Sunday, May 18, 2025
5/18/2025
Cocaine Addition and the Need-State Hypothesis - Project Summary. The Problem. In a recent paper entitled “Preaddiction - A Missing Concept for Treating Substance Use Disorders”, McLellan, Koob and Volkow [7] argue that intervention need not be limited to the final stage of the disease and likely would be more successful if administered early in the disease state. Treatment early in the disease of addiction, however, requires early identification of risk. At present, we do not necessarily have the tools to identify risky preaddiction in humans; and treatments for ‘preaddiction’, consequently, have not been well explored. That being said, we have used an animal model that can identify individual vulnerability early in the development of the disease and, then, can be used to study early intervention. The Model: If a cue precedes the delivery of drug, the cue will, with repeated pairings, come to elicit a conditioned behavioral/physiological response that opposes the impact of the coming drug. The valence and magnitude of this conditioned behavioral/physiological response reflects the nature and intensity of the impact of the drug on the organism. Thus, in our model, a saccharin cue predicts the impending availability of cocaine and rats that exhibit the greatest conditioned aversion (i.e., the greatest conditioned withdrawal) toward that saccharin cue ultimately exhibit the greatest drug seeking and taking. Treatment. This finding led us to hypothesize that addiction involves a hi-jacking of not only reward substrates, but of substrates involved in physiological need as well – i.e., in the need for drug. Given this need-state hypothesis, we predict that known satiety agents, such as glucagon-like peptide-1 (GLP-1), will reduce the need for drug as reflected by a reduced aversive conditioned response and reduced drug seeking and taking. Specific Aim 1 will challenge this hypothesis by testing if systemic treatment with a GLP-1 receptor agonist will block the aversive behavioral and physiological conditioned response to the taste cue (i.e., aversive taste reactivity behavior (gapes) and low dopamine in the nucleus accumbens shell) and subsequent cocaine seeking and taking in rats. Specific Aim 2 will measure c-Fos activation patterns in the entire brain to determine whether greater rejection of the cocaine- predicting cue in high taker/seekers is accompanied by activation of substrates involved in aversion/withdrawal and reward/seeking and, importantly, whether these patterns of activation also are reversed by treatment with a GLP-1R agonist. Specific Aim 3 will employ site-specific infusion of the GLP-1R antagonist, Extendin-9, to begin to interrogate the circuits identified in Aim 2. Thus, in the completion of three aims, we will use the conditioned withdrawal elicited by a cocaine-predicting saccharin cue to track the development of addiction in both vulnerable and resistant rats, we will identify neural circuitry associated with this need-state, and we will use a known satiety agent, a GLP-1R agonist, to reverse these patterns in brain and behavior early in the development of the disease – i.e., during ‘preaddiction.’
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