Neurobiological studies that focus on the incentive properties of abused drugs and their associated stimuli may lead to strategies for preventing compulsive drug seeking. According to the incentive salience hypothesis, the mesolimbic dopamine system becomes sensitized to drugs and associated stimuli, attributing """"""""incentive salience"""""""" to their neural representations. This neuroadaptation mediates the ability of drug-associated stimuli (conditioned incentives) to elicit drug seeking, even after abstinence. The hypothesis predicts that neurons mediating incentive salience will respond to stimuli that trigger drug seeking. Using the high temporal and spatial resolution of single-cell electrophysiology during cocaine self-administration in rats, we will test that fundamental prediction: target neurons of the mesolimbic dopamine system should acquire responsiveness to a discriminative stimulus, an audible tone, that signals cocaine availability, contingent upon a lever press. Single unit activity in the accumbens shell and core, primary targets of mesolimbic dopamine projections, shown to be necessary for cocaine self-administration, will be recorded from the same neurons throughout daily training. Each lever press during the tone will produce a cocaine infusion (0.35 mg/kg) and terminate the tone. Presses in the absence of the tone will have no programmed consequence. Acquisition of tone discrimination (70 tone presentations per day, 3-6 min inter-tone interval) will be measured as reaction time to the tone, and rate of lever pressing in the absence of the tone. In two animals trained thus far, the tone did become established as a conditioned incentive, indexed by gradually reduced reaction time, such that each tone elicited an abrupt initiation of movement toward the lever. Concomitantly, the tone evoked pronounced accumbens firing for the duration of individual tone-evoked movements toward the lever. Thus, certain phasic accumbens firing patterns do appear to correlate with drug-seeking behavior, possibly in a causal way. The data are not necessarily consistent with an enhancement of the neural representation of the conditioned incentive, in that the neurons did not fire before movement, in response to the tone per se, but fired during the tone evoked movement. Nonetheless, their sustained discharge throughout approach to the lever supports a separate prediction of the incentive salience hypothesis: once triggered by the conditioned incentive, the psychological process-a neural process- (possibly downstream of the neural representation of the conditioned incentive) should be sustained until the goal is reached. Thus preliminary data are consistent with the hypothesis that neurons in the mesolimbic system process information regarding conditioned incentives. Our design can test predictions directly on mesolimbic target neurons, which are focal to incentive-motivational theory, a framework with substantial explanatory power for approaching a neurobehavioral understanding of drug abuse.
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