Project Grant F31DA060004

CHARACTERIZING BLA DOPAMINERGIC AND GLUTAMATERGIC MECHANISMS OF DYNAMIC DRUG SEEKING - PROJECT SUMMARY RELAPSE AND CRAVING IN ADDICTION ARE HEAVILY CONTROLLED BY ENVIRONMENTAL CUES THAT EVOKE DYNAMIC MOTIVATIONAL STATES AND REINFORCE ACTIONS. BOTH THE BASOLATERAL AMYGDALA (BLA) AND DOPAMINE (DA) SIGNALING ARE CRITICAL FOR ASSOCIATIVE LEARNING PROCESSES AND CUE-DRIVEN MOTIVATIONAL STATES. THE BLA RECEIVES DENSE DOPAMINERGIC PROJECTIONS AND IS ENRICHED WITH D1 DA RECEPTORS (D1DRS), HOWEVER BLA DA FUNCTIONS IN ADDICTION REMAIN LARGELY UNEXPLORED. PRESENTATIONS OF COCAINE-PREDICTIVE STIMULI INCREASE EXTRACELLULAR DA LEVELS AND ACTIVATE NEURONS WITHIN THE AMYGDALA, WHILE BLA D1DRS INFLUENCE DRUG-SEEKING BEHAVIORS AND THEIR ACTIVATION INCREASES EXCITABILITY OF BLA PRINCIPAL NEURONS - A MAJOR TARGET OF DA INPUTS INTO THE BLA. AS THERE ARE EXTENSIVE EXCITATORY PROJECTIONS FROM THE BLA TO THE NUCLEUS ACCUMBENS (NAC), IF BLA DA AND D1-NEURONS ARE UNDERLYING FACETS OF STATE DYNAMICS-DRIVEN DRUG SEEKING BEHAVIORS, SYNAPTIC STRENGTH WITHIN THIS PATHWAY MAY BE UNIQUELY POTENTIATED FOLLOWING BINGE-LIKE COCAINE SEEKING. UNDERSTANDING THE ROLE OF BLA ACTIVITY AND DA SIGNALING IN DRUG SEEKING WILL REVEAL NOVEL INSIGHT INTO THE BRAIN CIRCUITRY THAT DRIVES EMOTIONAL LEARNING AND ADDICTION-RELATED BEHAVIORS TO PROVIDE A STRONG SCIENTIFIC FRAMEWORK FOR INVESTIGATING MECHANISMS UNDERLYING AFFECTIVE DISEASES. THIS PROPOSAL WILL MAKE USE OF NEW TOOLS TO RECORD AND MANIPULATE DA AND D1 NEURONS IN THE AMYGDALA TO INVESTIGATE THEIR CONTRIBUTIONS TO DYNAMIC COCAINE SEEKING BEHAVIORS (AIM 1) AND INVESTIGATE HOW BINGE-LIKE COCAINE SELF-ADMINISTRATION IMPACTS THE FUNCTIONAL CONNECTIVITY OF GLUTAMATERGIC BLA TO NAC CIRCUITS (AIM 2). FIRST, I WILL MEASURE IN VIVO DA SIGNALING AND D1-NEURON ACTIVITY IN THE BLA DURING COCAINE SELF-ADMINISTRATION USING FIBER PHOTOMETRY TO TEST THE HYPOTHESIS THAT BLA DA TRANSMISSION AND D1-NEURON ACTIVITY WILL TRACK THE EMERGENCE OF DYNAMIC, SENSORY-GUIDED DRUG SEEKING MOTIVATIONAL STATES. I WILL ALSO OPTOGENETICALLY INHIBIT BLA D1-NEURONS DURING THE SAME PARADIGM TO INVESTIGATE IF BLA D1-NEURONS PLAY A NECESSARY ROLE IN STATE-LEVEL CONTROL OF BINGE-LIKE DRUG SEEKING. FINALLY, IN AN EX VIVO PREPARATION, I WILL USE OPTOGENETICS TO STIMULATE THE TERMINALS OF GLUTAMATERGIC BLA PROJECTION NEURONS IN AN NAC SLICE WHILE RECORDING THE RESULTING LOCAL FIELD POTENTIALS AFTER RATS UNDERGO COCAINE SELF-ADMINISTRATION. THESE STUDIES WILL TEST THE HYPOTHESIS THAT BLA-NAC EXCITATORY SYNAPTIC STRENGTH WILL BE MODULATED BY THE PATTERN OF DRUG USE HISTORY VIA DRUG STATE-INTERMITTENCY INFORMATION FROM THE BLA. THIS PROPOSAL WILL ESTABLISH FUNDAMENTAL PRINCIPLES BY WHICH DOPAMINERGIC AND GLUTAMATERGIC MECHANISMS INTERACT WITHIN THE AMYGDALOSTRIATAL SYSTEM TO INFLUENCE THE EMERGENCE AND CONTROL OF DYNAMIC DRUG-SEEKING MOTIVATIONAL STATES.