Project Grant F31DA062412

ELUCIDATING THE MECHANISMS AND RELEVANCE OF COCAINE-INDUCED PLASTICITY OF INHIBITORY G PROTEIN SIGNALING IN THE PRELIMBIC CORTEX - PROJECT SUMMARY LIKE OTHER DRUGS OF ABUSE, PSYCHOSTIMULANTS ENHANCE DOPAMINE (DA) NEUROTRANSMISSION FROM THE VENTRAL TEGMENTAL AREA (VTA) TO DOWNSTREAM TARGETS INCLUDING THE MEDIAL PREFRONTAL CORTEX (MPFC) AND NUCLEUS ACCUMBENS (NAC). DIRECT STIMULATION OF VTA DA NEURONS IN RODENTS IS REINFORCING AND SUFFICIENT TO TRIGGER AN ARRAY OF MOLECULAR, CELLULAR, AND BEHAVIORAL ADAPTATIONS LINKED TO ADDICTION. PSYCHOSTIMULANTS CAN WEAKEN INHIBITORY G PROTEIN-DEPENDENT SIGNALING IN VTA DA NEURONS AND LAYER 5/6 PYRAMIDAL NEURONS OF THE PRELIMBIC (PL) SUB-REGION OF THE MPFC VIA SUPPRESSION OF G PROTEIN-GATED INWARDLY RECTIFYING K+ (GIRK) CHANNEL ACTIVITY. IN LAYER 5/6 PL PYRAMIDAL NEURONS, FOR EXAMPLE, REPEATED COCAINE EXPOSURE IN MICE WEAKENS GIRK CHANNEL REGULATION BY THE GABAB RECEPTOR (GABABR) IN A DA- AND PHOSPHORYLATION-DEPENDENT MANNER. GENETIC SUPPRESSION OF GIRK CHANNEL ACTIVITY IN PL PYRAMIDAL NEURONS OF DRUG-NAIVE MICE EVOKES SOME OF THE CELLULAR AND BEHAVIORAL HALLMARKS OF REPEATED COCAINE EXPOSURE. THE GOALS OF THIS PROJECT ARE TO ELUCIDATE THE CELLULAR AND NEUROCHEMICAL MECHANISMS UNDERLYING THE COCAINE-INDUCED SUPPRESSION OF GABABR-GIRK SIGNALING IN PL PYRAMIDAL NEURONS AND TO INVESTIGATE THE THERAPEUTIC POTENTIAL ASSOCIATED WITH RESCUING THIS SIGNALING PATHWAY IN THESE NEURONS. PROPOSED EXPERIMENTS TEST KEY ELEMENTS OF THE FOLLOWING CONCEPTUAL FRAMEWORK: COCAINE PROVOKES THE D1 DA RECEPTOR-DEPENDENT EXCITATION OF PL GABA NEURONS, DRIVING THE FEEDFORWARD INHIBITION OF PL PYRAMIDAL NEURONS. REPEATED GABAERGIC INPUT TO PL PYRAMIDAL NEURONS PROMOTES THE SUPPRESSION OF THE GABABR-GIRK SIGNALING PATHWAY. WEAKENING OF THIS INHIBITORY SIGNALING PATHWAY CONTRIBUTES TO THE HYPEREXCITABILITY OF PL PYRAMIDAL NEURONS, WHICH PROMOTES ABERRANT BEHAVIORS ASSOCIATED WITH REPEATED COCAINE EXPOSURE. MECHANISM-INFORMED INTERVENTIONS THAT RESTORE OR STRENGTHEN THE GABABR-GIRK SIGNALING PATHWAY IN PL PYRAMIDAL NEURONS, THEREFORE, WILL NORMALIZE BEHAVIORS LINKED TO REPEATED COCAINE EXPOSURE. THERE ARE TWO SPECIFIC AIMS: 1) ELUCIDATE MECHANISMS UNDERLYING THE COCAINE-INDUCED HYPEREXCITABILITY OF PL PYRAMIDAL NEURONS. USING SLICE ELECTROPHYSIOLOGICAL APPROACHES, I WILL TEST THE HYPOTHESIS THAT D1R ACTIVATION OF PL GABA NEURONS DRIVES THE FEEDFORWARD INHIBITION OF PL PYRAMIDAL NEURONS NECESSARY FOR THE COCAINE-INDUCED SUPPRESSION OF GABABR-GIRK SIGNALING. 2) TEST WHETHER MECHANISM-INFORMED INTERVENTIONS CAN RESCUE COCAINE-INDUCED BEHAVIORAL DEFICITS. USING COMPLEMENTARY PHARMACOLOGICAL AND NEURON-SPECIFIC VIRAL GENETIC INTERVENTIONS, I WILL TEST THE HYPOTHESIS THAT MECHANISM-INFORMED INTERVENTIONS THAT RESCUE AND/OR STRENGTHEN GABABR-GIRK SIGNALING IN PL PYRAMIDAL NEURONS CAN ALLEVIATE BEHAVIORAL DEFICITS PROVOKED BY REPEATED COCAINE EXPOSURE IN MICE. SUCCESSFUL COMPLETION OF THIS PROJECT WILL ADVANCE OUR UNDERSTANDING OF THE MECHANISMS AND RELEVANCE OF COCAINE-INDUCED SUPPRESSION OF GABABR-GIRK SIGNALING IN PL PYRAMIDAL NEURONS, AND PROVIDE VALUABLE TRAINING IN EX VIVO ELECTROPHYSIOLOGY, INTRACRANIAL GENETIC AND PHARMACOLOGICAL MANIPULATIONS, AND BEHAVIORAL ANALYSIS IN MICE, BUILDING A STRONG FOUNDATION FOR MY FUTURE CAREER AS AN INDEPENDENT INVESTIGATOR.