Defense Date

2008

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmacology & Toxicology

First Advisor

Dr. Aron H. Lichtman

Abstract

Genetic deletion or pharmacological blockade of the CB1 receptor has been reported to impair extinction learning in aversive conditioning (i.e., conditioned fear and Morris water maze) paradigms, but not in operant procedures in which food reinforcement is earned. It is difficult to discern whether the differential effects caused by CB1 receptor disruption on extinction result from the hedonics (i.e., aversive vs. appetitive) or is related to the required responses associated with these disparate tasks. In order to evaluate whether the hedonics is the determining factor, we used either aversive (i.e., escape from bright lights and air turbulence) or appetitive (i.e., to gain access to water) motivators in the Barnes maze task, a model in which mice are required to enter a hidden goal box. Administration of the CB1 receptor antagonist, rimonabant, disrupted extinction learning under aversive conditions, but not under appetitive conditions. This is the first study to show a differential effect of rimonabant on extinction in a task that required identical motor behaviors, but only differed in hedonic nature of the reinforcer. In addition, genetic ablation of CB1 receptor signaling impaired acquisition of the task under both aversive and appetitive conditioning procedures. Conversely, enhancing endocannabinoid signaling, via genetic deletion of the FAAH enzyme, accelerated acquisition of the task under aversive, but not appetitive, conditioning procedures. Accordingly, these data strongly support the hypothesis that the endogenous cannabinoid system plays a necessary role in the extinction of aversively motivated behaviors, but is expendable in appetitively motivated behaviors. While these findings underscore concerns over potential side effects associated with CB1 receptor antagonists, they also suggest that stimulating the endogenous cannabinoid system may be a promising pharmacological approach to treat maladaptive behaviors that arise from stress or trauma.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

June 2008

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