CUE CONTROLLED DRUG TAKING--ACCUMBAL NEUROPHYSIOLOGY

University Of Pennsylvania, Philadelphia PA

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Abstract

DESCRIPTION: (Applicant's Abstract) Drug addiction is a chronic relapse disorder characterized by compulsive drug seeking. The disorder can damage severely the health of the individual and has a variety of negative health and financial consequences for the public. The development of effective therapies for the treatment of addiction and the prevention of relapse is thus of great importance. Animal and human studies of addiction have demonstrated that the disorder has important neurobiological determinants. Incentive Motivation theories of addiction propose that central to those neurobiological determinants are actions of addictive drugs on incentive motivation circuitry of the brain. It is hypothesized that under normal conditions this circuitry is activated by natural primary incentives such as food. Situational stimuli associated with the neural activation accrue conditioned incentive stimulus properties and, therefore, directional influence over behavior. It is proposed that addictive drugs activate the same circuitry, although with significantly greater efficacy. As a consequence, drug-associated situational stimuli accrue disproportionately strong conditioned incentive properties and eventually exert a predominant role, relative to other stimuli, in organizing behavior. Consistent with this hypothesis, drug-related stimuli are reported by addicts to evoke an irresistible urge to seek drug and are considered major factors in precipitating relapse to drug-addicted behavior. Mesolimbic dopamine target neurons, including neurons within the nucleus accumbens (NAcc), are hypothesized to be important components of the drug-altered motivational circuitry that contributes to compulsive drug seeking, particularly that controlled by conditioned drug-related stimuli. The aims of the present proposal are to test several fundamental predictions of this "accumbal incentive motivation" hypothesis. These predictions include the following. First, individual NAcc neurons will exhibit regular changes in firing rate when a subject either 1) is exposed to conditioned drug associated incentive stimuli and/or 2) is engaged in drug-seeking behavior controlled by those stimuli. Second, NAcc neurons, including those responsive to drug-related stimuli, will be sensitive to drug administration. The proposed studies will use chronic in vivo extracellular recording techniques to record the activity of single NAcc core and shell neurons of freely-moving rats engaged in drug-seeking behavior during each of two behavioral sessions: 1) second-order intravenous cocaine self-administration sessions and 2) cue reinstatement sessions. The procedures employed during these sessions involve the presentation of exteroceptive stimuli previously paired with self-administered drug and additionally engender drug-seeking behavior that is demonstrably controlled by drug-associated stimuli. The presence or absence of the predicted neural responses during those sessions will thus provide important information regarding the validity of the accumbal incentive motivation hypothesis.