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Conditioned defensive burying : a new paradigm for the study of anxiolytic agents

University of British Columbia

In general, traditional animal behaviour paradigms have not provided a reliable basis for identifying compounds with potential anxiolytic action, or for delineating the mechanisms of their actions. However, the possibility that species-specific defense reactions could serve as a basis for the study of anxiolytic agents had been overlooked. The results of the present investigations showed that the rat's proclivity to bury objects associated with aversive stimulation is particularly sensitive to the effects of anxiolytic agents. The defensive burying behaviour of rats was rapidly suppressed by a single injection of the anxiolytic drug, diazepam, and as the dose of diazepam was increased, the magnitude of its suppressive effect was increased. In addition, the relative potencies of the anxiolytics diazepam, chlordiazepoxide, and pentobarbital in the conditioned burying paradigm compared favorably with their relative potencies in clinical settings. Furthermore, conditioned defensive burying seemed to be selectively sensitive to the effects of anxiolytics: four nonanxiolytic compounds, picrotoxin, pentylenetetrazol, d-amphetamine, and morphine, did not reliably suppress burying. One nonanxiolytic compound, chlorpromazine, did suppress conditioned defensive burying; however, its effects could be reliably dissociated from the effects of diazepam by varying the severity of the aversive stimulus. Chlorpromazine suppressed burying at both low and high shock intensities; whereas, diazepam suppressed burying only at the low shock intensity. Thus, the conditioned defensive burying paradigm appears to fulfil the three major criteria of a valid animal test of anxiolytic agents: sensitivity, relative potency, and selectivity. In the remaining studies, the conditioned defensive burying test was used as a model to study some of the putative mechanisms of action of anxiolytic agents. The observation that diazepam suppressed the unconditioned defensive burying elicited in the absence of painful stimulation ruled out the possibility that the suppressive effect of diazepam was due to analgesic, rather than anxiolytic, action. In subsequent experiments, altering the functions of GABA ergic neurons with picrotoxin was found to have no effect on either conditioned or unconditioned defensive burying. However, picrotoxin did reverse the suppressive effect of diazepam, suggesting that the mechanism whereby diazepam exerts its effect on burying may involve an interaction between diazepam and GABA ergic neural systems. The systematic and robust nature of the present results suggests that the conditioned defensive burying paradigm could prove to be a valuable tool for screening potential anxiolytic agents and for studying their mechanisms of action.

Text

2010-03-29

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http://hdl.handle.net/2429/22859

Psychology

University of British Columbia

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