RC1 Neural Mechanisms Linking the Responses to Incentive Stimuli to the Formation

Yale University, New Haven CT

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Abstract

These studies will identify neurobehavioral mechanisms underlying vulnerability to habitual ethanol-seeking behavior and relapse. We hypothesize that individual differences in the ability of incentive stimuli to control behavior can promote compulsive alcohol drinking in the face of adverse consequences. Our studies will test whether individual variation in the ability of cues to motivate behavior measured by the Pavlovian-to-lnstrumental Transfer (PIT) procedure, will predict habitual ethanol-seeking behavior (i.e., stimulus-response) and cue-induced reinstatement behavior in mice. Animals that show high levels of sucrose PIT will display enhanced ethanol habits measured by insensitivity to outcome devaluation and increased cue-induced reinstatement. Aberrant cognitive flexibility and regulation of control over reward-motivated behavior is central to these preexisting differences in PIT that we argue depend on altered dopaminergic and glutamatergic signaling in regions of the prefrontal cortex (PFC) and striatum. Our published data show that dopaminergic activation of the ventromedial (vm) PFC can restore goal-directed responding in animals that are responding habitually for food. We propose to determine if manipulations of dopaminergic and glutamatergic signaling can reduce habitual ethanol-motivated responding and cue-induced reinstatement in mice that show high levels of sucrose PIT. The role of these signaling pathways will be examined in the vmPFC and dorsal striatum given their known roles in habit formation and in the orbito-frontal cortex and nucleus accumbens, given their role in incentive Pavlovian (stimulus-outcome) learning. Aim 1 will test the hypothesis that individual variation in sucrose PIT predicts the transition from goal-directed to habitual ethanol-seeking behavior. Alterations in protein expression and activity in cortico-limbic-striatal regions will be examined in mice showing high vs. low levels of PIT and those expressing habitual vs. goal-directed ethanol-seeking behavior. Aim 2 will examine if individual differences in sucrose PIT predict reinstatement of cue-induced ethanol seeking. We will also determine if indirect stimulation of extra-synaptic metabotropic glutamate receptors with N-acetylcysteine or direct reduction in NMDA activity with memantine can prevent the expression of ethanol habits and reduce cue-induced reinstatement of ethanol seeking. Our proposed studies will provide the first direct investigation of preexisting mechanisms of incentive motivation and their relationship to habitual ethanol-seeking behavior. These data will provide a foundation for understanding potential genetic contributions to habitual ethanol behavior and identify mechanisms of dopaminergic and glutamatergic dysfunction in corticostriatal circuits that may underlie alcoholism vulnerability and relapse.