Project Grant F31AA033513

DETERMINING MECHANISMS OF PSYCHEDELIC ACTION ON REDUCING ALCOHOL CONSUMPTION - PROJECT SUMMARY EXTRACELLULAR MATRIX STRUCTURES CALLED PERINEURONAL NETS (PNNS), WHICH PRIMARILY SURROUND PARVALBUMIN (PV) INTERNEURONS AND RESTRICT PLASTICITY IN THE ADULT BRAIN, ACCUMULATE IN THE ANTERIOR INSULAR CORTEX (AIC) OF MICE AFTER CHRONIC ETHANOL CONSUMPTION. DISRUPTING PNNS IN THE AIC, EITHER THROUGH ENZYMATIC DEGRADATION OR BY KNOCKING OUT PNN CHONDROITIN SULFATE PROTEOGLYCAN COMPONENTS, DECREASES AVERSION-RESISTANT ETHANOL CONSUMPTION (AREC) IN MICE. PSILOCYBIN IS A PSYCHEDELIC COMPOUND THAT INCREASES NEUROPLASTICITY AND HAS BEEN SHOWN IN BOTH HUMANS AND RODENTS TO DECREASE ETHANOL CONSUMPTION; HOWEVER, THE MECHANISMS BY WHICH PSILOCYBIN REDUCES ETHANOL CONSUMPTION ARE UNKNOWN. PRELIMINARY DATA DEMONSTRATE THAT PSILOCYBIN DECREASES THE INTENSITY OF PNN STAINING IN THE AIC OF ETHANOL-NAIVE MICE, INDICATING THAT PNN MODULATION MAY PLAY A ROLE IN ITS THERAPEUTIC EFFECTS. THIS PROJECT WILL EMPLOY A SIX-WEEK CHRONIC DRINKING PARADIGM FOLLOWED BY A WEEK OF AREC, DURING WHICH TIME MICE WILL BE TREATED WITH PSILOCYBIN TO DETERMINE ITS EFFECT ON ETHANOL INTAKE. AFTER COMPLETION OF BEHAVIORAL TESTING, BRAIN TISSUE WILL BE COLLECTED FOR ANALYSIS OF STRUCTURAL AND FUNCTIONAL CHANGES IN THE AIC. THE CANDIDATE WILL BE TRAINED IN CONFOCAL MICROSCOPY AND IMAGE ANALYSIS TO QUANTIFY THE INTENSITY OF PNN STAINING AND EXCITATORY AND INHIBITORY PRESYNAPTIC INPUTS ONTO PV INTERNEURONS. IN THE SECOND PART OF THIS PROJECT, THE CANDIDATE WILL BE TRAINED IN ELECTROPHYSIOLOGY TO MEASURE INTRINSIC PROPERTIES, FIRING RATES, AND SYNAPTIC DRIVE ONTO PV INTERNEURONS. THIS PROJECT WILL PROVIDE IMPORTANT INSIGHTS INTO THE ALCOHOL-INDUCED CHANGES IN A BRAIN REGION THAT CONTRIBUTES TO COMPULSIVE DRINKING AND WILL TEST PSILOCYBIN'S ABILITY TO DECREASE AREC AND NORMALIZE PATHOPHYSIOLOGICAL CHANGES.