Date of Award

2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmacology and Experimental Therapeutics

Abstract

Addiction is a chronic, relapsing disorder for which strikingly few effective therapies exist, and there are no FDA-approved pharmacotherapies for methamphetamine (Meth) addition. There is an immense need to identify the neurobiological underpinnings of psychostimulant addiction and develop efficacious drug therapies to compliment the current mainstay treatment of behavioral/cognitive therapy.

Re-exposure to cues associated with psychostimulants (e.g., drug paraphernalia) increase neuronal activity and can elicit drug-craving and -seeking; an effect which is profound and long-lasting. A mechanism to disrupt those brain processes which are necessary to maintain the association may reduce the incidence of cue-elicited relapse.

Conditioned place preference (CPP) is a behavioral paradigm in which subjects (humans and rodents) learn to associate the rewarding properties of Meth with particular contextual cues. After the association develops subjects will choose to spend more time in the drug-associated context over a non-drug paired context. This behavior is thought to reflect the increased salience attributed to drug-associated cues. Thus, CPP is a valuable research tool to evaluate the neuronal adaptations associated with drug-induced associative learning and provides a means to evaluate the utility of potential pharmacotherapies to reduce the salience of drug-associated cues.

As the major inhibitory neurotransmitter in the brain, GABA neurotransmission influences a number of drug-induced behaviors (e.g., CPP) as well as mnemonic processes (e.g., learning and memory). Accordingly, the metabotropic GABAB receptor has recently emerged as a potential therapeutic target for drug addiction. Administration of the direct acting GABAB receptor agonist baclofen has revealed positive outcomes in clinical trials; however, the side effects associated with baclofen limit its clinical utility. Positive allosteric modulators (PAMs) of the GABAB receptor augment GABAB receptor signaling without the side effects of the agonist making it a better alternative to agonist therapy.

The current project sought to determine the role of the GABAB receptor in the maintenance of Meth-induced CPP. To do so, the GABAB receptor agonist baclofen and GABAB receptor positive allosteric modulators fendiline, GS39783, and CGP7930 were administered after the learned association developed (Meth-induced CPP) in order to determine if augmenting GABAB receptor signaling would disrupt the maintenance of the behavior.

These experiments will shed light on the role of GABAB receptors in the maintenance of Meth-induced associative learning and evaluate the utility of GABAB receptor activators to reduce the salience of psychostimulant-associated cues.

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