol-after groups. 55 DAY 4 DAY 5 AFTER BEFORE GROUP GROUP BASELINE TEST 56 FIGURE 5. Histology from Experiment 2. 57 H i s t o l o g i c a l analysis of the electrode placements revealed that a l l electrode t i p s were located in the amygdaloid complex or on i t s boundaries, with most electrodes terminating in the basolateral nuclei (see Figure 5) . Discussion. The r e s u l t s of Experiment 2 provide further evidence of the important r o l e of the response contingency in the development of tolerance to ethanol's anticonvulsant e f f e c t . As i n Experiment 1, the rats in the ethanol-before groups demonstrated substantial tolerance a f t e r just f i v e treatment t r i a l s . In contrast, there was no s i g n i f i c a n t tolerance development in the rats from the ethanol-after conditions. Even aft e r 20 treatment t r i a l s , there was only a s l i g h t i n d i c a t i o n of tolerance in the ethanol-after condition, but i t was not s t a t i s t i c a l l y s i g n i f i c a n t . 58 VI. EXPERIMENT 3 In Experiment 1, there was a s l i g h t i n d i c a t i o n of tolerance development in the r a t s from the ethanol-after condition that received the 2g/kg treatment dose of ethanol. In Experiment 2, there was a suggestion of tolerance development in the ethanol-after group that received 20 tolerance-development t r i a l s . However, t h i s e f f e c t was not s t a t i s t i c a l l y s i g n i f i c a n t in either study. Experiment 3 attempted to provide evidence of tolerance development i n the ethanol-after group by using a p a r t i c u l a r l y s e n s i t i v e measure of tolerance development. The measure of tolerance used in Experiment 3 was a savings measure (cf. Kalant et a l . , 1971). After 20 b i d a i l y tolerance-development t r i a l s , a l l of the rats i n Experiment 3 received a serie s of b i d a i l y t e s t i n j e c t i o n s , each 1 hr before convulsive stimulation, and the rate of tolerance development was assessed for each group of r a t s . The use of th i s t e s t was based on the assumption that i f the rats in the ethanol-after condition were in fact developing some tolerance which was not apparent on the f i r s t t e s t t r i a l , i t would be expressed as a savings in the rate of subsequent tolerance development ( c . f . Kalant et a l . , 1971). METHOD Of the 32 rats that completed the baseline phase of 59 Experiment 3, 2 rats did not display s u f f i c i e n t l y long clonus on the fourth baseline t r i a l and 1 did not disp l a y the reduction in clonus duration required on the f i f t h baseline t r i a l . Of the remaining 29 subjects, 23 completed the study. Treatment. After the baseline phase, the subjects were assigned to one of two treatment groups. The rats i n one group (the ethanol-after group, n=14), received a t o t a l of twenty b i d a i l y ethanol injections, each 1 hr a f t e r a convulsive amygdaloid stimulation. The rats in the second group, (the s a l i n e - a f t e r group, n=9), received the same number of injections of an isotonic s a l i n e solution 1 hr after each of th e i r b i d a i l y stimulations. Test. The test phase of the experiment was the same for a l l subjects and consisted of 10 more b i d a i l y ethanol i n j e c t i o n s (1.5 g/kg) administered 1 hr before convulsive stimulation. A rat was considered to have developed tolerance when the duration of forelimb clonus e l i c i t e d in that animal on two consecutive t e s t t r i a l s was at least 50% as long as the clonus e l i c i t e d in the same subject on the fourth baseline day. Analysis. A single t - t e s t was used to analyze the difference in the number of test t r i a l s required for the rats in each group to meet the c r i t e r i o n of tolerance development. 60 FIGURE 6 . Histology from Experiment 3 . 61 Results• The rats from the ethanol-after group required s i g n i f i c a n t l y fewer test t r i a l s (M=6.2) to meet the c r i t e r i o n of tolerance development than did the rats from the s a l i n e group (M=8.1) (t (20)=2.75, p_<.01). Figure 6 i l l u s t r a t e s the h i s t o l o g i c a l data from Experiment 3. A l l of the electrode t i p s were i n , or on the boundaries of, the amygdaloid complex, with most terminating in the basolateral nucleus. Discussion. The results of Experiment 3 provide the f i r s t unequivocal evidence of the development of tolerance to ethanol's anticonvulsant e f f e c t In the absence of the appropriate response contingency. Although there was no evidence of tolerance development in either group of rats on the f i r s t t est t r i a l , the rats from the ethanol-after group became tolerant s i g n i f i c a n t l y faster than the rats from the saline group once they were exposed to a series of ethanol-bef ore t r i a l s . Because th i s tolerance was not evident on the f i r s t t est t r i a l , i t i s referred to here as latent drug  tolerance. 62 VII. EXPERIMENT 4 The Role of the Response Contingency In  The Maintenance and Dissipation  of Tolerance to Ethanol's Anticonvulsant E f f e c t The response contingency i s c l e a r l y an important, i f not c r i t i c a l , factor in the development of tolerance to a wide var i e t y of ethanol's e f f e c t s . It i s therefore surprising that there are no reports of the response contingency having a role in the d i s s i p a t i o n of such tolerance once i t has developed. This i s e s p e c i a l l y true i n l i g h t of several reports in which the response contingency played a c r u c i a l role in the d i s s i p a t i o n of tolerance to the eff e c t s of other drugs. For example, Manning (1976a) demonstrated that tolerance to the disruptive e f f e c t s of delta-9-tetrahydrocannabinol on operant responding in the rat dissipated over a 14-day retention i n t e r v a l only i f the subjects were given the opportunity to perform the operant task i n a drug-free state. S i m i l a r l y , Poulos, Wilkinson, and Cappell (1981) demonstrated that the response contingency was an important factor in the d i s s i p a t i o n of tolerance to the anorexigenic effects amphetamine on sweet milk consumption; in t h e i r study, rats l o s t t h e i r tolerance only when given access to the sweet milk solution in the absence of the drug. F i n a l l y , Poulos and Hinson (1984) found that tolerance to scopolamine's adipsic e f f e c t in water-deprived rats dissipated only when the subjects were given access to water in the absence of the drug. In Experiment 4, the role of the response contingency in the maintenance and d i s s i p a t i o n of tolerance to ethanol's anticonvulsant e f f e c t was investigated. Is the r e l a t i o n between ethanol exposure and convulsive stimulation as important in the maintenance and d i s s i p a t i o n of tolerance to ethanol's anticonvulsant e f f e c t as i t i s to i t s development? Subjects. The subjects were 45 male, 300 to 400 g hooded rats purchase, maintained, and housed as i n the f i r s t three experiments. Surgery. The s u r g i c a l procedure was the same as that employed in the f i r s t three experiments. Kindling and Baseline Phases. The kindling and baseline phases were i d e n t i c a l to those in the f i r s t three experiments. Tolerance Development. Beginning 48 hr af t e r the l a s t baseline stimulation, every subject received a series of seven b i d a i l y ethanol injections (1.5 g/kg, IP), each administered 1 hr before a singl e convulsive stimulation. As usual, the f i r s t of these injections completely suppressed the forelimb clonus e l i c i t e d by amygdaloid stimulation in every rat; and tolerance to t h i s potent anticonvulsant e f f e c t developed quickly in roost of the r a t s . Thus, by the end of the tolerance-development phase 42 of the o r i g i n a l 45 subjects had met the c r i t e r i o n of tolerance, which was two consecutive t r i a l s on which the forelimb clonus e l i c i t e d by amygdaloid stimulation was at least 50% as long as that displayed by the same subject on the fourth baseline t r i a l . Because the purpose of Experiment 4 was to study the d i s s i p a t i o n of tolerance, the three rats not meeting t h i s c r i t e r i o n were dropped from the experiment at t h i s point. Tolerance D i s s i p a t i o n . The 42 rats meeting the c r i t e r i o n of tolerance development were assigned to f i v e treatment groups. The mean clonus duration on the l a s t two tolerance-development t r i a l s was calculated for each subject, and then the rats were assigned to t h e i r f i v e treatment groups so that the means of these scores were approximately the same for a l l f i v e groups. The subjects in each of the f i v e groups were treated in d i f f e r e n t ways during the ensuing 14-day retention period. The rats in the ETOH-before-STIM group (n=8) continued to receive b i d a i l y ethanol i n j e c t i o n s 1 hr before amygdaloid stimulation, whereas the rats in the STIM-before-ETOH group (n=9) received the same b i d a i l y treatments but i n the reverse order. The rats in the ETOH-noSTIM group (n=8) received the b i d a i l y ethanol i n j e c t i o n s but no stimulations during the 14-day retention i n t e r v a l , whereas the rats i n the STIM-noETOH group (n=9) received the b i d a i l y stimulations but not the ethanol i n j e c t i o n s . The rats in the l a t t e r group received injections of i s o t o n i c saline either 1 hr before (n=5) or 1 hr a f t e r (n=4) each b i d a i l y stimulation. The rats in the f i f t h and f i n a l group, the noETOH-noSTIM group (n=8), received neither ethanol injections nor convulsive stimulations during the retention i n t e r v a l . Each rat in t h i s group was weighed and handled every second day. Test. The test for tolerance retention occurred 14 days after the l a s t t r i a l of the tolerance-development phase. The test procedure was i d e n t i c a l to that of the tolerance development t r i a l s ; the e f f e c t of a single i n j e c t i o n of ethanol on the duration of forelimb clonus e l i c i t e d by amygdaloid stimulation administered 1 hr l a t e r was assessed in each r a t . Histology. The h i s t o l o g i c a l procedure was i d e n t i c a l to that followed in the f i r s t three experiments. S t a t i s t i c a l Analysis. The retention of tolerance was assessed by comparing the mean duration of the clonus e l i c i t e d in each rat on the l a s t two tolerance-development t r i a l s to the duration of forelimb clonus e l i c i t e d from that rat on the test t r i a l , and also by comparing the difference in the duration of forelimb clonus on the tes t day between the d i f f e r e n t treatment groups. Because the data of Experiment 4 se r i o u s l y v i o l a t e d the assumption of homogeneity of variance, the data were analyzed using Wilcoxon's Ranked-Signs Matched-Pairs te s t and the Mann-Whitney U test (Siegel, 1956), as in Experiments 1 and 2. Results. As i s evident i n Figure 7, the r e s u l t s of 66 Experiment 4 were remarkably unambiguous; tolerance dissipated only i n the rats that received convulsive stimulation in the absence of ethanol exposure. Although there was no substantial decline of tolerance i n the ETOH-before-STIM group, the ETOH-noSTIM group, and the noETOH-noSTIM group ( a l l Wilcoxon p_'s>.05), i t dissipated almost completely in the STIM-noETOH group and the STIM-before-ETOH group (both Wilcoxon p_'s<.01). Accordingly, on the test t r i a l the clonus of the ETOH-before-STIM group, the ETOH-noSTIM group, and the noETOH-noSTIM group was s i g n i f i c a n t l y longer than that of the STIM-noETOH group and the STIM-before-ETOH group ( a l l Mann-Whitney p_,s<.01). A l l of the electrode placements were In or near the amygdaloid complex, with the majority located in the basolateral nucleus (see Figure 8). Discussion. The r e s u l t s of Experiment 4 c l e a r l y e s t a b l i s h the importance of the response contingency In the retention of tolerance to ethanol's anticonvulsant e f f e c t . Considering the evidence implicating the response contingency i n the development of t h i s tolerance, the r e s u l t s of Experiment 4 were not unexpected. What was unexpected, however, was the observation that the withdrawal of ethanol had no e f f e c t whatsoever on the maintenance or d i s s i p a t i o n of tolerance. Tolerance to ethanol's anticonvulsant e f f e c t did not decline at a l l over the 14-day retention i n t e r v a l when ethanol was completely withdrawn If the rats did not receive convulsive 67 FIGURE 8. The ef f e c t of the response contingency on the d i s s i p a t i o n of tolerance to ethanol's anticonvulsant e f f e c t . Ethanol withdrawal had no e f f e c t on the d i s s i p a t i o n of tolerance, as the rats in the noETOH-noSTIM group demonstrated no loss of tolerance even though they were not administered ethanol during the retention i n t e r v a l . Furthermore, the administration of ethanol was not a necessary condition for the maintenance of tolerance, as the rats in the ETOH-afterSTIM group l o s t t h e i r tolerance even though they continued to receive ethanol on the same schedule of administration associated with the development of tolerance. The c r i t i c a l factor i n the d i s s i p a t i o n of tolerance to ethanol's anticonvulsant e f f e c t was the administration of stimulation in the absence of ethanol. noETOH-noSTIM ETOH-noSTIM ETOH-before-STIM STIM-before-ETOH STIM-noETOH BASELINE DEVELOPMENT RETENTION RETENTION TRIALS INTERVAL TEST 00 69 FIGURE 8. Histology from Experiment 4. 70 stimulation during the i n t e r v a l (the noETOH-noSTIM group). Furthermore, and perhaps more importantly, tolerance dissipated completely in nearly every rat that was maintained on exactly the same regimen of b i d a i l y ethanol injections associated with tolerance development i f these subjects (STIM-before-ETOH subjects) were stimulated before, rather than during, the periods of ethanol exposure. This r e s u l t i s e s p e c i a l l y important because i t i s the f i r s t demonstration that I am aware of where drug withdrawal ls not necessary for the d i s s i p a t i o n of tolerance. In a l l of the previous demonstrations in which the d i s s i p a t i o n of tolerance was shown to be influenced by the response contingency (e.g., Manning, 1974; Poulos et a l . , 1981; Poulos & Hinson, 1984), the e f f e c t of the response contingency was studied only in subjects that had been withdrawn from the regimen of drug exposure. In Experiment 4, the response contingency was shown to be c r i t i c a l to the d i s s i p a t i o n of tolerance even i n subjects that continued to receive ethanol on the same schedule associated with the development of tolerance. In Experiment 4, the c r i t i c a l factor In the d i s s i p a t i o n of contingent tolerance to ethanol's anticonvulsant e f f e c t appeared to be the e l i c i t a t i o n of convulsive a c t i v i t y — t h e c r i t e r i o n response--in the absence of ethanol. If seizures were e l i c i t e d in the absence of ethanol, tolerance to ethanol's anticonvulsant e f f e c t dissipated over the 14-day retention i n t e r v a l ; i f 71 t h i s condition was not met, then there was no decline in tolerance. 72 VIII. GENERAL DISCUSSION The general purpose of the four experiments contained in t h i s thesis was to c l a r i f y the nature of contingent tolerance to ethanol's anticonvulsant e f f e c t . Together, the r e s u l t s of these experiments provide unequivocal evidence of the important role that the response contingency has in both the development and subsequent retention of tolerance to ethanol's anticonvulsant e f f e c t . The f i r s t two sections of t h i s General Discussion deal with: 1) the f i r s t three experiments, which were designed to determine whether tolerance to ethanol's anticonvulsant e f f e c t could develop in rats that did not receive convulsive stimulation during periods of i n t o x i c a t i o n , and 2) the fourth experiment, which examined the importance of the response contingency in the retention of tolerance to ethanol's anticonvulsant e f f e c t . The f i n a l two sections of the General Discussion deal with: 3) the t h e o r e t i c a l explanations that have been advanced to account for contingent drug tolerance and their relevance to contingent tolerance to ethanol's anticonvulsant e f f e c t , and 4) the general implications of experiments contained i n t h i s t h e s i s . 73 1. General Discussion of Experiments 1,2, and 3 The purpose of the f i r s t three experiments was to answer the question "Does tolerance to ethanol's anticonvulsant e f f e c t develop in kindled rats that do not receive convulsive stimulation during periods of ethanol exposure?". The answer to t h i s question was found to be "Yes, there i s a small degree of tolerance development in the rats from the ethanol-after treatment condition." However, t h i s answer requires q u a l i f i c a t i o n . Although each of the f i r s t three experiments was designed to f a c i l i t a t e the detection of tolerance i n rats in the ethanol-after condition, t h i s proved to be d i f f i c u l t to do. Experiment 1 assessed the p o s s i b i l i t y that tolerance was not observed in the ethanol-after rats in Pinel et a l . ' s (1983) o r i g i n a l study because the high treatment dose (4.5 g/kg) was too high. However, in Experiment 1, there was l i t t l e evidence of tolerance in rats from the ethanol-after condition regardless of whether the treatment dose was high (5 g/kg) or low (2 g/kg). In Experiment 2, more treatment t r i a l s were administered to f a c i l i t a t e the development of tolerance in the absence of the response contingency; again, there was no s i g n i f i c a n t tolerance in the ethanol-after r a t s , even a f t e r 20 t r i a l s . Perhaps the ethanol-after 74 subjects would have eventually developed substantial tolerance i f they had received even more tolerance-development t r i a l s ; however, p i l o t studies have indicated that the subjects' health begins to s u f f e r i f any more treatment t r i a l s are administered. Such subject d e b i l i t a t i o n makes the r e s u l t s d i f f i c u l t to interpret and the experiments d i f f i c u l t to j u s t i f y on e t h i c a l grounds. Experiment 3 provided evidence that s t a t i s t i c a l l y s i g n i f i c a n t l e v e l s of tolerance can develop to ethanol's anticonvulsant e f f e c t i n the absence of the response contingency. In Experiment 3, a s e n s i t i v e m u l t i p l e - t r i a l , savings, test of tolerance f a c i l i t a t e d the detection of what I have c a l l e d latent tolerance to ethanol's anticonvulsant e f f e c t in the ethanol-after condition. It should be emphasized, however, that even the r e s u l t s of Experiment 3 provide evidence of the important role of the response contingency i n the development of tolerance to ethanol's anticonvulsant e f f e c t . In Experiment 3, the tolerance that developed in the ethanol-after rats was not apparent on the f i r s t test trial--hence the label latent tolerance--and was detectable only as an acceleration in the subsequent development of tolerance when the subjects were switched to the ethanol-before condition. In contrast, s i g n i f i c a n t l e v e l s of tolerance were detectable i n the ethanol-before rats a f t e r only 4 or 5 t r i a l s . 75 2. General Discussion of Experiment 4 The purpose of Experiment 4 was to determine whether the response contingency was as important in the d i s s i p a t i o n of tolerance to ethanol's anticonvulsant e f f e c t as i t was to i t s development. The r e s u l t s unequivocally e s t a b l i s h the response contingency as a key factor in the d i s s i p a t i o n of t h i s type of tolerance, and in so doing r a i s e some intriguing questions about the t r a d i t i o n a l assumption that the d i s s i p a t i o n of tolerance i s t o t a l l y dependent on drug withdrawal. In Experiment 4, the cessation of ethanol administration was neither necessary nor s u f f i c i e n t for the d i s s i p a t i o n of tolerance to ethanol's anticonvulsant e f f e c t , and the continuation of ethanol adminstration was neither necessary nor s u f f i c i e n t for the retention of t h i s tolerance once i t had developed. Instead, the c r i t i c a l factor i n the d i s s i p a t i o n of tolerance was the e l i c i t a t i o n of the c r i t e r i o n response—convulsive a c t i v i t y — i n the absence of ethanol; i f seizures were e l i c i t e d in the absence of ethanol, tolerance to ethanol's anticonvulsant e f f e c t dissipated over the 14-day retention i n t e r v a l ; i f t h i s condition was not met, then there was no decline in tolerance. In Experiment 4, there was complete retention of tolerance to ethanol's anticonvulsant e f f e c t when ethanol was completely withdrawn over the enti r e 14-day retention i n t e r v a l , i f the rats did not receive convulsive stimulation. More importantly, there was l i t t l e retention of tolerance in rats that continued to receive ethanol on the same b i d a i l y schedule associated with the development of tolerance development i f these subjects were stimulated before, rather than during, the periods of ethanol exposure. In the introductory d e s c r i p t i o n of the contingent tolerance phenomenon, the importance of the response contingency in the development of tolerance was i l l u s t r a t e d with an analogy to a perceptual phenomenon. The point was made that to expect tolerance to develop to a drug's e f f e c t s on a response that i s not performed during periods of drug exposure i s l i k e expecting adaptation to the di s r u p t i o n in visuomotor performance caused by l a t e r a l l y d i s p l a c i n g prisms to occur in the absence of an opportunity to perceive the disruption. Neither the adaptation to the disr u p t i v e e f f e c t s of v i s u a l displacement on visuomotor coordination nor the adaptation to the disr u p t i v e e f f e c t s of ethanol on kindled seizures can occur unless the disr u p t i v e e f f e c t s are ac t u a l l y experienced. This displaced-vision analogy i s also relevant to the role of the response contingency i n the d i s s i p a t i o n of tolerance. Once a subject has adapted to the e f f e c t s of displ a c i n g prisms, removing them produces another change in the r e l a t i o n between visu a l and motor feedback to which the subject must adapt. Just as the v i s u a l perception of s e l f -produced movement with the lenses on is necessary for adaptation to the introduction of displacing lenses, the v i s u a l perception of self-produced movement with them off i s necessary for adaptation to t h e i r removal. S i m i l a r l y , Experiment 4 demonstrates that the c r i t i c a l event in the d i s s i p a t i o n of tolerance to ethanol's anticonvulsant e f f e c t is the experience of kindled seizures in the absence of ethanol. The d i s s i p a t i o n of tolerance i s not a simple consequence of drug withdrawal; the d i s s i p a t i o n of tolerance requires that the absence of the drug e f f e c t on the c r i t e r i o n response (the convulsive response) can be experienced. 3. Theoretical Explanations of Contingent Tolerance A number of d i f f e r e n t explanations have been advanced to account for the phenomenon of contingent drug tolerance. Three of these models are reviewed in t h i s subsection, and their a b i l i t y to account for the importance of the response contingency to the development and d i s s i p a t i o n of tolerance to ethanol's anticonvulsant e f f e c t i s discussed. The three explanations that are considered are: i ) the reinforcement-density model; l i ) the state-dependency model; and i i i ) the homeostatic-conditioning model of tolerance. 78 1). The Reinforcement-Densitv Model of Contingent Tolerance. The reinforcement-density model of contingent tolerance (Demellweek & Goudie, 1983; Kumar & Stolerman, 1977) assumes that tolerance develops to the e f f e c t s of drugs that decrease the density of appetitive reinforcement or increase the density of aversive reinforcement, but not to the effects of drugs that have no e f f e c t on the density of reinforcement. For example, Schuster, Dockens, and Woods (1966) found that tolerance to the e f f e c t s of amphetamine on a bar-press response developed only when the increase in response rate produced by amphetamine led to a decrease in appetitive reinforcement. In Schuster et a l . ' s study, rats that were trained to bar-press on a combination fixed interval/differential-relnforcement-for-low-rates-of-responding (FI/DRL) schedule developed tolerance to the effects of amphetamine in the DRL portion of the schedule (where the increase in response rate would decrease the number of reinforcements) but not in the FI portion of the schedule (where the increase in response rate would not a f f e c t , or even increase, the number of reinforcements). Based upon the p r i n c i p l e s of operant conditioning, the idea is that subjects learn to assume behavioral strategies that counteract disruptive drug e f f e c t s because these s t r a t e g i e s lead to an increase in positive reinforcement or a decrease in negative reinforcement. Thus, according to the reinforcement-density model of contingent tolerance only the 79 subjects in the drug-before condition develop tolerance to the drug's e f f e c t s on the c r i t e r i o n response because only these subjects experience the change in the density of reinforcement caused by performing the c r i t e r i o n response while under the influence of the drug. The reinforcement-density hypothesis can account for those examples of contingent drug tolerance in which operant reinforcement p r i n c i p l e s can be r e a d i l y applied. For example, i t i s possible that tolerance to ethanol's disruptive e f f e c t on treadmill performance develops only in subjects that receive ethanol before they perform the task because only these subjects experience the increase i n footshock associated with poor performance on the t r e a d m i l l . The problem i s that the hypothesis i s t o t a l l y incapable of accounting for examples of contingent tolerance which are not e a s i l y f i t t e d into an operant conditioning framework. For example, the reinforcement-density hypothesis cannot r e a d i l y account for the development of tolerance to ethanol's anticonvulsant e f f e c t because the i n i t i a l e f f e c t of ethanol on the c r i t e r i o n response (convulsions) appears to be a b e n e f i c i a l one for the subject (a diminution in seizure s e v e r i t y ) , and the development of tolerance thus represents a decline in the magnitude of a b e n e f i c i a l e f f e c t . It i s d i f f i c u l t to explain how the reinforcement-density hypothesis could account for the development of tolerance to the therapeutic effect of any drug. 80 Furthermore/ the reinforcement-density hypothesis makes no predict i o n whatsoever about the role of the response contingency in the d i s s i p a t i o n of tolerance. i i . The State-Dependency Model of Contingent Tolerance. The term state-dependency refers to situations i n which the e f f i c i e n t performance of a response i s dependent upon a subject being tested in the same psychological state that existed when the response was acquired (Overton, 1966; 1984). According to the state-dependency hypothesis of drug tolerance (Chen, 1972; Cicero, 1980; Feldman & Quenzer, 1984), a response that was acquired by a subject in a drug-free state i s poorly performed following the administration of a drug because the drug-induced change in the subject's psychological state impairs the subjects' a b i l i t y to retrieve the information necessary to perform the task; the development of tolerance to t h i s drug-induced impairment i s presumed to r e f l e c t the a c q u i s i t i o n of the response in the drugged state. Furthermore, withdrawal symptoms are attributed in part to an impairment in the subjects' a b i l i t y to perform the response in an undrugged state that i s caused by an i n a b i l i t y to retrieve the Information relevant to the task i n a drug-free state. This impairment i s presumed to la s t u n t i l the task is reacquired in the drug-free state. Thus, according to the state-dependency model of contingent tolerance, only the subjects in the drug-before group develop tolerance to the drug's e f f e c t s on the c r i t e r i o n 81 response because only these subjects get the opportunity to perform ( i . e . , acquire) the c r i t e r i o n response while under the influence of the drug. The u t i l i t y of the state-dependency model explanation of contingent tolerance to ethanol's anticonvulsant e f f e c t i s limited for two reasons. The f i r s t i s i t s e x p l i c i t prediction that the performance of the c r i t e r i o n response by tolerant subjects should be impaired when the drug i s withdrawn u n t i l the subject reacquires the response in the drug-free state. However, in the present experiments there was no evidence whatsoever that the convulsions e l i c i t e d in tolerance rats were affected i n any way by the withdrawal of ethanol. The second reason i s the fact that the sta t e -dependency model i s r e s t r i c t e d to paradigms i n which the state of the subject can be reasonably expected to int e r f e r e with the r e t r i e v a l of information required for the e f f i c i e n t performance of a response (e.g., a maze task); i t is d i f f i c u l t to account for an anticonvulsant e f f e c t in terms of a f a i l u r e to ret r i e v e the information necessary to perform the response. i i i . The Homeostatic-Conditioning Model of Tolerance. The homeostatic-conditioning model of drug tolerance (Poulos et a l . , 1981; Poulos & Hinson, 1984) represents an important advance in the study of the e f f e c t s of behavioral variables on drug tolerance because i t attempts to integrate the 82 phenomena of context-specific tolerance and contingent tolerance into a single theory. According to Poulos and his associates, the development of tolerance represents a homeostatic adaptation to a drug's e f f e c t s on the c r i t e r i o n response, and thus the development of tolerance is contingent upon the performance of the c r i t e r i o n response during periods of drug exposure. However, the manifestation of the homeostatic changes responsible for the tolerance is co n t e x t - s p e c i f i c ; that i s , the manifestation of the tolerance i s dependent upon the drug being administered in the context i n which the subject previously experienced the drug's e f f e c t s . For example, Poulos et a l . (1981) found that the development of tolerance to amphetamine's anorexigenic e f f e c t was contingent upon the subjects having access to food during periods of amphetamine exposure, and that the manifestation of t h i s tolerance was r e s t r i c t e d to the context i n which the subjects normally received the drug. Poulos and his colleagues contend that t h i s contextual s p e c i f i c i t y i s the product of Pavlovian conditioning. Although the synthesis of the areas of contingent and context-speci f i c tolerance offered by the homeostatic-conditioning model of drug tolerance i s appealing, i t cannot account for contingent tolerance to ethanol's anticonvulsant e f f e c t for two reasons. F i r s t , P i n e l and Puttaswamaiah (1985) have shown that the manifestation of contingent 83 tolerance to ethanol's anticonvulsant e f f e c t is not context-s p e c i f i c . The results of Experiment 3 off e r support for th i s view--albeit i n d i r e c t . In Experiment 3, the rats in the ethanol-after group received a t o t a l of 20 tolerance-development t r i a l s , in which ethanol was administered a f t e r convulsive stimulation, before the test t r i a l s began. The contextual s t i m u l i ( e s p e c i a l l y the cue properties of the ethanol; Greeley et a l . , 1984) that should serve as conditional s t i m u l i according to a Pavlovian theory of context-specific tolerance were presented a t o t a l of 20 times before the test t r i a l s began. According to a Pavlovian model of tolerance, t h i s extensive CS preexposure should have lead to latent i n h i b i t i o n and therefore a slower rate of tolerance development. This was not the c a s e — r e c a l l that in Experiment 3 the rats from the ethanol-after group developed tolerance faster than did the s a l i n e -control r a t s . The second reason that the homeostatic-conditioning model of tolerance cannot account for contingent tolerance to ethanol's anticonvulsant e f f e c t i s that such an extension of the model would necessarily assume that seizures are homeostatically regulated and that t h e i r i n h i b i t i o n r e f l e c t s a deviation from--rather than a return to--homeostasis. To my knowledge, there i s no evidence whatsoever to support such a counter-intuitive view. One possible way around t h i s problem i s to argue that the development of tolerance to 84 ethanol's anticonvulsant e f f e c t does not represent a horoeostatic adaptation to the anticonvulsant e f f e c t i t s e l f , but to the general depressant e f f e c t s of ethanol on the central nervous system. Although t h i s sounds p l a u s i b l e , t h i s argument cannot account for the importance of the response-contingency to the development of tolerance to ethanol's anticonvulsant effect--homeostatic adaptation to ethanol's general depressant e f f e c t s should be just as prevalent in the rats from the ethanol-after group as the ethanol-before group, and therefore tolerance should r e a d i l y develop in both groups of subjects. This i s c l e a r l y not the case. It i s obvious that the contingent tolerance phenomenon cannot be convincingly accounted for by any of the three e x i s t i n g theories. One possible reason for t h i s i s that each theory has been generated to explain the phenomenon of contingent tolerance within a limited number of paradigms. For example, the generality of the reinforcement-density hypothesis of contingent tolerance i s li m i t e d to paradigms in which the rules of operant conditioning can be e a s i l y applied (e.g., maze running, bar-press responding). S i m i l a r l y , the homeostatic-conditioning model of contingent tolerance i s r e s t r i c t e d to paradigms in which the c r i t e r i o n response is under homeostatlc regulation and the manifestation of tolerance i s co n t e x t - s p e c i f i c . F i n a l l y , the state-dependency model of contingent tolerance i s 85 r e s t r i c t e d to paradigms in which the state of the subject can be reasonably expected to i n t e r f e r e with the r e t r i e v a l of information required for the e f f i c i e n t performance of a learned response. Although i t i s considerably easier to generate a model of contingent tolerance that i s based upon only a few instances of the phenomenon, such a strategy compromises one of the basic features of contingent t o l e r a n c e — i t s generality. The response contingency has been found to be a c r u c i a l factor in the development of tolerance to the e f f e c t s of a wide v a r i e t y of pharmacologically disparate drugs: 1) psychostimulants (e.g., amphetamine, Carlton & Wolgin, 1971; Demellweek & Goudie, 1982; cocaine, Woolverton et a l . , 1979); 2) cannabinoids (e.g., delta-9-tetrahydrocannabinol, Manning, 1976); 3) sedative-hypnotics (e.g., diazepam, Mana, P i n e l , & Kim, in preparation; Tizzano, Bannon, Liberto, Anderson, Roberts, Muchow, & Kallman, 1986; and ethanol, Alkana et a l . , 1982; Chen, 1968; Pinel et a l . , 1983; 1985); 4) and opioids (e.g., morphine, Kayan & M i t c h e l l , 1969; Smith, 1979). Equally impressive i s the v a r i e t y of behaviors which have been manipulated as the c r i t e r i o n response in demonstrations of contingent tolerance: 1) barpress responding (Branch, 1979; Woolverton et a l . , 1979); 2) drinking (Poulos and Hinson, 1984) and 3) feeding (Carlton & Wolgin, 1971); 4) maze running (Chen, 1968); 5) nociception (Jorgenson & Hole, 1984); 6) posttetanic potentiation 86 (Traynor et a l . , 1982); 7) thermoregulation (Alkana et a l . 1982); 8) treadmill running (LeBlanc et a l . , 1972); and 9) seizures (Pinel et a l . , 1983; 1985). The generality of the phenomenon, and the magnitude of the e f f e c t s generated by manipulating the performance of the c r i t e r i o n response, c l e a r l y indicate that the response contingency i s a key factor in the development of many forms of drug tolerance--in f a c t , the response contingency even appears to play a c r i t i c a l role in the adaptation to nonpharmacological disruption such as displaced v i s i o n . C l e a r l y , an adequate theory of contingent tolerance must r e f l e c t the scope of the phenomenon. 4. Conclusions and Future Directions Given the i n a b i l i t y of any of the present models to account for contingent tolerance to ethanol's anticonvulsant e f f e c t , i t would be f i t t i n g at t h i s point to introduce a new model of contingent tolerance that would explain our current knowledge of the phenomenon and also generate a number of testable predictions about other aspects of tolerance that would be influenced by the response contingency. However, in my view, i t would be premature to propose such a model; our knowledge of contingent tolerance i s too li m i t e d to permit the presentation of an adequate theory of the phenomenon. For example, in spite of almost two decades of research, i t i s s t i l l not known whether the development of 87 contingent tolerance to a drug's e f f e c t s is att r i b u t a b l e to the same change or changes that underlie the tolerance that develops in the absence of an e x p l i c i t response contingency. Furthermore, the circumstances in which the response contingency w i l l a f f e c t the development of tolerance to drug's e f f e c t s remain unknown. I have found that the development of tolerance to diazepam's anticonvulsant e f f e c t i s contingent upon kindled rats receiving convulsive stimulation during periods of drug exposure (Mana, P i n e l , & Kim, in preparation); yet Loscher and Schwark (1985) has demonstrated the development of tolerance to diazepam's anticonvulsant e f f e c t s in kindled rats that were not stimulated at a l l during chronic exposure to the drug. There are many variables which may have contributed to t h i s difference — for example the dose, the schedule of administration, the stimulation schedule—and u n t i l we begin to understand the effects of these variables on the importance of the response contingency any model of contingent tolerance w i l l be s e r i o u s l y d e f i c i e n t . In order to broaden our understanding of the importance of the response contingency to the development of tolerance, a greater va r i e t y of paradigms must be developed to study the phenomenon. One c r i t i c i s m of much of the research to date i s that there has been l i t t l e e f f o r t directed at defining i t s generality: for example, the resources of three d i f f e r e n t laboratories and almost two decades were spent 88 attempting to resolve the issue of whether tolerance to ethanol's e f f e c t s could develop in the absence of the response contingency using only two paradigms—a maze task and a treadmill task. Although i t i s important to understand the importance of the response contingency in the development of tolerance to a single drug e f f e c t , i n a single paradigm, i t i s c r i t i c a l that any attempt to generate a t h e o r e t i c a l account of a phenomenon evolve from as diverse a data base as possible. In t h i s vein, one of the distinguishing features of the present thesis was i t s use of a new and unique paradigm--Pinel's model of contingent tolerance to ethanol's anticonvulsant e f f e c t — t o study the importance of the response contingency in the development and retention of tolerance to ethanol's anticonvulsant e f f e c t . The fact that existing theories cannot account for t h i s type of contingent tolerance i l l u s t r a t e s the f u t i l i t y of developing theories without a broader data base. Two aspects of Pinel's paradigm merit consideration in the development of paradigms to study the contingent tolerance phenomenon. The f i r s t i s that i t permits complete control over the response contingency, a feature that is c r i t i c a l in any paradigm used to study the e f f e c t s of the response contingency on the development of tolerance, yet one that i s avail a b l e in only a few of the e x i s t i n g paradigms (e.g., the Aplysia ganglia preparation used by Traynor and his colleagues to study contingent tolerance to 89 ethanol e f f e c t s on the decay of posttetanic potentiation, and the t a i l f l i c k preparation used by Jorgenson's group to study contingent tolerance to ethanol's analgesic e f f e c t s in s p i n a l l y transected r a t s ) . The second aspect of Pinel*s paradigm merits consideration i s that i t involves tolerance to a therapeutic e f f e c t . Unlike many drug e f f e c t s , the suppression of seizures produced by ethanol is a b e n e f i c i a l e f f e c t , and the development of tolerance represents a decline In t h i s b e n e f i c i a l e f f e c t . As I pointed out in the previous section, evidence of tolerance to the therapeutic ef f e c t s of a drug provides a c r i t i c a l test of the theories used to explain i t . Because most research focuses on adverse drug e f f e c t s , the theories r e s u l t i n g from them frequently have d i f f i c u l t y accounting for the b e n e f i c i a l consequences of drug exposure. The present findings rai s e some int e r e s t i n g questions concerning the role of the response contingency in the eventual development of ethanol withdrawal seizures. According to the usual view of the r e l a t i o n between tolerance and dependence, these phenomena r e f l e c t a common adaptation. The physiological change that is presumed to oppose a drug's unconditional e f f e c t s , and therefore produce tolerance, i s also assumed to trigger withdrawal e f f e c t s opposite to the unconditional e f f e c t s of the drug once i t has been eliminated from the subject's body (Balster, 1984; Cicero, 1980). Thus, the development of tolerance to ethanol's anticonvulsant e f f e c t in the present experiments implies that withdrawal convulsions (e.g., Mucha, Pinel & Van Oot, 1975) should occur once ethanol administration ceases. Although there was no systematic attempt in the present experiments to observe the rats for the f u l l 48-hr i n t e r v a l between ethanol administrations, casual observations were made each day, and there was no indication of spontaneous convulsive a c t i v i t y at any time during any of the experiments. Furthermore, in Experiment 4 there was no evidence of an increase in the duration of e l i c i t e d seizures when ethanol was completely withdrawn during the retention i n t e r v a l . The study of contingent tolerance has already led to a reevaluation of two of the t r a d i t i o n a l p r i n c i p l e s about drug t o l e r a n c e — t h a t the development of tolerance i s s o l e l y a function of drug administration, and that the d i s s i p a t i o n of tolerance i s caused by the cessation of drug administration. Future studies may force a reevaluation of a t h i r d fundamental assumption about drug tolerance: the assumption that tolerance and dependence are i n e x t r i c a b l y r e l a t e d . 91 References Alkana, R.L., D.A. Finn and R.D. Malcolm. (1983). The importance of experience in the development of tolerance to ethanol hypothermia. L i f e Sciences 32: 2685-2692. Allan, F. D. and Swinyard, C. A. (1944). Evaluation of tissue tolerance to ethyl alcohol by a l t e r a t i o n in electroshock seizure threshold. Anat Rec 103: 419. Baker, T. B. and T i f f a n y , S. T. (1985). Morphine tolerance as habituation. Psvch Rev 92: 78-108. Balster, R. L. (1984). In L. S. Seiden and R. L. Balster (eds.), Behavioral Pharmacology: The Current Status, pp. 403-418. New York: Alan R. L i s s . Branch, M. (1983). Behavioral tolerance to the stimulating effects of pentobarbital: a within-subject determination. Pharm Biochem Behav 18: 25-30. Campbell, J. C. and Seiden, L. S. (1973). Performance influence on the development of tolerance to amphetamine. Pharm Biochem Behav 1: 703-708. Cappell, H. and LeBlanc, A.E. (1979). Tolerance and physical dependence: do they play a role in alcohol and drug s e l f -administration? In: Research Advances in Alcohol and Drug  Problems, (Ed. Y. I s r a e l , F. B. Glaser, H. Kalant, R. E. Popham, W. Schmidt, and R. G. Smart. New York: Plenum Press, pp. 159-196. Carder, B. and Olson, J . (1973). Learned behavioral tolerance to marijuana in r a t s . Pharm Biochem Behav 1: 73-76. Carlton, P. L. and D. L. Wolgin. (1971). Contingent tolerance to the anorexigenic e f f e c t s of amphetamine. Physiol Behav 7: 221- 223. Chen, C. S. (1968). A study of the alcohol tolerance e f f e c t and an introduction of a new behavioral technique. Psychopharm 12: 433-440. Chen, C. S. (1972). A further note on studies of acquired behavioural tolerance to ethanol. Psychopharm 27: 269-274. Chen, C. S. (1979). A c q u i s i t i o n of tolerance to ethanol as a function of reinforced practice i n the r a t . Psychopharm 63: 285-288. 92 Cicero, T. J. (1980). Alcohol s e l f - a d m i n i s t r a t i o n , tolerance and withdrawal in humans and animals: t h e o r e t i c a l and methodological issues. In H. Rigter and J.C. Crabbe (eds.), Alcohol Tolerance and Dependence, pp. 1-51. Amsterdam: Elsevier-North Holland. Commissaris, R. L. and Rech, R. H. (1981). Tolerance to pentobarbital and ethanol following chronic pentobarbital administration i n the r a t . Substance Ale Action/Misuse 516: 331-339 . Dafters, R. and Anderson, G. (1982). Conditioned tolerance to the tachycardia e f f e c t of ethanol in humans. Psychopharm 78: 365-367. Demellweek, C , and Goudie, A. J . (1982). The role of reinforcement loss in the development of amphetamine anorectic tolerance. IRCS Med Scl 10: 903-904. Demelweek, C. and Goudie, A. J . (1983a). An analysis of behavioral mechanisms involved in the a c q u i s i t i o n of amphetamine anorectic tolerance. Psychopharm 79: 58-66. Demellweek, C. and Goudie, A. J . (1983b). Behavioral tolerance to amphetamine and other psychostimulants: The case for considering behavioral mechanisms. Psychopharmacol 80: 287-307. DeSouza Moreira, L. F., Capriglione, M. J . , and Masur, J. (1981). Development and r e a c q u i s i t i o n of tolerance to ethanol administered pre- and p o s t - t r i a l to r a t s . Psychopharm 73: 165-167 . Dews. P. B. (1978). Behavioral tolerance. In Behavioral  Tolerance: Research and Treatment Implications, NIDA Research Monograph No. 18. U.S. Department of Health, Education and Welfare: R o c k v i l l e , Maryland, pp. 18-26. Eikelboom, R. and Stewart, J . (1982). Conditioning of drug-induced p h y s i o l o g i c a l changes. Psych Rev 89: 507-528. Elsmore, T. F. (1972). E f f e c t s of delta-9-tetrahydrocannabinol on temporal and auditory discrimination performance of monkeys. Psychopharm 26: 62-72. Emmett-Oglesby, M. W. and Taylor, R. E. (1981). Role of dose interval in the a c q u i s i t i o n of tolerance to methylphenidate. Neuropharm 20: 995-1002. Emmett-Oglesby, M. W., Spencer, D. G., Wood, D. M., and L a i , H. (1984). Task-specific tolerance to d-amphetamine. Neuropharm 23: 563-568. 93 Feldman, R. S. and Quenzer, L. F. (1984). Fundamentals of  Neuropsvchopharmacoloav. Sunderland, Mass.: Sinauer and Associates. Ferguson, R. K. and M i t c h e l l , C. L. (1969). Pain as a factor in the development of tolerance to morphine analgesia in man. C l i n Pharm Ther 10: 372-382. F o l t i n , C. and Schuster, C. (1982). Behavioral tolerance and cross-tolerance to d-cathinone and d-amphetamine in r a t s . J Pharm Exp Ther 222: 126-131. Goldstein, D. (1979). Physical dependence of ethanol: i t s r e l a t i o n to tolerance. Drug Ale Pep 4: 33-42. Goldstein, D. (1983). Pharmacology of Alcohol. New York: Oxford University Press. Goudie, A. J. and G r i f f i t h , J . W. (1985). An i n t e r d i s c i p l i n a r y approach to drug tolerance. Trends in  Pharmacological Sciences: 355-356. Greeley, J., Le, D. A., Poulos, C. X., and Cappell, H. (1984). Alcohol is an e f f e c t i v e cue in the c o n d i t i o n a l control of tolerance to alcohol. Psychopharm 83: 159-162. Hayes, R. L. and Mayers, D. J . (1978). Morphine tolerance: Is there evidence for a conditioning model? Science 200: 343-344. Held. R. (1972). P l a s t i c i t y in sensory-motor systems. In Perception: mechanisms and models, Reading from S c i e n t i f i c American, pp. 372-399. San Francisco, W.H. Freeman. Hinson, R. E., Poulos, C. X., and Cappell, H. (1982). The e f f e c t s of pentobarbital and cocaine in rats expecting pentobarbital. Pharm Biochem Behav 16: 661-666. Hinson, R. E. and Selgel, S. (1980). The contribution of Pavolvlan conditioning to ethanol tolerance and dependence. In H. Rigter and J.C. Crabbe (eds.), Alcohol Tolerance and  Dependence, pp. 181-199. Amsterdam: Elsevier-North Holland. Hug, C. C. (1972). C h a r a c t e r i s t i c s and theories related to acute and chronic tolerance development. In S. J . Mule and H. B r i l l (eds.), Chemical and B i o l o g i c a l Aspects of Drug  Dependence, pp. 307-358. Cleveland: CRC Press. J a f f e , J . H. (1980). Drug addiction and drug abuse. In A. G. Gilman, L. S. Gilman and A. Gilman (Eds.) The Pharmacological  Basis of Therapeutics, (6th e d i t i o n ) , pp. 535-584. New York: Macmillan Publishing. 94 Jorgenson, H.A., Berge, 0., and Hole, K. (1985). Learned tolerance to ethanol i n a spinal r e f l e x separated from supraspinal con t r o l . Pharmacol Biochem Behav 22; 293-295. Jorgenson, H.A., Fasmer, 0. B., and Hole, K. (1986). Learned and pharmacologically-induced tolerance to ethanol and cross-tolerance to morphine and clonidine. Pharmacol Biochem Behav  24: 1083-1088. Jorgenson, H. A. and Hole, K. (1984). Learned tolerance to ethanol in the spi n a l cord. Pharmacol Biochem Behav 20: 789-792. Kalant, H., LeBlanc, A. E., and Gibbins, R. J . (1971). Tolerance to, and dependence on, some non-opiate psychotropic drugs. Pharm Rev 23: 135-191. Kayan, S., and M i t c h e l l , C. L. (1969). Further studies on the development of tolerance to the analgesic e f f e c t s of morphine. Arch Int Pharmacodvn 182: 287-294. Kayan, S., woods, L. A., and M i t c h e l l , C. L. (1969). Experience as a factor in the development of tolerance to the analgesic e f f e c t s of morphine. Eur J Pharmacol 6: 333-339. Kesner, R. P. and Baker, T. B. (1981). A two-process model of opiate tolerance. In J . L. Martinez, R. A. Jensen, R. B. Messing, H. Rigter, and J. McGaugh (Eds.) Endogenous Peptides  and Learning and Memory Processes (pp. 459-479) New York: Academic Press. Kesner, R. P. and Cook, (1983). Role of habituation and c l a s s i c a l conditioning in the development of morphine tolerance. Behav Neurosci 97: 4-12. Krank, M. D., Hinson, R. E., and Seigel, S. (1981). Conditioned hyperalgesia is e l i c i t e d by environmental signals for morphine. Behav Neural Bio 32: 148-157. Krasnegor, N. A. (1978). Introduction to behavioral tolerance. In Behavioral Tolerance: Research and Treatment  Implications. NIDA Research Monograph No. 18. U.S. Department of Health, Education and Welfare: Roc k v i l l e , Maryland, pp. 1-4. Kumar, R. and Stolerman. J. P. (1977). Experimental and c l i n i c a l aspects of drug dependence. In L. L. Iversen and S. D. Iversen (Eds.), P r i n c i p l e s of Behavioral Pharmacology.  Vol. 1. (pp. 321-367). New York: Plenum Press. 95 LeBlanc, A. E., Kalant, H., Glbblns, R. J . , and Berman, N. D. (1969). Acqui s i t i o n and loss of tolerance to ethanol by the rat . J Pharm EXP Ther 168: 244-250. Leblanc, A. E., Gibbins, R. J., and Kalant, H. (1973). Behavioral augmentation of tolerance to ethanol in the r a t . Psvchopharmacologia 30: 117-122. Leblanc, A. E., Gibbins, R. J., and Kalant, H. (1975). Generalization of behaviorally-augmented tolerance to ethanol, and i t s r e l a t i o n to physical dependence. Psychopharmacoloqy 44: 241-256. L i s t e r , R. G., F i l e , S. E., and Greenblatt, D. J . (1983). Functional tolerance to lorazepam in the r a t . Psychopharmacoloqy, 81: 292-294. Loscher, W., and Schwark, W. S. (1985). Development of tolerance to the anticonvulsant e f f e c t of diazepam in amygdala-kinldled r a t s . Exp Neurol 90: 373-384. McQuarrie, D. G. and F i n g l , E. (1972). E f f e c t s of si n g l e doses and chronic administration of ethanol on experimental seizures in mice. J Pharmacol Exp Ther 180: 203-215. Mansfield, J . G. and Cunningham, C. L. (1980). Conditoning and extinc t i o n of tolerance to the hypothermic e f f e c t of ethanol i n r a t s . J Comp Physiol Psych 94: 962-969. Manning, F. J. (1976a). Role of experience in a c q u i s i t i o n and loss of tolerance to ethanol in the r a t . Pharmacol Biochem  Behav 5: 269-273. Manning, F. J. (1976b). Chronic delta-9-tetrahydrocannabinol: transient and long-lasting e f f e c t s on avoidance behavior. Pharm Biochem Behav 4: 17-21. Melchior, C. L. and Tabakoff, B. (1981). Modification of environmentally cued tolerance to ethanol in mice. J Pharm  EXP Ther 219: 175-180. Mellanby, E. (1919). M.R.C. (Gt. B r i t . ) . Special Report No.  31, London. Melmon, K. L., Gilman, A. G., and Mayer, S. E. (1980). P r i n c i p l e s of therapeutics. In A. G. Gilman, L. S. Gilman and A. Gilman (Eds.) The Pharmacological Basis of Therapeutics, (6th e d i t i o n ) , pp. 40-55. New York: Macmillan Publishing. Moore, J. E. (1983). Arginine vasopressin enhances retention of morphine tolerance. Pharm Biochem Behav 19: 561-565. 96 Mycek. M. J. and Brezenoff, H. E. (1976). Tolerance to c e n t r a l l y administered phenobarbital. Biochem Pharm 25: 501-504. Okamoto, M., Boisse, N. R., Rosenberg, H. C , and Rosen, R. (1978). Characteristics of functional tolerance during barbiturate physical dependency production. J Pharm Exp Ther  207: 906-915. Overton, D. (1966). State-dependent learning produced by depressant and atropine-like drugs. Psychopharm 10: 6-31. Overton, D. (1984). State-dependent learning and drug discriminations. In L. L. Iversen, S. D. Iversen and S. Snyder (eds.), Handbook of Psychopharmacoloqy, Vol. 18, pp. 59-127. New York: Plenum Press. Paxinos, G. and Watson, C. (1982). The Rat Brain In  Stereotaxic Coordinates. New York: Academic Press. P i n e l , J.P.J., Colbourne, B., Si g a l e t , J. P., and Renfrey, G. (1983). Learned tolerance to the anticonvulsant e f f e c t s of alcohol in r a t s . Pharmacol Biochem Behav 18: suppl 1, 507-510. P i n e l , J . P. J. and Mana, M. J . (1986). Kindled seizures and drug tolerance. In J . Wada (ed.), Kindling 3, pp. 393-408. New York: Raven Press. P i n e l , J . P. J . , Mana, M. J . , and Renfrey, G. (1985). Contingent tolerance to the anticonvulsant e f f e c t of al c o h o l . Alcohol 2: 495-499. P i n e l , J . P. J . , and Puttaswamaiah, S. (1985). Tolerance to alcohol's anticonvulsant e f f e c t i s not under Pavlovian co n t r o l . Pharmacol Biochem Behav 23: 959-964. P i n e l , J . P. J . and Rovner, L. (1978). Experimental epileptogenesis: Kindling-induced epilepsy in r a t s . Exp  Neurol 58: 190-202. P i n e l , J . P. J. and Van Oot, P. H. (1975). The generality of the kindling phenomenon: Some c l i n i c a l implications. Canadian  J Neurol Scl 2: 467-475. Poulos, C.X. and Hinson, R. E. (1984). A homeostatic model of Pavlovian conditioning: tolerance to scopolamine-induced adip s i a . J Exp Psychol: Animal Behav Proc 10: 75-89. 97 Poulos, C.X., Wilkinson, D. A., and Cappell, H. (1981). Horoeostatic regulation and Pavlovian conditioning in tolerance to amphetamine-induced anorexia. J Comp Physiol  Psvchol 95: 735- 746. Racine, R.(1978). Kindling: the f i r s t decade. Neurosurgery 3: 234-252. Rebec, G. V. and Lee, E. H. (1983). Tolerance to amphetamine-induced i n h i b i t i o n of neuronal a c t i v i t y in the ce n t r a l amygdaloid nucleus. Pharm Biochem Behav 19: 219-223. Rock, I. and Harris, C. S. (1972). Vision and touch. In: Perception: mechanisms and models. Readings from S c i e n t i f i c American. San Francisco: W.H. Freeman, pp. 269-277. Ross, D. H., Garrett, K. M., and Cardenas, H. L. (1979). Role of calcium in ethanol-membrane interactions: a model of tolerance and dependence. Drug and Alcohol Dependence 4: 183-188. Rowland, N. and Carlton, J. (1983). Different behavioral mechanisms underlie tolerance to the anorectic e f f e c t s of fenfluramine and guipazine. Psychopharmacology 81: 155-157. Rozin, P., Reff, D., Mark, M., and Schull, J . (1984). Conditioned opponent responses in human tolerance to caffeine. B u l l Psychonomic Soc 22: 117-120. Schuster, C. R. (1978). Theoretical basis of behavioral tolerance: Implications of the phenomenon for problems of drug abuse. In Behavioral Tolerance: Research and Treatment  Implications. NIDA Research Monograph No. 18. U.S. Department of Health, Education and Welfare: Rockville, Maryland, pp. 4-17. Schuster, C. R., Dockens, W. S., and Woods, J. H. (1966). Behavioural variables a f f e c t i n g the development of amphetamine tolerance. Psychopharm 9: 170-182. Seeman, P. Brain dopamine receptors. (1980). Pharmacol Rev 32: 229-313. Siegel, S. (1956). Nonparametrlc s t a t i s t i c s . New York: McGraw H i l l . Siegel, S. (1975). Evidence from rats that morphine tolerance is learned. J Comp Physio Psych 89: 189-199. Siegel, S. (1977). Morphine tolerance a c q u i s i t i o n as an associative process. J Exp Psych : Animal Behav Proc 3: 1-13. 98 Siegel, S. (1978). Tolerance to the hypothermic e f f e c t of morphine i s a learned response. J Comp Physiol Psvch 92: 1137-1149. Siegel, S. and MacRae, J. (1984). Environmental s p e c i f i c i t y of tolerance. Trends in Neurosciences 7: 140-143. Shapiro, N. R., Dudek, B. C , and R o s e l l i n i , R. A. (1983). The role of associative factors i n tolerance to the hypothermic e f f e c t s of morphine on mice. Pharmacol Biochem  Behav 19: 327-333. Siggins, G. R. (1979). C y c l i c nucleotides i n the development of alcohol tolerance and dependence: A commentary. Drug and  Alcohol Dependence 4: 307-319. Skinner, J.E. (1971). Neuroscience: A laboratory manual. Philadelphia: W.B. Saunders. Smith, J . B. (1979). Behavioral influences on tolerance to the e f f e c t s of morphine on schedule-induced behavior. Psychopharm 66: 105-107. Solomon, R. L. (1977). An opponent-process theory of acquired motivation: The a f f e c t i v e dynamics of addiction. In J . D. Masur & M. E. P. Seligman (Eds.), Psychopathology: Experimental models (pp 66-103). San Francisco: Freeman Press. Tabakoff, B. and Yanai, j . (1979). Cortexolone antagonizes development of alcohol tolerance in mice. Psychopharmacology  64: 123-124. Tiffany, S. T., Petrie, E. C , Baker, T. B., and Dahl, J. L. (1983). Conditioned morphine tolerance in the r a t : absence of a compensatory response and cross-tolerance with s t r e s s . Behav Neurosci 97: 335-353. Tizzano, J . , Bannon, A., Liberto, R., Anderson, J . , Roberts, D., Muchow, D., and Kallman, M. (1986). Behavioral tolerance to diazepam as a consequence of the dose administered c h r o n i c a l l y . Soc Neurosci Abs, 16th Annual Meeting for Neurosciences, Washington, D.C. T u l l i s , K. V., Sargent, W. 0., Simpson, J. R., and Beard, J. 0. (1977). An animal model for the measurement of acute ethanol tolerance. L i f e Sciences 20: 875-882. Traynor, A., Schlapfer, W., and Barondes, S. (1980). Stimulation i s necessary for the development of tolerance to a neuronal e f f e c t of ethanol. J Neurobiol 11: 633-637. 99 V o l l l c e r , L. and Ullman, M. D. (1985). I n h i b i t i o n of benzodiazepene receptor binding by urinary extracts: e f f e c t of ethanol. Alcoholism: C l i n & EXP Ther 9: 407-410. Wagner, A. R. (1978). Expectancies and the priming of STM. In S. Hulse, H. Fowler, and K. W. Honig (Eds.), Cognitive  Processes in Animal Behavior, (pp. 177-209). H i l l s d a l e , N.J.: Erlbaum. Wagner, A. R. (1981). SOP: A model of automatic memory processing in animal behavior. In N. E. Spear and R. R. M i l l e r (Eds.), Information Processing i n animals: Memory  Mechanisms, (pp. 5-47). H i l l s d a l e , N. J . : Erlbaum. Wenger, J . R., B e r l i n , V., and Woods, S. C. (1980). Learned tolerance to the behaviorally disruptive e f f e c t s of ethanol. Behav Neur Bio 28: 418-430. Wenger, J.R, Tiffany, T.M., Bombardier, C , N i c h o l l s , K., and Woods. S. C. (1981). Ethanol tolerance in the rat i s learned. Science 213: 575-577. Wiggell, A. H. and Overstreet, D. H. (1984). A c q u i s i t i o n of behaviourally augmented tolerance to ethanol and i t s rel a t i o n s h i p to muscarinic receptors. Psychopharm 83: 88-92. Wikler, A. (1948). Recent progress in research on the neurophysiological basis of morphine addiction. Amer J  Psychlat, 105: 329-338. Wikler, A. (1973). Conditioning of successive adaptive responses to the i n i t i a l e f f e c t s of drugs. Conditional Reflex 8j. 193-210. Wilkinson, P. K., Wagner, J. G., and Sedman, A. J . (1975). Sensitive head-space chromatographic method for the determination of ethanol using c a p i l l a r y blood samples. Anal  Chem 47: 1260-1360. Wood, W.G. (1977). F a c i l i t a t i o n by dexamethasone of tolerance to ethanol in the r a t . Psychopharmacology 52: 67-72. Woolverton, W. L., Kandel, D., and Schuster, C. R. (1978). Tolerance and cross-tolerance to cocaine and d-amphetamine in rats. J Pharm EXP Ther 205: 525-535. 

Cite

Citation Scheme:

        

Citations by CSL (citeproc-js)

Usage Statistics

Share

Embed

Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                        
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            src="{[{embed.src}]}"
                            data-item="{[{embed.item}]}"
                            data-collection="{[{embed.collection}]}"
                            data-metadata="{[{embed.showMetadata}]}"
                            data-width="{[{embed.width}]}"
                            async >
                            </script>
                            </div>
                        
                    
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:
https://iiif.library.ubc.ca/presentation/dsp.831.1-0097021/manifest

Comment

Related Items