Project Grant F31DA066289

ANGIOTENSIN CONVERTING ENZYME INHIBITION AS A POTENTIAL THERAPEUTIC INTERVENTION FOR OPIOID RELAPSE - PROJECT SUMMARY/ABSTRACT OPIOID USE DISORDERS ARE CHRONIC, RELAPSING BRAIN CONDITIONS THAT HAVE HISTORICALLY BEEN DIFFICULT TO TREAT DUE TO A LACK OF EFFECTIVE TREATMENTS FOR REDUCING CRAVING AND RELAPSE. RELAPSE INCREASES THE RISK OF FATAL OVERDOSE, WHICH MAKES IT IMPERATIVE TO INVESTIGATE THE UNDERLYING MECHANISMS OF RELAPSE TO INFORM THE DEVELOPMENT OF NEW THERAPEUTIC INTERVENTIONS. THE NUCLEUS ACCUMBENS (NAC) IS A KEY BRAIN REGION INVOLVED IN RELAPSE. THE NAC CONTAINS TWO PRINCIPAL POPULATIONS OF MEDIUM SPINY PROJECTION NEURONS: THOSE THAT EXPRESS THE DOPAMINE RECEPTOR DRD1 (D1-MSNS) AND THOSE THAT EXPRESS THE DOPAMINE RECEPTOR DRD2 (D2-MSNS). INCREASED D1-MSN ACTIVITY IS CANONICALLY THOUGHT TO DRIVE DRUG RESPONSES, SUGGESTING THAT SELECTIVELY TARGETING INCREASED EXCITATORY INPUT TO D1-MSNS COULD REPRESENT A NEW THERAPEUTIC AVENUE FOR TREATING RELAPSE. NAC D1-MSN ACTIVITY CAN BE SELECTIVELY MODULATED THROUGH ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITION. IN THE BRAIN, ACE IS HIGHLY ENRICHED IN NAC D1-MSNS AND DEGRADES THE ENDOGENOUS OPIOID PEPTIDE MET-ENKEPHALIN-ARG-PHE (MERF). PREVENTING MERF DEGRADATION THROUGH ACE INHIBITION DECREASES GLUTAMATE RELEASE ONTO D1-MSNS VIA ACTIVATION OF PRESYNAPTIC MU OPIOID RECEPTORS. OUR PRELIMINARY DATA INDICATE THAT SYSTEMIC ACE INHIBITION VIA CAPTOPRIL IN DRINKING WATER ATTENUATES CUE-INDUCED REINSTATEMENT OF FENTANYL-SEEKING BEHAVIOR IN MICE. THEREFORE, THE GOAL OF THIS PROPOSAL IS TO INVESTIGATE WHETHER ACE INHIBITION CAN COUNTERACT THE MALADAPTIVE FORMS OF NAC NEUROPLASTICITY THAT ARE NORMALLY ASSOCIATED WITH CUE-INDUCED REINSTATEMENT. TO THIS END, AIM 1 WILL DETERMINE HOW SYSTEMIC ACE INHIBITION IMPACTS NAC MSN ACTIVITY DURING OPIOID-SEEKING BEHAVIOR. THIS WILL BE DONE THROUGH MEASURING D1- AND D2-MSN CALCIUM RESPONSES DURING A TEST OF CUE-INDUCED REINSTATEMENT, FOLLOWING 24 HOURS OF ORAL CAPTOPRIL ADMINISTRATION. AIM 2 WILL DETERMINE HOW SYSTEMIC ACE INHIBITION IMPACTS THE STRENGTH OF GLUTAMATERGIC INPUT TO NAC MSNS FOLLOWING OPIOID-SEEKING BEHAVIOR. THIS WILL BE DONE THROUGH OPTOGENETICALLY EVOKING GLUTAMATERGIC RELEASE FROM PREFRONTAL CORTEX (PFC) AXONS IN THE NAC USING CHRIMSONR AND RECORDING THE CALCIUM RESPONSES FROM D1- AND D2-MSNS BEFORE AND AFTER A TEST OF CUE-INDUCED REINSTATEMENT. THESE EVOKED RECORDINGS WILL OCCUR 24 HOURS AFTER ORAL CAPTOPRIL ADMINISTRATION. AIM 3 WILL USE LOCALIZED, INTRA-ACCUMBAL MICROINFUSIONS OF CAPTOPRIL TO EVALUATE CIRCUIT-SPECIFIC ACTION. THESE WILL BE PERFORMED PRIOR TO CUE-INDUCED REINSTATEMENT, IN BOTH THE ABSENCE AND PRESENCE OF CHEMOGENETIC ACTIVATION OF THE PFCANAC PROJECTION TO AUGMENT REINSTATEMENT. COMPLETION OF THIS FELLOWSHIP WILL PROVIDE THE PI WITH ADVANCED TECHNICAL TRAINING, LEAVING HER WELL POSITIONED FOR HER LONG-TERM GOAL OF BECOMING AN INDEPENDENT RESEARCHER INVESTIGATING THE NEUROBIOLOGY OF SUBSTANCE USE DISORDERS.