Nonhuman Primate Model of Benzodiazepine Relapse

Harvard University (Medical School), Boston MA

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Abstract

DESCRIPTION (provided by applicant): The purpose of this R03 proposal (PAR-00-059) is to develop a new model for investigating relapse to benzodiazepine (BZ) drug seeking following a period of abstinence. BZs are widely prescribed for the management of anxiety and sleep disorders, but their usefulness is constrained by liability for abuse and dependence. A critical factor contributing to BZ abuse and dependence is their potential for relapse. Although the factors responsible for relapse to drugs of abuse are not understood completely, there is now a substantial body of evidence implicating environmental stimuli associated with previous drug use (cues) and acute re-exposure to drugs (priming) as triggers of craving and relapse. Our proposed research will make use of i.v. self-administration techniques in rhesus monkeys to investigate environmental and pharmacological factors contributing to the reinstatement of extinguished BZ-seeking behavior and to evaluate potential medications for the management of relapse. Monkeys will be given histories of i.v. self-administration of either the BZ/a 1 -preferring agonist zolpidem or the non-selective agonist triazolam under conditions in which persistent drug seeking is maintained jointly by drug injections and by drug-associated stimuli (second-order schedule). Drug seeking then will be extinguished by substituting vehicle for the BZ and eliminating the drug-associated stimulus. Using this model, we will (1) study the role of drug-associated stimuli and priming injections as relapse triggers (2) study pharmacological specificity of priming-induced relapse with experiments targeting abused drugs with similar mechanisms of action to the BZs, and (3) identify candidate medications for relapse prevention. Concurrent observational studies will provide information on the role of physical dependence in relapse to BZ seeking. Identification of compounds lacking relapse potential in our studies will provide valuable information for developing safer and more broadly effective anti-anxiety medications, as well as compounds that may be beneficial in the pharmacological management of BZ dependence.