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The relation between drug exposure and tolerance: contingent drug tolerance reexamined Kippin, Tod Edward 1994

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THE RELATION BETWEEN DRUG EXPOSURE AND TOLERANCE: CONTINGENT DRUG TOLERANCE REEXAMINED by TOD EDWARD KIPPIN B.Sc, University of British Columbia , 1991 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF ARTS in THE FACULTY OF GRADUATE STUDIES Department of Psychology We accept this thesis as conforming the the required standard THE UNIVERSITY OF BRITISH COLUMBIA August 1994 © Tod Edward Kippin, 1994 In presenting this thesis in partial fulfillment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. (Signature) Department of Psychology The Universi ty of B r i t i s h Columbia Vancouver, Canada Date Aug. 31/94 ii ABSTRACT The finding that the performance of a response during periods of drug exposure facilitates the development of tolerance to the effects of the drug on that response is commonly referred to as contingent drug tolerance. Contingent tolerance is typically demonstrated in before-and-after design experiments. One group of subjects receives drug before the performance of the criterion response (drug-before-test condition) and a second group of subjects receives drug after the performance of the criterion response (the drug-after-test condition). The usual finding is that substantial tolerance develops in the drug-before-test condition, but no tolerance whatsoever develops in the drug-after-test condition. Such demonstrations of contingent tolerance have led to the drug-effect theory of tolerance: the theory that tolerance to a particular drug effect is an adaptive response to the experience of that particular drug effect. The purpose of this thesis was to clarify the relation between drug exposure, drug effects, and the development of tolerance. Several experiments have demonstrated that no tolerance whatsoever develops to anticonvulsant drug effects if convulsive stimulation is administered prior to each drug injection (drug-after-test condition), rather than afterwards (drug-before-test condition). Be that as it may, a different experimental design was used in Experiments 1 and 2 to show that small amounts of tolerance develop in the absence of concurrent convulsive stimulation. Rats that received either 3 intraperitoneal injections of diazepam (5.0 mg/kg) per day for 10 days (Experiment 1) or 1 gastric intubation of ethanol (5 g/kg) for 21 days (Experiment 2) were significantly more tolerant than vehicle controls; however, the tolerance could be detected only by a sensitive savings measure. The purpose of Experiment 3 was to test a novel interpretation for the inconsistency between Experiments 1 and 2 on the one hand and the repeated failure to observe tolerance to anticonvulsant drugs following drug exposure without concurrent convulsive stimulation in the drug-after-test condition of before-and-after experiments on the other. This hypothesis is that iii small amounts of tolerance do develop following each drug injection in the drug-after-test condition but that it is dissipated the next day by the convulsive activity experienced in the absence of the drug. To test this hypothesis, one group of amygdala-kindled rats received 15 diazepam injections (2.5 mg/kg) each before a convulsive stimulation, one group received 15 diazepam injections each after a convulsive stimulation, one group received 15 diazepam injections with no convulsive stimulation, and one group received 15 vehicle injections either with or without convulsive stimulations. The drug-before-stimulation rats developed substantial tolerance as has been frequently reported, and the hypothesis was confirmed by the finding that the drug-only rats developed tolerance significantly faster than the rats in the drug-after-stimulation group and the rats in the vehicle-control group. The results of these experiments make two important points. First, tolerance develops following drug exposure even when the criterion response is not performed during drug exposure —albeit substantially less than when it is performed. Presumably, this is because a few of the neural circuits that are active during a convulsion are spontaneously active following the drug administration. Second, the reason why the subjects in the drug-after condition display no evidence of tolerance is because the drug-free performance of the criterion response prior to each drug exposure causes any tolerance that has developed to dissipate. IV TABLE OF CONTENTS ABSTRACT ii TABLE OF CONTENTS iv LIST OF FIGURES vi LIST OF TABLES vii GENERAL INTRODUCTION 1 1. Contingent Drug Tolerance 1 2. Generality of Contingent Drug Tolerance 2 3. The Kindled-convulsion Model of Drug Tolerance 8 4. The Drug-Effect Theory of Tolerance 12 5. General Purpose and Rationale 16 GENERAL METHODS 19 Subjects 19 Surgery 19 Kindling 19 Baseline Phase 20 Treatment Phase 21 Tolerance-Test Phase 21 Histology 21 EXPERIMENT 1: THE INFLUENCE OF CHRONIC EXPOSURE TO DIAZEPAM ALONE ON THE DEVELOPMENT OF TOLERANCE TO THE ANTICONVULSANT EFFECTS OF DIAZEPAM 22 Methods 26 Subjects 26 Drug 26 Baseline Phase 26 Treatment Phase 27 Tolerance-Test Phase 27 Statistics 27 Results 27 Discussion 30 EXPERIMENT 2: THE INFLUENCE OF EXPOSURE TO ETHANOL ALONE ON THE DEVELOPMENT OF TOLERANCE TO THE ANTICONVULSANT EFFECTS OF ETHANOL 3 6 Methods 36 Subjects 36 Drug 36 Baseline Phase 36 Treatment Phase 37 Tolerance-Test Phase 37 Statistics 37 Results 38 Discussion 38 EXPERIMENT 3: THE INFLUENCE OF DRUG-FREE CONVULSIVE STIMULATION ON THE TOLERANCE TO THE ANTICONVULSANT EFFECT OF DIAZEPAM PRODUCED BY DIAZEPAM EXPOSURE ALONE 44 Methods 45 Subjects 45 Drug 45 Baseline Phase 45 Treatment Phase 46 Tolerance-Test Phase 46 Statistics 47 Results 47 Discussion 52 GENERAL DISCUSSION 55 1. General Discussion of Experiments 1 and 2 55 2. General Discussion of Experiment 3 57 3. Implications for Theories of Drug Tolerance 59 3.1. The Reinforcement-Density Theory of Drug Tolerance 59 3.2. The State-Dependency Theory of Drug Tolerance 62 3.3. The Drug-Effect Theory of Drug Tolerance 63 4. General Conclusions 64 REFERENCES 64 LIST OF FIGURES VI Figure 1. Contingent tolerance to the anticonvulsant effect of diazepam. 11 Figure 2. Tolerance to the anticonvulsant effect of diazepam revealed on the first tolerance-test trial of Experiment 1 29 Figure 3. Tolerance to the anticonvulsant effect of diazepam as revealed by the savings in the subsequent rate of tolerance development in Experiment 1 33 Figure 4. Tolerance to the anticonvulsant effect of ethanol revealed on the first tolerance-test trial of Experiment 2 40 Figure 5. Tolerance to the anticonvulsant effect of ethanol as revealed by the savings in the subsequent rate of tolerance development in Experiment 2. 42 Figure 6. Tolerance to the anticonvulsant effect of diazepam revealed on the first tolerance-test trial of Experiment 3 49 Figure 7. Tolerance to the anticonvulsant effect of diazepam as revealed by the savings in the subsequent rate of tolerance development in Experiment 3 51 LIST OF TABLES vn Table 1. Review of the Contingent Drug Tolerance Phenomenon 3 Table 2. Review of the Evidence for Lack of Tolerance in the Drug-After-Test Condition of Before-and-After Design Experiments 23 Table 3. Individual Forelimb Clonus Duration Scores of the Rats in the Drug Group 31 1 GENERAL INTRODUCTION Drug tolerance is any decrease in the effect of a drug that occurs as the result of experience with that drug. Drug tolerance has been a major focus of pharmacologic research for several decades, nevertheless the adaptive mechanisms of drug tolerance remain poorly understood. Progress in the study of the mechanisms of drug tolerance has been impeded by a general lack of understanding of the conditions that are critical for its development; in particular, it has been impeded by the general assumption that exposure of the nervous system to sufficient quantities of drug is the critical event that triggers tolerance development. The general purpose of this thesis is to contribute to the rapidly growing body of findings that challenge this fundamental assumption. The three experiments that compose this thesis focused on the phenomenon of contingent drug tolerance; specifically they focus on the development of contingent tolerance to anticonvulsant drug effects on kindled convulsions. The rationale on which they were based was derived from the drug-effect theory of drug tolerance and from an analysis of the before-and-after experimental protocol that is typically used in investigation of contingent tolerance. Accordingly, Section 1 of the Introduction introduces the phenomenon of contingent drug tolerance and the before-and-after design; Section 2 assesses the generality of the phenomenon of contingent drug tolerance; Section 3 reviews the research on the development of contingent tolerance to the effects of anticonvulsant drugs; and Section 4 introduces the drug-effect theory of tolerance. Finally, Section 5 develops the rationale for the present experiments. 1. Contingent Drug Tolerance Newman and Card (1937) may have been the first to propose that the behavior of a subject during periods of drug exposure can influence the development of tolerance to the effects 2 of the drug; however, it was not until the seminal reports of Chen (1968) and Carlton and Wolgin (1971) that the idea began to attract significant attention. The term contingent tolerance was first used by Carlton and Wolgin (1971) to describe their observation that the development of tolerance to the anorexigenic effect of amphetamine was contingent upon subjects having access to food during the periods of amphetamine exposure. This and most subsequent demonstrations of contingent tolerance have employed Chen's (1968) before-and-after design. In Chen's original before-and-after experiment, one group of rats, the drug-before-test group, received an ethanol injection each day 10 min before performing a maze task; and another group of rats, the drug-after-test group, received an ethanol injection 1 min after performing a maze task. Thus, on each trial, subjects in the drug-before-test group experienced the effect of ethanol on the performance of the maze task, whereas those in the drug-after-test group did not. Then, on the tolerance test, the rats in both groups performed the maze task while under the influence of ethanol. Chen found that significant tolerance to the disruptive effect of ethanol on maze running developed in the drug-before-test group but none whatsoever developed in the drug-after-test group. He, thus, concluded that drug exposure alone is not sufficient for the development of tolerance: that practice of the criterion response while under the influence of the drug is the critical factor. 2. Generality of Contingent Drug Tolerance Since Chen's original report, the development of tolerance to a wide variety of drug effects has been shown to be contingent on the performance of the criterion response while drugged. Reports of the phenomenon of contingent drug tolerance are summarized in Table 1. As Table 1 shows, the majority of studies in which contingent tolerance has been observed have employed Chen's before-and-after design. The strength of the before-and-after design for the Table 1. Review of the Drug Effect Contingent Drug Tolerance Phenomenon Acceleration in the decay of posttetanic potentiation Adipsia Analgesia Drug ethanol scopolamine ethanol morphine Anorexigenia amphetamine apomorphine cathinone cocaine methylpenidate Experimental Design References before-and-after before-and-after before-and-after drug and test vs drug vs vehicle before-and-after before-and-after before-and-after drug and test vs drug vs vehicle drug and test vs drug vs vehicle drug and test vs drug vs vehicle drug and test vs drug vs vehicle Traynor et al. (1976) Traynoretal. (1980) Poulos & Hinson (1984) Advokat (1989) Jorgensen & Hole (1984) Jorgensen et al. (1985) Jorgensen et al. (1986) Ferguson & Mitchell (1969) Kayan& Mitchell (1969) Kayan et al. (1969) Moore (1983) before-and-after before-and-after before-and-after before-and-after differential tolerance before-and-after differential tolerance before-and-after before-and-after before-and-after before-and-after before-and-after before-and-after before-and-after Carey (1979) Carlton &Wogin (1971) Demellweek & Goudie (1982) Demellweek & Goudie (1983 a) Emmett-Olgesby et al. (1984) Foltin & Schuster (1982) Pearl & Seiden (1976) Poulos etal. (1981) Streather & Hinson (1985) Woolverton et al. (1978a) Streather & Hinson (1985) Foltin & Schuster (1982) Woolverton et al. (1978a) Emmett-Olgesby & Taylor (1981) Table 1. (cont'd) Drug Effect Anorexigenia Anticonvulsant Drug methylpenidate quipazine abenarnil carbamazepine clobazam diazepam ethanol pentobarbital valproate Disruption of motor coordination delta-9-THC ethanol Experimental Design References differential tolerance before-and-after drug and test vs drug vs vehicle before-and-after before-and-after before-and-after before-and-after before-and-after before-and-after before-and-after before-and-after before-and-after before-and-after before-and-after before-and-after before-and-after before-and-after before-and-after before-and-after before-and-after before-and-after before-and-after differential tolerance drug and test vs drug vs vehicle drug and test vs drug vs vehicle before-and-after before-and-after before-and-after Pearl & Seiden (1976) Rowland & Carlton (1983) Loscher et al. (1991) Clark etal. (1993) Manaetal. (1991) Weiss et al. (1993) Wiess & Post (1991) Tietz (1992) Manaetal. (1991) Pinel et al. (1983) Pinel & Puttaswamaiah (1985) Pinel et al. (1985) Kim etal. (1991) Pinel et al. (1989) Mana et al. (1991) Weiss et al. (1993) Webster et al. (1973) Beirness & Vogel-Sprott (1984) Bixler& Lewis (1986) Chen (1968) Chen (1972) Haubenreisser & Vogel-Sprott (1983) Le et al. (1986) Le et al. (1987) Le etal. (1989) Leblancetal. (1973) Leblanc et al. (1976) Mann & Vogel-Sprott (1981) Table 1. (cont'd^ Drug Effect Drug Disruption of motor coordination ethanol pentobarbital Disruption of operant tasks amphetamine chlordiazepoxide cocaine delta-9-THC ethanol morphine oxazepam Experimental Design References before-and-after before-and-after before-and-after before-and-after differential tolerance before-and-after differential tolerance differential tolerance differential tolerance differential tolerance differential tolerance differential tolerance before-and-after differential tolerance differential tolerance differential tolerance before-and-after before-and-after differential tolerance drug and test vs drug vs vehicle drug and test vs drug vs vehicle before-and-after drug and test vs drug vs vehicle before-and-after before-and-after differential tolerance before-and-after drug and test vs drug vs vehicle differential tolerance Mansfield et al. (1983) Rawana & Vogel-Sprott (1985) Wenger et al. (1980) Wengeretal. (1981) Le et al. (1986b) Campbell &Seiden (1973) Emmett-Olgelsby et al. (1984) Schuster & Zimmerman (1961) Schuster et al. (1966) Smith & McKearney (1977) Smith (1986a) Cook &Sepinwall (1975) Herberg & Montgomery (1987) McMillan & Leander ( 1978) Hoffman et al. (1987) Woolverton et al. (1978b) Tizzanoetal. (1986) Carder & Olsson (1973) Elsmore (1972) Smith (1986b) Manning (1976) Chen (1979) DeSouzaetal. (1981) Rumbold& White (1987) Wigell & Overstreet (1984) MacMillan & Morse (1967) Sannerud & Young (1986) Smith (1979) Margules & Stein (1968) Table 1. (cont'd) Drug Effect Disruption of operant tasks Drug pentobarbital phenobarbital Hyposexuality Hypothermia ethanol ethanol Experimental Design References before-and-after differential tolerance before-and-after before-and-after Branch (1983) Smith & McKearney (1977) Harris & Snell (1980) Tang & Falk (1978) before-and-after Pinel et al. (1991) before-and-after before-and-after Alkana et al. (1983) Hjeresen et al. (1986) Q\ 7 study of contingent tolerance is that both groups of subjects receive the same exposure to the drug and the same experience with the criterion response; consequently, any difference in the development of tolerance between the two groups must reflect the difference in the contingency between drug exposure and the criterion response. Indeed, several authors have argued that the before-and-after design is the definitive test of the importance of the response contingency in the development of tolerance (Kumar & Stolerman, 1978; Mana, 1990; Wolgin, 1989). Be that as it may, contingent drug tolerance has occasionally been studied in experiments that lack a drug-after-test control group (see Table 1). These experiments typically include a drug-only control group, which receives the drug without the opportunity to perform the criterion response during the treatment phase, and a vehicle control group, which receives vehicle injection prior to the performance of the criterion response during the treatment phase (e.g., Advokat, 1989; Kayan, Woods, & Mitchell, 1969). Similarly, other studies, which examine the development of tolerance to differential drug effects, have found that tolerance develops to the effects of drugs only on tasks that the subjects perform during drug exposure. For example, in a study by Schuster, Dockens, and Woods (1966) the development of tolerance to amphetamine's effects on operant responding was specific to the schedule of reinforcement that was used during periods of drug exposure. One group of rats that practiced on a fixed interval reinforcement schedule during drug exposure became tolerant to amphetamine's effect on that schedule, but not to amphetamine's effects on differential reinforcement of low rates of responding; similarly, another group of rats that practiced on the differential reinforcement schedule during drug exposure became tolerant to amphetamine's effects on that schedule, but not to amphetamine's effects on the fixed interval schedule. Noteworthy for their reliable and large effects have been several studies of contingent tolerance to the effects of anticonvulsant drugs on kindled convulsions—most by Pinel and his 8 colleagues (e.g., Mana, Kim, Pinel, & Jones, 1991; Pinel, Mana, & Renfrey, 1985; Pinel, Colbourne, Sigalet, & Renfrey, 1983; Pinel, Mana, & Kim, 1990). Because this thesis focuses on contingent tolerance to the effects of anticonvulsant drugs on kindled convulsions, the next section is dedicated to describing the research on this particular contingent tolerance phenomenon. 3. The Kindled-Convulsion Model of Contingent Drug Tolerance Periodic administration of initially subconvulsive electrical stimulations to certain brain structures results in the development and progressive intensification of elicited motor seizures; this phenomenon is referred to as kindling (Goddard, 1967; Goddard, Mclntyre, & Leech, 1969; McNamara, 1988; Racine, 1972). For example, an initial stimulation of the rat amygdala at an intensity just sufficient to evoke afterdischarges elicits little or no behavioral response; however, with each subsequent stimulation, the afterdischarges generalize further from the site of stimulation, and motor seizures begin to accompany them. After about 15 daily stimulations, each rat responds reliably to each stimulation with a generalized electrographic and motor seizure, which is characterized in sequence by behavioral arrest, jaw clonus, head clonus, forelimb clonus, rearing, and loss of equilibrium (McNamara, 1988; Racine, 1972). Kindling is permanent (Silver, Shin, & McNamara, 1991); kindled rats that have been left unstimulated for many months usually respond to subsequent stimulation with a generalized convulsion. Kindled convulsions have proven useful for the study of contingent tolerance to anticonvulsant drug effects (see Kim, 1989; Mana, 1990; Pinel, Mana, & Kim, 1990a & b; Weiss & Post, 1991). In the protocol that has been developed by Pinel and his colleagues, all rats are first kindled by 45 amygdalar stimulations administered over 3 weeks—the measure of the severity of the convulsion is the duration of forelimb clonus elicited by each stimulation. Then, they 9 receive a series of "bidaily" (one every 2 days) stimulations to establish the predrug baseline—this bidaily schedule of stimulations is subsequently maintained until the end of the experiment. During the drug-treatment phase, subjects receive an anticonvulsant drug either 1 hr before (drug-before-stimulation group) or 1 hr after (drug-after-stimulation group) each stimulation. Finally, on the tolerance test trial, all rats receive the drug 1 hr before the stimulation. Using their before-and-after kindled-convulsion protocol, Pinel and his colleagues have shown that tolerance to the anticonvulsant effects of several anticonvulsant drugs is contingent on the administration of convulsive stimulation during the periods of drug exposure: to ethanol (Pinel et al., 1983; Pinel et al., 1985); pentobarbital (Pinel et al., 1989; Kim, Pinel, & Roese, 1991); carbamazepine, diazepam, and sodium valproate (Mana, Kim, Pinel, & Jones, 1991). Figure 1 illustrates the results for one experiment in this series, a study of the development of contingent tolerance to the anticonvulsant effects of diazepam (Mana et al., 1991). The rats that received diazepam before each bidaily convulsive stimulation during the tolerance-development phase displayed substantial tolerance to the anticonvulsant effects of diazepam on the tolerance test; in contrast, there was no evidence whatsoever of tolerance in the rats that received diazepam after each convulsive stimulation during the tolerance-development phase, even though the rats in this condition received the same amount of drug exposure as the rats that received diazepam before each bidaily stimulation. Although Pinel and his colleagues have been preeminent in the study of contingent tolerance to anticonvulsant drugs, three prominent groups of investigators have confirmed and extended their findings: Loscher, Rundfelt, and Hornack (1991) demonstrated that the development of tolerance to the anticonvulsant effect of abecarnil in kindled rats was facilitated by the occurrence of convulsions during the period of drug exposure; Tietz (1992) reported that kindled rats that received periodic benzodiazepine injections, each followed by an 10 FIGURE 1. Contingent tolerance to the anticonvulsant effect of diazepam on kindled convulsions elicited in rats by amygdala stimulation. On the no-drug baseline test (NB), the stimulation elicited about 45 s of forelimb clonus; on the drug baseline test (DB), diazepam exerted a potent anticonvulsant effect; and on the drug tolerance test (T), the rats in the drug-before-stimulation group displayed tolerance, but those in the drug-after-stimulation group displayed no tolerance whatsoever. [From Mana et al., 1991, p. 123] MEAN FORELIMB CLONUS DURATION (sec ) Z CD O CO H 0 i— m 73 > Z n m O m < m r-o 3) £ m Z H n. N> \ W -* -cn-o»-V I -0 0 -u>-o-T IT 12 amygdalar stimulation developed tolerance to the anticonvulsant effects of the benzodiazepines, whereas rats that received the benzodiazepine injections after each stimulation did not; Weiss and Post (1991) confirmed that the response contingency is an important factor in the development of tolerance to the anticonvulsant effect of carbamazepine. These results, together with those of Pinel and his colleagues, have established the reliability, magnitude, and generality of the facilitatory effect of convulsive stimulation during the periods of drug exposure on the development of tolerance to anticonvulsant drug effects. 4. The Drug-Effect Theory of Tolerance The phenomenon of contingent drug tolerance was the primary basis for the development of the drug-effect theory of functional drug tolerance (see Pinel, Mana, & Kim, 1990a & b; Poulos & Cappell, 1991). The drug-effect theory views functional drug tolerance as a form of neural adaptation. Its central assertion is that the critical factor in the development of tolerance to a drug is the effect of that drug on concurrent patterns of neural activity. This is a significant departure from the traditional assumption that drug exposure is sufficient for the development of tolerance (see Pinel & Mana, 1986; Mana, 1990). The major prediction of the drug-effect theory is that tolerance will not develop to a given drug effect unless that effect is at least partially manifested during the period of drug exposure; it assumes that drug exposure is necessary, but not sufficient, for the development of tolerance. Like all forms of neural adaptation, the critical event in the initiation of adaptive changes is the perturbation of ongoing patterns of neural activity by the disruptive agent (e.g., a drug) not the mere presence of the agent. The distinction between the traditional drug-exposure theory of tolerance and the drug-effect theory of tolerance can be illustrated with reference to better understood forms of neural adaptation, for example, to the adaptation that occurs to the disruptive effects of visual 13 displacement on visual-motor coordination (cf. Pinel & Mana, 1986; Poulos & Hinson, 1984). When a subject first wears displacing prisms that shift his or her visual world a few degrees to one side, the performance of tasks that involve visual-motor coordination is severely impaired. But after some experience with the prisms, the subject adapts (i.e., becomes tolerant) to the disruptive effect of visual displacement on visual-motor coordination, and performance returns to normal. What is the critical factor that leads to this adaptation? Is it the exposure to the displacing prisms (a theory analogous to the drug-exposure view of tolerance), or is it the experience of the effects of disruption of visual-motor coordination on the performance of tasks (a theory analogous to the drug-effect theory of tolerance)? The evidence overwhelmingly supports the latter view. Little visual-motor adaptation develops to the effects of displacing prisms in subjects that do not perform visual-motor tasks while wearing them: It is the experience of the disruptive effects of the prisms on the performance of visual-motor tasks that is critical for the adaptation to occur (Held, 1972; Rock & Harris, 1972). In the same way, the drug-effect theory asserts that tolerance is an adaptive reaction to the disruptive effects of the drug on concurrent patterns of neural activity. A major strength of the drug-effect theory of tolerance is that it provides an explanation for one of the most puzzling features of drug tolerance: The fact that tolerance can develop to some effects of a drug while at the same time not developing to other effects of the same drug in the same subjects. For most drug effects, the distinction between drug exposure and experiencing the effect of the drug is academic because, under normal circumstances, most drug effects are inevitable consequences of drug exposure. For example, a mobile rat injected with an ataxia-producing drug, such as ethanol, will inevitably experience ethanol's effect on motor activity. In these situations, the drug-exposure view and the drug-effect theory both make the same predictions about the development of tolerance. However, there are cases in which the effects of 14 a drug are expressed only if the subject engages in a particular response while under the influence of the drug. In these cases, experiments can be conducted to determine whether it is the drug exposure or the drug effect that is the critical factor in tolerance development. The drug-effect theory predicts that the development of tolerance to a drug effect will be contingent on the repeated manifestation of that particular effect during periods of drug exposure; whereas, the drug-exposure theory predicts that it will not. Kim, Pinel, Dalai, Kippin, Kalynchuk, and Payne (under review) recently performed a study to test these predictions. They compared the development of tolerance to the ataxic, hypothermic, and anticonvulsant effects of ethanol in three groups of kindled rats. Each group received two injections and a convulsive stimulation on each trial. One group received ethanol before and saline after each convulsive stimulation, the second group received saline before and ethanol after each convulsive stimulation, and the third group received saline before and after each convulsive stimulation. As predicted by the drug-effect theory of tolerance, tolerance to the hypothermic and ataxic effects of ethanol developed in both groups that received ethanol because these effects were automatically experienced in both conditions, whereas tolerance to the anticonvulsant effect of ethanol developed only in the subjects that received ethanol prior to a convulsive stimulation because this effect of ethanol was not experienced by the subjects in the other group. The study of Kim et al. extends earlier work by Woods and his colleagues. In one study (Mansfield, Benedict, & Woods, 1983), they found that tolerance to the ataxic effect of ethanol developed only in rats which were allowed to practice a treadmill task in the drugged state; whereas, tolerance to the hypothermic effect of ethanol developed in all rats that received ethanol. In a follow up study (Hjeresen, Reed, & Woods, 1986), some rats were injected with ethanol and placed in a heated environment so that the hypothermic effect of ethanol was not experienced, and others were injected and kept at room temperature so that the hypothermic effect was experienced. All rats, whether they were allowed 15 to experience the hypothermic effect or not, were allowed to practice the treadmill task in the drugged state. Tolerance developed to the hypothermic effect of ethanol in only those rats that experienced the hypothermic effect, whereas, all rats developed tolerance to the ataxic effect of ethanol. The results of these two studies, like those of the study by Kim et al., indicate that it is the expression of a particular drug effect that is critical for the development of tolerance to that effect. Another type of support for the drug-effect theory was provided by the innovative study of Mana and Pinel (1987). They showed that the administration of convulsive stimulations in the absence of ethanol is the critical factor in the dissipation of tolerance to the anticonvulsant effect of ethanol on kindled convulsions. In their experiment, there was no loss of tolerance over a 14-day retention interval in rats that received either bidaily ethanol injections each followed by a convulsive stimulation, bidaily ethanol injections alone, or neither ethanol injections nor convulsive stimulations. However, tolerance dissipated completely in rats given bidaily convulsive stimulations alone or bidaily convulsive stimulations each followed by an ethanol injection. Thus, the cessation of ethanol administration during the retention interval was neither necessary nor sufficient for the dissipation of tolerance to the anticonvulsant effect of ethanol on kindled-convulsions. As predicted by the drug-effect theory, the critical factor in the dissipation of tolerance to anticonvulsant drug effects proved to be the administration of convulsive stimulation in the absence of ethanol. Just as subjects that have adapted to the effects of vision-displacing prisms must experience the effects of the removal of the prisms on visual-motor coordination for their adaptation to dissipate (Rock, 1966), so too subjects tolerant to the anticonvulsant effect of ethanol must experience convulsions in the absence of ethanol for their tolerance to dissipate. Subsequently, Mana (1990) and Kalynchuk, Kippin, Mclntyre, and Pinel (in press) confirmed that the administration of convulsive stimulation in the absence of drug is the key factor in both the 16 development and dissipation of tolerance to the anticonvulsant effects of diazepam, and Weiss and Post (1991) extended this finding to carbamazepine. A mechanistic drug-effect theory model of the development of tolerance to the anticonvulsant effect of diazepam was proposed by Mana, Kim, Pinel, and Jones (1991) . According to this model, tolerance to the anticonvulsant effect of diazepam results from the concurrent binding of diazepam and GAB A to the GABAA-benzodiazepine receptor complex (GBRC) while convulsive neural circuits involving these receptors are active (Mana et al., 1991). The relative contribution to the development of tolerance of diazepam exposure and experiencing the anticonvulsant effect of diazepam can be explained using this model. When diazepam is presented without convulsive stimulation, the activity of neurons to which it binds is low, resulting in little tolerance development. However, when diazepam administration is followed by convulsive stimulation, the ensuing activity of neurons expressing GBRC concurrent with binding of diazepam and GAB A is markedly higher, resulting in relatively larger and more permanent changes. In support of this model, changes in the GBRC have been found to be related to contingent tolerance to the anticonvulsant effect of carbamazepine (Clark, Massenburg, Weiss, & Post, 1993). One strength of this model is that by stressing the central role of activity-dependent neurophysiological change in the development of drug tolerance, it relates drug tolerance to other forms of learning and adaptation which are currently believed to be products of similar mechanisms (see Bear, 1987). 5. General Purpose and Rationale The general purpose of this thesis was to further clarify the relation between drug exposure, convulsions, and the development of tolerance to anticonvulsant drug effects. It focused not on the development of tolerance in the drug-before-stimulation group, but on the 17 apparent lack of tolerance development in the drug-after-stimulation group. That is it focused on the question: Does any tolerance at all develop when the criterion response is not explicitly performed during the periods of drug exposure? The specific rationale for the present series of experiments was derived from an inconsistency between before-and-after demonstrations of contingent tolerance phenomena and a prediction of the drug-effect theory. This inconsistency is that no tolerance whatsoever is typically observed in the drug-after-test condition of before-and-after experiments (e.g., Chen, 1968; Carlton & Wolgin, 1971; Pinel, Mana, & Renfrey, 1983) even though the drug-effect theory predicts that some tolerance should develop in this condition—albeit less than in the drug-before-test condition. For example, according to the drug-effect theory, some tolerance to the disruptive effect of ethanol on maze running should have developed in the drug-after-test condition of Chen's classic experiment. Even though the maze-running response was not explicitly performed during the periods of ethanol exposure some tolerance should have developed in this condition because some of the neural circuits involved in maze running would have been active when the rats moved about their home cage in the postinjection period. However, as is typically observed in before-and-after experiments, Chen observed no tolerance whatsoever in his drug-after-test condition. The point here is that the results of most before-and-after experiments are inconsistent with the drug-effect theory because their results are too good: According to the drug-effect theory, the only situation in which no tolerance would be expected to develop in the drug-after-test condition is one in which none of the neural circuits involved in the explicit performance of the criterion response would be active following the drug injection when the test is not administered. The purpose of Experiments 1 and 2 was to show that a moderate, but statistically significant, level of tolerance does develop to anticonvulsant drug effects even when the criterion 18 response is not explicitly performed during the periods of drug exposure. In Experiments 1 and 2 tolerance developed to the anticonvulsant effects of diazepam and ethanol, respectively. The purpose of Experiment 3 was to test an original explanation for the apparent inconsistency between the typical results of before-and-after experiments on the one hand and the drug-effect theory and the results of Experiments 1 and 2 on the other. This original explanation and the testable hypothesis that was derived from it will be presented in the introduction section of Experiment 3. 19 GENERAL METHODS This section describes the methods common to all three experiments. Any specific additions to this general methodology are described in the Methods sections of each experiment. Subjects The subjects in all three experiments were male Long-Evans rats (Charles River, Canada), weighing between 250 and 350 g at the time of surgery. They were individually housed in steel hanging cages in a colony room with an ambient temperature of about 21 degrees C and a 12:12-hr light:dark cycle (lights on at 8:00 a.m.). Purina rat chow and water were available continuously. Surgery A single bipolar electrode (Plastic Products company, MS-303-2) was implanted in the left basolateral amygdala of each rat, under sodium pentobarbital anesthesia (65 mg/kg). The electrode tip was stereotaxically aimed at a site 2.8 mm posterior, 5.0 mm left, and 8.5 mm ventral to the skull surface at bregma, with the incisor bar set at -3.3 mm (coordinates from Paxinos & Watson, 1982). The electrode was secured to the skull with four stainless steel screws and dental acrylic. Powdered tetracycline was sprinkled on the incision prior to suturing in order to prevent infection. Kindling Following a postsurgical recovery period of at least 5 days, an electrical stimulation ( I s , 60 Hz, 400 uA) was applied through the electrode of each rat three times per day, 5 days per week, for 3 weeks, with a minimum of 2 hr between each stimulation. Prior to each stimulation, 20 each rat was placed in a plastic box (58 x 58 x 25 cm) containing a thin layer of commercial bedding, and the stimulation lead was attached. The stimulation was delivered within a few seconds, and the rat was returned to its cage once all convulsive activity had ceased. As is usual (see Pinel & Rovner, 1978), the initial stimulations produced no behavioral response other than a momentary behavioral arrest, but by the end of this regimen of 45 kindling stimulations, almost every stimulation elicited a clonic convulsion characterized by facial clonus, forelimb clonus, rearing, and loss of equilibrium. Baseline Phase Following kindling, the rats in each experiment received at least five baseline stimulations, which were administered either daily or bidaily (one every 48 hr), depending on the experiment. A vehicle injection was administered 1 hr prior to the second to last baseline stimulation—this trial is henceforth referred to as the vehicle baseline test. On the final baseline trial, all rats received an injection of the drug under investigation 1 hr before the convulsive stimulation—this trial is henceforth referred to as the drug baseline test. The dependent measure of convulsion severity was the duration of forelimb clonus. Any rat that displayed less than 20 s of forelimb clonus on the vehicle baseline test or more than 10 s of forelimb clonus on the drug baseline test was eliminated from the study. These rejection criteria were adopted because the development of tolerance can be obscured by the inclusion of subjects that do not display either reliable convulsions following stimulation or large initial anticonvulsant effects. The numbers of rats eliminated from each experiment because they failed to meet these criteria is reported in the Methods sections of each experiment. 21 Treatment Phase The remaining rats that met the criteria for inclusion were assigned to groups in such a way that their mean weight and mean forelimb clonus scores on the two baseline tests were approximately the same. The treatment phase varied from experiment to experiment. Tolerance-Test Phase Following the treatment phase, the development of tolerance in each group was assessed by administering a series of tolerance-test trials, each of which was identical to the drug baseline test. Tolerance was measured in two ways: by the diminished ability of the drug under investigation to reduce the duration of convulsions on the first tolerance-test trial, and by the increased rate at which rats subsequently achieved the criterion of tolerance. A rat was considered to have achieved the criterion of tolerance when the duration of its forelimb clonus elicited on two consecutive tolerance-test trials was at least 50% as long as the clonus elicited in the same rat on the vehicle baseline test. Histology At the conclusion of each experiment, all subjects were sacrificed with CO2. Their brains were removed, fixed in formalin, sliced along the coronal plane, mounted on slides, and then stained with creysl violet to confirm the location of the electrode placements. 22 EXPERIMENT 1: THE INFLUENCE OF CHRONIC EXPOSURE TO DIAZEPAM ALONE ON THE DEVELOPMENT OF TOLERANCE TO THE ANTICONVULSANT EFFECTS OF DIAZEPAM. According to the mechanistic model of the drug-effect theory of tolerance proposed by Mana, Kim, Pinel, and Jones (1991), the critical factor in the development of tolerance to a particular drug effect is the concurrent binding of the drug to its receptors and activity in the neural circuits involved in the manifestation of that effect. This theory explains the facilitatory effect of the performance of the criterion response during periods of drug exposure: However, it also suggests, in most situations, that some tolerance should develop even when the criterion response is not fully manifested during drug exposure. For example, following the administration of an anticonvulsant drug, there would likely be some activity in some of the circuits involved in convulsions, even in the absence of convulsive stimulation, and thus, some tolerance to the anticonvulsant effect should develop following repeated drug exposure without convulsive stimulation. However, this is not what has been observed in before-and-after experiments: As shown by Table 2, the usual finding is that no tolerance whatsoever develops in the drug-after-test condition. The purpose of Experiment 1 was to test the hypothesis that tolerance develops to the anticonvulsant effect of diazepam on kindled convulsions even when there is no epileptic activity during the periods of drug exposure. In contrast to the lack of tolerance to the anticonvulsant effect of diazepam on kindled convulsionsthat has been observed in the diazepam-after-stimulation condition of before-and-after experiments (e.g. Mana et al., 1991; Tietz, 1992), both Loscher and Schwark (1985) and Mana (1990) had observed small amounts of tolerance to diazepam's anticonvulsant effect in the absence of convulsive stimulation. In order to provide a test of the hypothesis that tolerance to the anticonvulsant effect of diazepam can develop in the Table 2. Review of the Evidence for Lack of Tolerance in the Drug-After-Test Condition of Before-And-After Design Experiments Drug Effect Acceleration in the posttetanic potentii Adipsia Analgesia Anorexigenia Anticonvulsant decay of ation Drug ethanol scopolamine ethanol amphetamine apomorphine cathinone cocaine methylpenidate quipazine carbamazepine clobazam Toler none none none none none none none none none none none none none none none none none none none none none none none none ance in Drug -After Condition References Traynor et al. (1976) Traynoretal. (1980) Poulos& Hinson (1984) Jorgensen & Hole (1984) Jorgensen et al. (1985) Jorgensen et al. (1986) Carey (1979) Carlton &Wogin (1971) Demellweek & Goudie (1982) Demellweek & Goudie (1983 a) Foltin& Schuster (1982) Poulosetal. (1981) Streather & Hinson (1985) Woolverton et al. (1978a) Streather & Hinson (1985) Foltin& Schuster (1982) Woolverton et al. (1978) Emmett-Olgesby & Taylor (1981) Rowland & Carlton (1983) Clark et al. (1993) Manaetal. (1991) Weiss etal. (1993) Wiess& Post (1991) Tietz(1992) Table 2. (cont'd) Drug Effect Drug Anticonvulsant diazepam ethanol pentobarbital valproate Disruption of motor coordination delta-9-THC ethanol Disruption of operant tasks amphetamine chlordiazepoxide delta-9-THC ethanol Condition References Manaetal. (1991) Pineletal. (1983) Pinel & Puttaswamaiah (1985) Pineletal. (1985) Kim et al. (1991) Pineletal. (1989) Mana et al. (1991) Weiss etal. (1993) Webster et al. (1973) Beirness & Vogel-Sprott (1984) Bixler& Lewis (1986) Chen (1968) Chen (1972) Haubenreisser & Vogel-Sprott (1983) Leblanc et al. (1973) Leblanc et al. (1976) Mann & Vogel-Sprott (1981) Mansfield et al. (1983) Rawana & Vogel-Sprott (1985) Wenger et al. (1980) Wengeretal. (1981) Campbell &Seiden (1973) Herberg & Montgomery (1987) Tizzano et al. (1986) Carder & Olsson (1973) Chen (1979) Rumbold & White (1987) Wigell & Overstreet (1984) Table 2. (cont'd) Drug Effect Tolerance in Drug -After Condition References morphine pentobarbital phenobarbital none none none none Sannerud & Young (1986) Branch (1983) Harris & Snell (1980) Tang & Falk (1978) Hyposexuality ethanol none Pineletal. (1991) Hypothermia ethanol none none Alkana et al. (1983) Hjeresen et al. (1986) 1. Tolerance found only after repeated cycles of drug-after-stimulation trials and drug-after-stimulation tests. 2. No tolerance on three measures of tolerance and significant tolerance on one measure of tolerance. 26 absence of epileptic activity, I incorporated in Experiment 1 a combination of the methods used in the Loscher and Schwark (1985) and Mana (1990) experiments—a combination that I felt would increase the likelihood that tolerance would develop and be detected. Two groups of kindled rats were compared: One received three injections of diazepam (5 mg/kg, i.p.) each day for 10 days; the other received equivalent injections of the vehicle. Methods Subjects The subjects were 57 male Long-Evans rats. Drugs Both the diazepam (Hoffman-LaRoche) and the 2% tween 80 (J.T. Baker) in isotonic saline vehicle were administered by intraperitoneal (i.p.) injection in a volume of 5 ml/kg. Baseline Phase After kindling, all rats received eight bidaily stimulations, followed 48 hr later by the vehicle baseline test. On this test, each rat was injected with the vehicle 1 hr prior to the scheduled convulsive stimulation. On the drug baseline test 48 hr later, each rat received diazepam (2 mg/kg in vehicle) 1 hr before the scheduled convulsive stimulation. The rats that displayed less than 20 s of forelimb clonus on the vehicle baseline test (n=4) or more than 10 s of forelimb clonus on the drug baseline test (n=3) were not studied further. In addition, during the course of the experiment, 2 rats developed running fits and were not studied further. Thus, 48 rats began the treatment phase. 27 Treatment Phase The 48 rats that began the treatment phase were divided into two groups. The treatment phase began 48 hr after the drug baseline test. The rats were assigned to these groups in such a way that both of the groups had approximately the same mean body weight and the same mean duration of forelimb clonus on both the vehicle baseline test and the drug baseline test. The treatment phase consisted of three injections per day for 10 days; the drug group (n=32) received injections of diazepam (5 mg/kg in vehicle) and the vehicle group (n=16) received injections of vehicle. During the treatment phase, the rats in the two groups received no stimulations. Tolerance-Test Phase Forty-eight hr following the final injection of the treatment-phase, the tolerance of the rats to the anticonvulsant effect of diazepam was assessed by a series of 15 bidaily tolerance-test trials. Each test was identical to the drug baseline test; each rat received an injection of diazepam (2.0 mg/kg) 1 hr before a convulsive stimulation. Statistics Independent measures t-tests were used to assess the significance of differences between the two groups. The level of significance was 0.05 for all comparisons. Results Figure 2 illustrates the mean convulsive response on the vehicle baseline test, the drug baseline test, and the first tolerance-test trial for the two groups. It is readily apparent from Figure 2 that the 2.0 mg/kg dose of diazepam produced a large anticonvulsant effect on the drug 28 FIGURE 2. Tolerance to the anticonvulsant effect of diazepam as revealed on the first tolerance-test trial. The mean duration of forelimb clonus on the vehicle baseline test, the drug baseline test, and the first tolerance-test trial for the two groups. It is clear that on the drug baseline test the 2.0 mg/kg dose of diazepam had a potent anticonvulsant effect. On the first tolerance-test trial, the difference between the two groups was not statistically significant (p_>0.05) 29 < LU • DRUG GROUP • VEHICLE GROUP VEHICLE BASELINE TEST DRUG BASELINE TEST TOLERANCE TEST TRIAL 1 30 baseline test and the first tolerance-test trial. However, although there was a suggestion of tolerance on the first tolerance-test trial, it failed to reach statistical significance; the drug and vehicle groups did not differ significantly on the first tolerance-test trial (t=1.904, p>0.05). Mana (1990) reported that although the average tolerance to the anticonvulsant effect of diazepam is only slight when no convulsive stimulation is administered during drug exposure, a few subjects displayed large tolerance effects on a single tolerance test. The same was true in Experiment l~see Table 3. Of the 28 subjects, 6 displayed substantial tolerance effects on test trial 1; they displayed convulsions with forelimb clonus duration 50% or more of that displayed by the same rat on the vehicle baseline test. Figure 3 illustrates the mean number of tolerance-test trials that it took the rats in the two groups to achieve the criterion of tolerance during the 15 tolerance-test trials. The rats in the drug group required significantly fewer trials to achieve the criterion of tolerance development than did the rats in the vehicle group (t=3.036, p<0.01). Histological analysis revealed that all the electrode tips were in the amygdala, with the majority lying within the basolateral nucleus. Discussion The results of Experiment 1 support the previous demonstrations that tolerance to diazepam's anticonvulsant effect on kindled-convulsions can develop in the absence of convulsive stimulations. Although the difference between the drug group and the vehicle group on the first tolerance-test trial of the present experiment failed to reach statistical significance, the fact that the drug group achieved the criterion of tolerance significantly faster than the vehicle group supports the conclusions of Mana (1990) and Loscher and Schwark (1985) that a modest amount of tolerance to diazepam's anticonvulsant effect is produced by diazepam exposure without 31 Table 3. Individual Forelimb Clonus Duration Scores of the Rats in Tolerance-Test Trial 1 71.07 69.56 44.30 28.69 22.04 19.24 10.23 10.23 9.30 5.51 3.51 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0..00 0.00 Vehicle Baseline Test 57.29 51.08 36.48 46.24 40.11 37.08 44.21 41.70 38.74 35.34 48.48 50.97 48.99 45.42 43.97 41.28 40.81 38.86 38.56 37.96 37.07 36.71 36.24 32.41 31.60 30.97 30.29 28.43 Drug the Dru2 Group Baseline Test 0.00 0.00 0.00 8.77 8.01 0.00 0.00 0.00 0.00 post hoc criterion of tolerance * 2.38 0.00 0.00 0.00 0.00 9.11 0.00 0.00 0.00 0.00 0.00 2.82 0.00 0.00 0.00 0.00 0.00 0.00 0.00 * the post hoc criterion of tolerance to the anticonvulsant effect of diazepam was forelimb clonus on the first tolerance-test trial of duration at least 50% of the duration of forelimb clonus elicited in the same rat on the vehicle baseline test. 32 FIGURE 3. Tolerance to the anticonvulsant effect of diazepam as revealed by savings in the subsequent rate of tolerance development. The mean number of tolerance-test trials required by each group to the achieve the criterion of tolerance to the anticonvulsant effect of diazepam. The rats in the drug group required significantly fewer trials to achieve criterion than did the rats in the vehicle group. TOLERANCE-TEST TRIALS TO CRITERION © - • r o w - ^ c n o - s i c o t o o • i i i i i i i i i i i i i i i i i i i • < m a n a ^d o *d 8 o o 34 concurrent convulsive stimulation. The small magnitude of the tolerance effect that was observed in Figure 1 is noteworthy in two aspects. First, it is noteworthy because several of the procedures that were used in Experiment 1 were incorporated into the methods because they would facilitate either the development of tolerance or its detection (see Kalant & Khanna, 1990)-- for example, three injections per day (Loscher & Schwark, 1985; Mana, 1990), high treatment doses (5 mg/kg; Loscher & Schwark, 1985), a sensitive test dose (2 mg/kg; Mana, 1990), and a savings measure of tolerance (Mana, 1986; LeBlanc et al., 1976). Second, it is noteworthy because of the massive effects that have been observed following only 10 bidaily diazepam injections (2 mg/kg) when convulsive stimulation is administered following each injection (Mana et al., 1991) The results of Mana (1990) suggest one factor that may have reduced the magnitude of the tolerance that was observed in Experiment 1. Mana found that tolerance to the diazepam's anticonvulsant effect produced without convulsive stimulation dissipates spontaneously over time. Accordingly, I may have detected larger tolerance effects if I had tested the subjects sooner than 24 hr after the last injection of the treatment phase. However, the detection of tolerance at a shorter time may have been obscured by the accumulation of diazepam as reported by Loscher and Schwark (1985). Although the reports by Mana (1990) and Loscher & Schwark (1985) are the only reports of tolerance to the anticonvulsant effect of diazepam on kindled convulsions following diazepam exposure in the absence of convulsive activity, similar effects have been reported with other convulsion models. Tolerance to diazepam's anticonvulsant effect on convulsions elicited by pentylenetetratzol, picrotoxin, and bicuculline has been demonstrated without elicited convulsions during diazepam exposure (File, 1983; Gallager & Gonsalves, 1988; Rosenberg, Chui, & Tietz, 1985; Frey et al., 1986; Swinyard, 1980). However, these convulsion models produce 35 convulsions that are highly variable in form and duration, are difficult to measure, and are associated with substantial subject mortality and neuronal damage (see Swinyard, 1980; Voskuyl, Meinardi, & Postel-Westra, 1986). For this reason, these models are of little use for the study of contingent tolerance effects because convulsions can not be elicited repeatedly. Thus, as hypothesized, exposure to diazepam in the absence of epileptic activity does lead to the development of modest tolerance effects. This finding appears to be at odds with previous reports that no tolerance whatsoever develops to anticonvulsant drug effects in the drug-after-stimulation conditions of before-and-after designs—even when high doses and many injections are administered (Mana, 1986; Pinel et al., 1985). This apparent inconsistency was the focus of Experiment 3. 36 EXPERIMENT 2: THE INFLUENCE OF EXPOSURE TO ETHANOL ALONE ON THE DEVELOPMENT OF TOLERANCE TO THE ANTICONVULSANT EFFECTS OF ETHANOL. The purpose of Experiment 2 was to assess the generality of the results of Experiment 1. In Experiment 2, the effect of exposure to ethanol in the absence of convulsive stimulation on the development of tolerance to the anticonvulsant effect of ethanol was examined. Ethanol was the drug of choice in this experiment for three reasons. First, it is a potent anticonvulsant. Second, tolerance to its anticonvulsant effect develops rapidly and reliably. Third, it has been frequently used in studies of contingent drug tolerance. Methods Subjects The subjects were 40 male Long-Evans rats. Drugs Both ethanol and the isotonic saline vehicle were administered by i.p. injection in a volume of 5 ml/kg on the baseline tests and the tolerance-test trials and they were administered by gavage (intubation) in 15% v/w istotonic saline solution on the treatment trials. Gavage administration was selected on the treatment trials because frequent i.p. injections of ethanol are associated with severe irritation that can result in substantial subject loss. Baseline Phase After kindling, all rats received eight bidaily stimulations, followed 48 hr later by the vehicle baseline test. On this test, each rat was injected with the vehicle 1 hr prior to the 37 scheduled convulsive stimulation. On the drug baseline test 48 hr later, each rat received ethanol (2 g/kg) 1 hr before the scheduled convulsive stimulation. One rat that displayed more than 10 s of forelimb clonus on the drug baseline test was not studied further. In addition, during the course of the experiment, 2 rats lost their caps and 3 developed running fits. Thus, 34 rats remained in the experiment at the start of the treatment phase. Treatment Phase The 34 rats that began the treatment phase of the experiment were divided into two groups. The rats were assigned to these groups in such a way that both of the groups had approximately the same mean body weight and the same mean duration of forelimb clonus on both the vehicle baseline test and the drug baseline test. The treatment phase began 48 hr after the drug baseline test. It consisted of 21 daily gavage administrations of either 5 g/kg of ethanol in vehicle (drug group) or vehicle (vehicle group). Six rats were lost due to complications with the gavage treatment. Thus, 28 rats completed this phase of the experiment (drug group n=14; vehicle group n=14). Tolerance-Test Phase Forty-eight hr following the final gavage treatment, the tolerance of the rats to the anticonvulsant effect of ethanol was assessed by a series of 10 bidaily tolerance-test trials. Each test was identical to the drug baseline test; each rat received an injection of ethanol (2.0 g/kg) 1 hr before a convulsive stimulation. Statistics Independent measures t-tests were used to assess the significance of differences between 38 the two groups. The level of significance was 0.05 for all comparisons. Results Figure 4 illustrates the mean convulsive response on the vehicle baseline test, the drug baseline test, and the first tolerance-test trial for the two groups. It is readily apparent from Figure 4 that the 2.0 g/kg dose of ethanol produced a large anticonvulsant effect and that the drug group did not display significant tolerance to the anticonvulsant effect on the first tolerance-test trial (t=0.169, p>0.05). Figure 5 illustrates the mean number of tolerance-test trials that it took the rats in the two groups to achieve the criterion of tolerance during the tolerance-test phase. During the tolerance-test phase, the rats in the drug group required significantly fewer trials to achieve the criterion of tolerance development than did the rats in the vehicle group (t= 2.115, p_<0.05). Histological analysis revealed that all the electrode tips were in the amygdala, with the majority lying within the basolateral nucleus. Discussion The results of Experiment 2 extend the results of Experiment 1 to ethanol: A modest level of tolerance developed to ethanol's anticonvulsant effect following ethanol exposure in the absence of the criterion response. As in Experiment 1, there was no significant difference between the drug group and the vehicle group on the first tolerance-test trial, but the savings measure detected significantly more tolerance in the drug group. Experiment 2 makes two important points about the development of tolerance. First, the results of Experiment 2 demonstrate that tolerance to anticonvulsant effect of ethanol can develop in the absence of concurrent convulsive activity, albeit at a much lower rate. This finding 39 FIGURE 4. Tolerance to the anticonvulsant effect of ethanol as revealed on the first tolerance-test trial. The mean duration of forelimb clonus on the vehicle baseline test, the drug baseline test, and the first tolerance-test trial for the two groups. It is clear that on the drug baseline test the 2.0 g/kg dose of ethanol had a potent anticonvulsant effect. On the first tolerance-test trial, the difference between the two groups was not statistically significant (p_>0.05) 40 50n • DRUG GROUP • VEHICLE GROUP VEHICLE BASELINE TEST DRUG BASELINE TEST TOLERANCE TEST TRIAL 1 41 FIGURE 5. Tolerance to the anticonvulsant effect of ethanol as revealed by savings in the subsequent rate of tolerance development. The mean number of tolerance-test trials required by each group to the achieve the criterion of tolerance to the anticonvulsant effect of ethanol. The rats in drug group required significantly fewer trials to achieve criterion than did the rats in the vehicle group. TOLERANCE-TEST TRIALS TO CRITERION O - • N W j _ _ l i I i L_ Cn O) CO • < m X o I -m O O c "0 O 73 C o a 73 o c •a 4* 43 is particular interesting in comparison to the findings of Pinel, Mana, & Renfrey (1985). They found that no tolerance developed to ethanol's anticonvulsant effect following 20 ethanol (5 g/kg) administrations each preceded by a convulsive stimulation. The reason for this apparent inconsistency is the focus of Experiment 3. Second, Experiment 2 demonstrates the utility of the savings measure for the study of tolerance; statistically significant tolerance effects were not detected by comparisons of the performance of the rats on the first tolerance-test trial, but they were detected by comparisons in the rate at which the two group subsequently developed tolerance. 44 EXPERIMENT 3: THE INFLUENCE OF DRUG-FREE CONVULSIVE STIMULATION ON THE TOLERANCE TO THE ANTICONVULSANT EFFECT OF DIAZEPAM PRODUCED BY DIAZEPAM EXPOSURE ALONE. Experiments 1 and 2 demonstrated that drug exposure in the absence of concurrent convulsive stimulation does produce a modest degree of tolerance to the anticonvulsant effects of diazepam and ethanol. Although, these results are consistent with the drug-effect theory of tolerance, they are not consistent with the findings of most before-and-after experiments that no tolerance whatsoever develops unless the criterion response is explicitly performed during the periods of drug exposure. The purpose of Experiment 3 was to resolve this apparent inconsistency by challenging a fundamental assumption on which the interpretation of virtually every before-and-after experiment has been based. Chen and others who have subsequently conducted before-and-after experiments have assumed that the amount of tolerance in the drug-after-test condition is the amount that develops as a consequence of drug exposure alone, that is, as a consequence of drug exposure in the absence of the criterion response (Chen, 1968). This point was originally made by Chen's(1968) reference to the drug-after-test condition as: "..mere experience of alcohol alone..." [pp. 439] However, the results of Mana and Pinel (1987) suggest that this assumption may be incorrect. Recall that Mana and Pinel found that the performance of the criterion response in the absence of the drug causes contingent tolerance to dissipate. It may be the case then that tolerance does develop following each injection in the drug-after-test condition of before-and-after experiments only to be dissipated by the performance of the criterion response in the nondrugged state on the next trial. 45 Experiment 3 tested the hypothesis that tolerance to the anticonvulsant effect of diazepam does indeed develop in the absence of concurrent convulsive stimulation, but that it is actively dissipated by the convulsive stimulation that the subjects in the drug-after-stimulation condition receive prior to drug exposure. This was accomplished by adding two additional groups to the classic before-and-after design: a drug-only group and a vehicle-control group. The drug in Experiment 3 was diazepam. My key predictions were that the drug-only group would display significantly more tolerance than the vehicle-control group, but that the drug-after-stimulation group would not. Of course, I predicted that the drug-before-stimulation group would display substantially more tolerance than the other drug groups. Methods Subjects The subjects were 52 male Long-Evans rats. Drugs Both the diazepam (Hoffman-LaRoche) and the 2% tween 80 (J.T. Baker) in isotonic saline vehicle were administered by intraperitoneal (i.p.) injection in a volume of 5 ml/kg. Baseline Phase After kindling, all rats received 10 daily stimulations followed 24 hr later by the vehicle baseline test. On the vehicle baseline test, each rat was injected with 2% tween 80 in isotonic saline 1 hr prior to the scheduled convulsive stimulation. On the drug baseline test 24 hr later, 46 each rat received diazepam (2.5 mg/kg in vehicle) 1 hr before the scheduled convulsive stimulation. Treatment Phase In the interval between the drug baseline test and the beginning of the treatment phase, the rats were divided into four groups: a drug-before-stimulation group (n=6), a drug-after-stimulation group (n=l 1), a drug-only group (n=10), and a vehicle-control group (n=l 1). The rats were assigned to these groups in such a way that all of the groups had approximately the same mean body weight and the same mean duration of forelimb clonus on both the vehicle baseline test and the drug baseline test. During the treatment phase, the rats in the drug-before-stimulation group received 15 daily injections of diazepam, each 1 hr before a convulsive stimulation. The rats in the drug-after-stimulation group received 15 daily injections of diazepam, each 1 hr after a convulsive stimulation. The rats in the drug-only group received 15 daily injections of diazepam either 1 hr before or after being connected to the stimulator without stimulation. The rats in the vehicle-control group received 15 daily injections of the vehicle either 1 hr before or 1 hr after being connected to the stimulator and either with or without current being delivered. Because the two subgroups of the drug-only group were similar in their performance during the tolerance-test phase, their data were combined for the purposes of statistical analysis. Similarly, the data of the four subgroups of the vehicle-control group were combined. Tolerance-Test Phase The tolerance-test phase began 24 hr following the final trial of the treatment phase, 47 tolerance to the anticonvulsant effect of diazepam (2.5 mg/kg) was assessed by a series of 20 daily tolerance-test trials. Statistics The level of tolerance following the tolerance-test phase was assessed using a one-way ANOVA. Significant F values were followed up with one-tailed Newman-Keuls multiple paired comparisons. The level of significance was 0.05 for all comparisons. Results Figure 6 illustrates each groups' mean convulsive response on the vehicle baseline test, the drug baseline test, and the first tolerance-test trial. It is readily apparent from Figure 6 that the 2.5 mg/kg dose of diazepam produced a large anticonvulsant effect and that only the drug-before-stimulation group displayed substantial tolerance to that anticonvulsant effect on the first tolerance-test trial. One-way ANOVA of the first tolerance-test trial data revealed significant differences in the duration of forelimb clonus among the groups, F(3,34) = 19.572, p < 0.001. Subsequent Newman-Keuls analysis of the duration of forelimb clonus data revealed that the drug-before-stimulation group differed from the drug-only group, q = 4.200, p < 0.05, from the drug- after-stimulation group, q = 4.082, p < 0.05, and from the vehicle-control group, q = 4.173, p < 0.05. No other pairwise comparisons were statistically significant. Figure 7 illustrates the mean number of tolerance-test trials that it took the rats in each group to achieve the criterion of tolerance during the tolerance-test phase. During the tolerance-test phase, the rats in the drug-before-stimulation group required substantially fewer trials to achieve the criterion of tolerance development than did the rats in the other three groups. Furthermore, as hypothesized, the rats in the drug-only group required significantly fewer trials to 48 Figure 6. Tolerance to the anticonvulsant effect of diazepam as revealed on the first tolerance-test trial. The mean duration of forelimb clonus on the vehicle baseline test, the drug baseline test, and the first trial of the tolerance-test phase for the four groups. On the first trial of the tolerance-test phase, the drug-before-stimulation group displayed significantly longer forelimb clonus duration than the other three groups (rj<0.05), which did not differ significantly from one another (p_>0.05). • DRUG-BEFORE-STIMULATION @ DRUG-ONLY 0 DRUG-AFTER-STIMULATION • VEHICLE-CONTROL VEHICLE BASELINE TEST DRUG TOLERANCE BASELINE TEST TEST TRIAL 1 50 FIGURE 7. Tolerance to the anticonvulsant effect of diazepam as revealed by savings in the subsequent rate of tolerance development. The mean number of trials to achieve the criterion of tolerance during the tolerance-test phase of the experiment. The drug-before-stimulation group achieved the criterion of tolerance in significantly fewer trials than the drug-only group, the drug-after-stimulation group, and the vehicle-control group (p<0.05); and the drug-only group achieved the criterion of tolerance in significantly fewer trials than the drug-after-stimulation group and the vehicle control group (p<0.05). The latter two groups did not differ significantly from each other (p>0.05). 51 20i 15 t 10-5-0 • DRUG-BEFORE-STIMULATION B DRUG-ONLY 0 DRUG-AFTER-STIMULATION • VEHICLE-CONTROL JL I k I I 52 achieve the criterion than did the rats either in the vehicle-control and drug-after-stimulation groups. The overall statistical significance of these results was established by ANOVA, F(3,34) = 7.790, p < 0.001. Follow-up paired comparisons revealed that the drug-before-stimulation group differed significantly from the drug-only group q = 3.672, p < 0.05, from the drug-after-stimulation group, q = 6.341,p<0.001, and from the vehicle-control group, q = 5.739, p <0.001, and furthermore, that the drug-only group differed significantly from the drug-after-stimulation group, q = 3.025, p < 0.05, and the vehicle-control group, q = 2.399, p < 0.05. As hypothesized, the drug-after-stimulation group and the vehicle-control group did not differ significantly. Histological analysis revealed that all the electrode tips were in the amygdala, with the majority lying within the basolateral nucleus. Discussion The results of Experiment 3 confirm previous reports of contingent tolerance to the anticonvulsant effects of diazepam in kindled rats: On the first tolerance-test trial, only the drug-before-stimulation subjects displayed tolerance to the anticonvulsant effects of diazepam (see Figure 6), and they subsequently attained the criterion of tolerance in significantly fewer trials than did the subjects in the other three groups (see Figure 7). Moreover, as in previous studies of contingent tolerance to anticonvulsant drug effects, no tolerance whatsoever developed in the drug-after-stimulation subjects: They did not differ significantly from the vehicle-control group in terms of either of the tolerance measures. In addition, the results confirmed the key experimental hypotheses: Although the drug-after-stimulation, drug-only, and vehicle-control groups did not differ significantly on the first tolerance-test trial, the drug-only subjects attained the criterion of tolerance significantly more rapidly than the vehicle-control subjects, and the drug-after-53 stimulation subjects attained the criterion of tolerance significantly more slowly than the drug-only subjects. The results of Experiment 3 have two important methodological implications. First, the observation that the drug-only subjects achieved the criterion of tolerance before the drug-after-stimulation and vehicle-control subjects challenges the implicit assumption on which the interpretation of most before-and-after studies are based: It suggests that the drug-after-test condition does not provide an estimate of the amount of tolerance that develops in response to drug exposure without the concurrent performance of the criterion response. The drug-only condition was associated with a modest degree of tolerance development, which, as predicted by the results of Mana and Pinel (1987), was eliminated by the addition of a convulsive stimulation prior to each injection. This finding suggests that drug-only control groups should be included in before-and-after experiments in which the amount of tolerance that develops in the absence of the criterion response is being assessed. Second, the present results illustrate the sensitivity of savings measure in the study of drug tolerance. On the first tolerance-test trial, only the contingent tolerance effect was evident; the other three groups did not differ significantly among themselves (see Figure 6) However, there were significant differences among these three groups in the rate at which they subsequently developed tolerance on a drug-before-stimulation schedule (see Figure 7). This finding suggests that experiments designed to detect slight differences in tolerance should employ similar savings measures. The findings of Experiment 3 make two theoretical points: one pertaining to the development of tolerance; and the other to its blockade. First, as predicted by the drug-effect theory of tolerance, exposure to diazepam without the convulsive stimulation produced small amounts of tolerance to its anticonvulsant effect. This finding supports previous reports that tolerance to diazepam's anticonvulsant effect developed following chronic exposure without 54 convulsive activity (e.g. Loscher & Schwark, 1985; Mana, 1990); however, the present results represent the first report of tolerance to diazepam's anticonvulsant effect produced by periodic exposure in the absence of convulsive activity. The second theoretical point is an extension of previous reports that the occurrence of drug-free convulsive stimulation dissipates contingent tolerance to the anticonvulsant effects of diazepam (Kalynchuk, Kippin, Pinel, & Mclntyre, in press; Mana, 1990), carbamazepine (Weiss & Post, 1991), and ethanol (Mana & Pinel, 1987). The present results demonstrate that drug-free convulsive stimulation also interferes with tolerance to anticonvulsant effects produced by drug exposure in the absence of convulsive stimulation. 55 GENERAL DISCUSSION This thesis was a study of contingent drug tolerance. Specifically, it reexamined the typical finding that no tolerance whatsoever develops in the drug-after-test condition of before-and-after experiments. Each of the three experiments assessed the development of tolerance to anticonvulsant drug effects. Experiments 1 and 2 showed that either diazepam (Experiments 1) or ethanol (Experiment 2) exposure in the absence of convulsive stimulation results in a statistically significant amount of tolerance development to anticonvulsant drug effects. Experiment 3 showed that the development of such tolerance is disrupted by drug-free convulsive stimulation. The General Discussion of this thesis is divided into 4 sections. Section 1 deals with the major findings of Experiments 1 and 2 and Section 2 deals with those of Experiment 3. Section 3 discusses the possible relevance of the present findings for various theories of drug tolerance. And finally, Section 4 discusses the general conclusions of this work. 1. General Discussion of Experiments 1 and 2 The purpose of Experiments 1 and 2 was to investigate the effect of drug exposure in the absence of the performance of the criterion response on the development of tolerance. It was motivated by the inconsistency between numerous reports that no tolerance whatsoever develops in drug-after-test condition of before-and-after experiments on one hand and the prediction of the drug-effect theory that tolerance should develop. In Experiments 1 and 2, amygdala-kindled rats received either drug or vehicle without convulsive stimulation. The drugs studied in Experiments 1 and 2 were diazepam and ethanol, respectively. On the first tolerance-test trial in both experiments, neither of the groups of rats displayed significant tolerance to the anticonvulsant drug effect under investigation. However, during the remainder of the tolerance-test phase of both experiments, the rats in the drug group developed tolerance in significantly fewer trials than 56 the rats in the vehicle group. The results of Experiments 1 and 2 confirmed the experimental hypothesis: that drug exposure in the absence of convulsive stimulation would produce a statistically significant amount of tolerance to anticonvulsant drug effects. The issue of whether or not any tolerance develops when the criterion response is not performed during drug exposure is not new. In fact, the discovery of contingent drug tolerance raised a controversial debate over this question: Chen (1968; 1972) and Wenger and his colleagues (Wenger et al., 1980; 1981) defended Chen's original conclusion that ethanol exposure per se is not a sufficient stimulus for the development of tolerance to its disruptive effects on maze running; whereas, LeBlanc, Gibbins, and Kalant (1973; 1976) attacked this claim. However, several studies failed to conclusively determine whether tolerance can develop to ethanol's effects on responses not performed during periods of intoxication. This failure was due largely to the fact that the effect of ethanol on maze running, the task used in this series of experiments, can not be completely dissociated from mere exposure to ethanol. Some components of the maze running task, such as walking and other visuomotor activity, inevitably occur in conscious mobile subjects after drug injections regardless of whether or not this task is explicitly performed. A major advantage of the kindled-convulsion model of contingent tolerance is that it avoids this confound; it allows the experimenter complete control over the performance of the criterion response—convulsive activity occurs only when the stimulation is administered. Thus, Experiment 1 confirmed previous reports that at least modest amounts of tolerance develop during diazepam exposure when the criterion response is not performed and Experiment 2 is the first to demonstrate this effect with ethanol. The results of Experiment 1 and 2 make an interesting point about the nature of tolerance. The point is that contingent tolerance and tolerance produced by drug exposure in the absence of the criterion response are at least to some degree related. The fact that exposure to diazepam and 57 ethanol without concurrent convulsive stimulation facilitated the development of tolerance on the drug-before-stimulation trials (a protocol that produces contingent tolerance to anticonvulsant drugs) demonstrates that the tolerance produced by these different procedures is at least partially additive. This qualifies Mana and Pinel's (in preparation) claim that tolerance produced by these two protocol are physiologically distinct from one another. Their claim is based on their finding that the tolerance to anticonvulsant effect of diazepam produced by diazepam exposure without concurrent stimulation, once developed, dissipates in a few days and its expression can be blocked by a single injection of the benzodiazepine antagonist RO 15-1788, whereas contingent tolerance does not dissipate over a 16-day diazepam-free period and is not blocked by RO 15-1788. However, Mana and Pinel failed to examine contingent tolerance either at a longer retention period or with a larger dose of RO 15-1788, thus leaving open the possibility that the difference between contingent tolerance to anticonvulsant drug effects and the tolerance that develops in the absence of convulsive stimulation is quantitative rather than qualitative. Together the results of Experiments 1 and 2 and Mana and Pinel (in preparation) indicate that this issue requires further investigation. 2. General Discussion of Experiment 3 The purpose of Experiment 3 was to resolve the inconsistency between the results of typical before-and-after experiments on the one hand and the results of Experiments 1 and 2 and the predictions of the drug-effect theory of tolerance on the other. Specifically, the purpose of Experiment 3 was to test the hypothesis that tolerance does indeed develop without the performance of the criterion response, but that it is actively dissipated by the drug-free performance of the criterion response that the subjects in the drug-after-test condition engage in on each trial prior to drug exposure. The findings that the rats in the drug-only group, but not the 58 drug-after-test group, displayed significant tolerance confirmed this hypothesis. Furthermore, Experiment 3 strengthened previous findings that no tolerance whatsoever develops in the drug-after-test condition by assessing the subsequent development of tolerance in this condition with the sensitive savings measure. The results of Experiment 3 make two theoretical points about tolerance. First, as previously reported and found in Experiments 1 and 2, drug exposure without the concurrent performance of the criterion response is sufficient for the development of modest levels of tolerance; however, the present experiment represents the first report of tolerance produced by distributed drug exposure in the absence of criterion response performance. Second, the results of Experiment 3 extend previous reports that the drug-free performance of the criterion response causes contingent tolerance to dissipate (Poulos, Wilkinson, & Cappell, 1981; Mana & Pinel, 1987; Mana, 1990; Weiss & Post, 1991; Kalynchuk, Kippin, Pinel, & Mclntyre, in press); Experiment 3 extended these previous findings to include tolerance that is produced by drug exposure in absence of criterion response performance. The results of Experiment 3 have two important methodological implications. First, the finding that the drug-only group, but not the drug-after-test group, displayed significant tolerance suggests that contrary to the assumption made in many previous reports, the drug-after-test condition does not provide an estimate of the amount of tolerance that develops in response to drug exposure without the concurrent performance of the criterion response. Accordingly, the drug-only condition should be incorporated into before-and-after experiments when the amount of tolerance that develops in the absence of the criterion response is being assessed. Second, the results of Experiments 1, 2, and 3 illustrate the sensitivity of the savings measure in the study of drug tolerance. If tolerance had been assessed only on the first tolerance-test trial, the effects found in these experiments would have gone undetected. In fact, if the savings measure had not been used and the conclusions would have been the opposite. Accordingly, the savings measure should be used in any experiment that is conducted to detect modest levels of tolerance. 3. Implications for Theories of Drug Tolerance Prior to the discovery of the contingent tolerance phenomenon, all theories of drug tolerance were based on the implicit assumption that tolerance was an inevitable consequence of drug exposure. Further, these theories considered the only variables that influenced the development of tolerance were pharmacologic ones, such as, the dose and schedule of drug administration (see Kalant & Khanna, 1990). With its discovery, contingent tolerance has fostered the growth of a new view of drug tolerance: The view that the behavior of the drug recipient is an important variable in the development of tolerance to the effects of drugs. Despite their common behavioral emphasis, a number of recent theories which have attempted to explain the phenomenon of contingent tolerance are far from homogenous. The following three subsections evaluates three theories of drug tolerance that have been developed to account for the phenomenon of contingent drug tolerance. The first subsection, deals with the reinforcement-density theory of drug tolerance; the second, with the state-dependency theory of drug tolerance; and the third, with the drug-effect theory of drug tolerance. 3.1. The Reinforcement-Density Theory of Drug Tolerance The reinforcement-density theory of tolerance (Corfield-Sumner & Stolerman, 1978; see also Demellweek & Goudie, 1983a,b; Schuster et al., 1966; Wolgin, 1989) is based upon the observation that tolerance to a drug's behavioral effects often develops only "when the initial effect of the drug causes a loss of reinforcement; when the drug has no effect on reinforcement or when it increases the frequency of reinforcement, no tolerance occurs" [Wolgin, 1989; pp.19]. 60 Based upon the principles of operant conditioning, the central premise of the reinforcement-density theory is that tolerance to a drug's effects emerges as the drug recipient develops behavioral strategies that compensate for the drug effects that are responsible for the loss of reinforcement. The activity of the drug recipient during periods of drug exposure is important because it allows the drug recipient to interact with the reinforcement schedule that is in place; accordingly, only the subjects in the drug-before-test condition develop tolerance to the effect of the drug on the criterion response because only these subjects can experience the loss of reinforcement that results when the criterion response is performed while they are under the influence of the drug. The reinforcement-density theory provides a plausible explanation of those examples of contingent drug tolerance in which the principles of operant reinforcement are involved. For example, the reinforcement-density theory provides a reasonable account of contingent tolerance to the disruptive effects of drugs on maze running, operant responding, or eating—in each case, the drugs reduce reinforcement only in the drug-before-test subjects, and tolerance is associated with its subsequent recovery. In its early years, the study of contingent tolerance focused almost entirely on the effects of drugs on maze running, operant responding, and eating, and the reinforcement-density theory provided a reasonable explanation for much of the early research. However, the generality of the reinforcement-density theory has at least five major shortcomings. First, there is no evidence independent of the phenomenon of contingent tolerance that instrumental learning is involved (Demellweek & Goudie, 1983b; Goudie, 1988; Wolgin, 1989; though see Wolgin & Salisbury, 1985; Wolgin et al., 1987); as Goudie (1988) has pointed out, "the empirical observation of contingent behavioral tolerance does not allow the conclusion that the mechanism by which tolerance developed necessarily involved instrumental learning." [pp. 546]. 61 Second, as noted by Wolgin (1989) there are several instances in which contingent tolerance has failed to develop to a drug effect that produces an obvious loss of reinforcement and there are several other documented instances in which contingent tolerance develops to drug effects that increase the amount of reinforcement that a subject receives (see also Demellweek & Goudie, 1983b). The remaining three weaknesses of the reinforcement-density theory are particularly relevant to demonstrations of tolerance to anticonvulsant drug effects. The third major shortcoming of the reinforcement-density theory is its inability of account for demonstrations of tolerance development to a drug's effects when the criterion response is not performed during drug exposure. For example, the results of Experiments 1, 2, and 3 demonstrate that tolerance to the anticonvulsant effects of diazepam and ethanol develop even in the absence convulsive stimulation. The fourth major shortcoming of the reinforcement-density theory of tolerance is its inability to account for instances of tolerance that do not seem to involve a reinforcement process. For example, the development of tolerance to anticonvulsant drug effects cannot be readily explained by the reinforcement-density theory; there is no evidence that kindled convulsions can serve as either a positive or a negative reinforcer and anticonvulsant drug effects would at least superficially appear to be beneficial to the drug recipient (although see Poulos & Cappell, 1991). The reinforcement-density theory has similar difficulties accounting for tolerance to the analgesic effects ethanol (e.g., Jorgensen et al., 1985; 1986) and morphine (e.g., Advokat, 1989) in spinally transected rats, or to the effects of ethanol on the decay of posttentanic potentiation in the abdominal ganglia of Aplysia (e.g., Traynor et al., 1980). The fifth major shortcoming of the reinforcement-density theory is that it cannot readily account for the effect that performance of the criterion response in the absence of drug exposure has on the dissipation of tolerance. The performance of the criterion response in the absence of the drug has been shown to be an 62 important factor in the dissipation of contingent tolerance in three model: to amphetamine's anorexigenic effect (Poulos et al., 1981); to scopolamine's adipsic effect (Poulos & Hinson, 1984); and to anticonvulsant drug effects (e.g., Mana & Pinel, 1987; Mana, 1990; Weiss & Post, 1991). 3.2. The State-Dependency Theory of Drug Tolerance The term state-dependency refers to situations in which the efficient performance of a response is 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 theory of drug tolerance (Chen, 1972; Feldman & Quenzer, 1984; Wolgin, 1989), a response that was acquired by a subject in a drug-free state is poorly performed during periods of drug exposure because the drug-induced change in psychological state impairs the subject's ability to retrieve the information necessary to perform the task. The development of tolerance to this drug-induced impairment is presumed to reflect the acquisition of the response in the drugged state. Thus, instances of contingent tolerance are accounted for by the fact that only the subjects in the drug-before-test group have the opportunity to perform the criterion response in a drugged state. Like the reinforcement-density theory, the state-dependency theory accounts well for tolerance that develops to the disruptive effects of drugs on the performance of instrumental learning tasks. However, outside this realm, it encounters difficulty. The utility of the state-dependency theory as an explanation for tolerance to anticonvulsant drug effects is limited in at least three ways. First, the state-dependency theory cannot account for the present demonstrations that tolerance develops to a drug's effects following drug exposure without criterion response performance. Second, the state-dependency theory cannot account for the effect that drug-free performance of the criterion response has on 63 the dissipation of tolerance to a drug's effects. And third, the central role of memory retrieval processes in the state-dependency theory limits usefulness to reports of contingent tolerance in which a change in the psychological state of the subject might influence the retrieval of information required for the efficient performance of the task. For example, a state-dependency theory is more capable of accounting for tolerance to ethanol's effects on a subject's performance of a maze task than to its effect on such as convulsions (e.g. Pinel et al., 1983), spinal reflexes (e.g., the tail-flick response; Jorgensen & Hole, 1985), or responses in invertebrate preparations (e.g., posttetanic potentiation in the isolated abdominal ganglion of Aplysia: Traynor et al., 1980). 3.3. The Drug-Effect Theory of Drug Tolerance The drug-effect theory of tolerance is described in the Introduction of this thesis. In summary, it is the theory that tolerance develops to a given drug effect only if that effect is at least partially manifested during the periods of drug exposure. The drug-effect theory of tolerance is based on the premise that drug tolerance is a form of neural adaptation. By viewing drug tolerance as a form of neural adaptation, insights into the mechanisms of drug tolerance can be gained from other better understood forms of neural adaptation (e.g., changes in neuromuscular ganglia, Landmesser, 1980; development of ocular dominance columns, Stryker & Harris, 1986; long-term potentiation, Bliss & Lynch, 1989). Such insights led to the development of the hypotheses that were tested by the present experiments. Because the results of Experiments 1, 2, and 3 were predicted by the drug-effect theory of tolerance, it readily accounts for them. In addition to the results of the present series of experiments, the drug-effect theory can also explain several of the findings that are difficult for the reinforcement-density and state-dependency theories of tolerance. First, the finding that tolerance develops even when the criterion response is not performed during the periods of drug exposure is readily explained by 64 assuming that some of the neural activity that underlies the performance of the criterion response is likely to occur when the criterion response is not performed. Second, the effect of drug-free performance of the criterion response on the dissipation of tolerance can be explained by the drug-effect theory using the same very principles of activity-dependent change. Following, the changes in the neural circuits involved in the criterion response which constitute drug tolerance, neural activity is required in the absence of the drug to bring about a reverse change in these neural circuits such that the effect of the drug on the activity is restored in the same way that activity-dependent reversals have been demonstrated to be involved in the disruption of long-term potentiation (see Steward, White, Korol, & Levy, 1989). Finally, because the drug-effect theory of tolerance does not employ highly restrictive constructs (e.g., level of reinforcement; cognitive processes) its generality is not limited to explaining only a few instances of drug tolerance. The drug-effect theory can readily explain the development of tolerance when a drug has no effect on the level of reinforcement or even increases it, as long as the drug disrupts normal patterns of neural activity. Further, because the drug-effect theory does not rely on the invocation of psychological states in the development of tolerance, it can readily explain the development of drug tolerance in reflexive systems or invertebrates preparations. 4. General Conclusions One of the major impediments in the study of drug tolerance has been the lack of understanding of the factors that are involved in its development. Even today, much of the research on drug tolerance is based on the implicit assumption that the development of tolerance is solely a function of drug exposure. Be that as it may, the discovery of the phenomenon of contingent drug tolerance clearly shows that the behavior of the drug recipient during periods of 65 drug exposure is also a key factor in tolerance development. However, it has not been clear whether the performance of the criterion response while drugged is a permissive or critical factor in the development of tolerance. The results of Experiment 1, 2, and 3 demonstrate that tolerance develops to the effect of a drug on a given behavior even when that particular behavior is not performed during drug exposure. Additionally, the results of Experiment 3 indicate that, like contingent tolerance, tolerance produced by drug exposure without performance of the criterion response is reduced by the drug-free performance of the criterion response. The results of these experiments are important for two general reasons. First, they suggest that contingent tolerance is not completely distinct from tolerance that is produced with the explicit performance of the criterion response. The demonstration that the mechanism of contingent tolerance are comparable to the mechanisms of tolerance that develops in the absence of the criterion response bades well for the development of a comprehensive theory of drug tolerance. The study of drug tolerance would be greatly facilitated by the development of a general theoretical framework from which to explore all manifestations of functional drug tolerance. The drug-effect theory seems to have such a potential. The second general reason the results of these experiments are important because they illustrate the benefit of viewing tolerance as a form of neural adaptation. This approach was beneficial in at least four ways. 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