Project Grant F31DA065458

PERINATAL EXPOSURE TO CONCOMITANT OPIOID AND ANTIDEPRESSANT MEDICATIONS: EFFECTS ON THE MATERNAL BRAIN, BEHAVIOR, AND OFFSPRING NEURODEVELOPMENT IN A TRANSLATIONAL RODENT MODEL - PROJECT SUMMARY OPIOID USE HAS REACHED EPIDEMIC PROPORTIONS AND IS A SIGNIFICANT PUBLIC HEALTH CONCERN PARTICULARLY AMONG PREGNANT WOMEN. NOTABLY, THE PREVALENCE OF OPIOID USE DISORDER (OUD) HAS INCREASED FOUR-FOLD WITHIN THE PAST TWO DECADES AND STEADILY CONTINUES TO RISE WITH MATERNAL OPIOID RELATED DIAGNOSES INCREASING BY 131% FROM 2010-2017. OUD DURING PREGNANCY HAS BEEN ASSOCIATED WITH MATERNAL-INFANT BONDING IMPAIRMENTS AND DEFICITS IN PERINATALLY EXPOSED CHILDREN (I.E. LOW BIRTH WEIGHT, NEONATAL WITHDRAWAL SYNDROME, ETC.). TO MITIGATE THESE EFFECTS, OPIOID-DEPENDENT WOMEN ARE OFTEN PRESCRIBED MEDICATIONS FOR OUD (MOUD), SUCH AS BUPRENORPHINE (BUP), AS BUP PRODUCES MORE FAVORABLE INFANT OUTCOMES COMPARED TO OTHER MOUDS OR CONTINUED ILLICIT USE. OF ADDITIONAL CONCERN, PSYCHIATRIC COMORBIDITIES ARE COMMON AMONG PREGNANT WOMEN TAKING MOUDS, SO POLYSUBSTANCE EXPOSURE IS REPORTED IN MOST CLINICAL CASES. ACCUMULATING EVIDENCE INDICATES THAT INFANTS EXPOSED TO BOTH MOUDS AND SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIS) EXHIBIT MORE SEVERE NEONATAL WITHDRAWAL SYMPTOMS AND HAVE LONGER HOSPITAL STAYS COMPARED TO INFANTS EXPOSED TO ONLY ONE OF THESE MEDICATIONS. ALTHOUGH MOUDS AND SSRIS, LIKE SERTRALINE, ARE DEEMED RELATIVELY SAFE FOR USE DURING PREGNANCY, THERE REMAINS A SIGNIFICANT GAP IN OUR UNDERSTANDING OF THEIR UNIQUE AND COMBINED EFFECTS ON THE MATERNAL BRAIN, BEHAVIOR, PHYSIOLOGY AND OFFSPRING OUTCOMES THAT STEMS FROM INSUFFICIENT OR INCONSISTENT RESEARCH FINDINGS. MATERNAL NEURAL CIRCUITRY IS COMPRISED OF VARIOUS SYSTEMS, INCLUDING THE ENDOGENOUS OPIOID SYSTEM, NEUROTRANSMITTER SYSTEMS, AND PEPTIDE AND STEROID HORMONES, THAT CONTRIBUTE SIGNIFICANTLY TO FACILITATING PHYSIOLOGICAL CHANGES THAT UNDERLIE SUCCESSFUL MATERNAL NEURAL AND BEHAVIORAL ADAPTATIONS. IT REMAINS UNCLEAR HOW EXOGENOUS OPIOIDS AND SSRIS MAY INTERACT TO MODULATE THESE SYSTEMS THAT ARE NECESSARY FOR MATRESCENCE AND REGULATION OF MATERNAL CARE FOLLOWING PARTURITION. IN OUR PROPOSED STUDY, FEMALE RATS (N=48) WILL BE EXPOSED TO VEHICLE, BUP (1.0MG/KG), SERTRALINE (20MG/KG), OR BOTH MEDICATIONS IN A TRANSLATIONALLY RELEVANT PARADIGM STARTING BEFORE CONCEPTION AND CONTINUED THROUGHOUT POSTPARTUM. THE SPECIFIC AIMS OF THIS PROJECT ARE TO 1.) ASSESS THE EFFECTS OF BUP AND SERTRALINE EXPOSURE ON THE INITIATION AND MAINTENANCE OF MATERNAL BEHAVIOR; 2.) INVESTIGATE THE NEUROCHEMICAL AND BEHAVIORAL EFFECTS OF BUP AND SERTRALINE EXPOSURE ON OFFSPRING DEVELOPMENT; 3.) EVALUATE THE IMPACT OF BUP AND SERTRALINE EXPOSURE ON THE MATERNAL BRAIN AND PHYSIOLOGY. THE OVERALL HYPOTHESIS IS THAT PERINATAL EXPOSURE TO BUP WILL RESULT IN DECREASED ACTIVATION OF IMPORTANT AREAS OF THE MBN AND THE PRESENCE OF ADDITIONAL SEROTONIN THROUGH SERTRALINE EXPOSURE WILL EXACERBATE THIS DECREASED ACTIVATION AND THUS HINDER THE INITIATION OF MATERNAL CARE AND MOTIVATION. THIS IN TURN WILL LEAD TO POORER OFFSPRING OUTCOMES. THIS TRAINING PROJECT WILL PROVIDE ME WITH THE CRITICAL SKILLS AND RESEARCH TRAINING TO SUBSEQUENTLY EXPAND ON THIS WORK AS A POSTDOCTORAL RESEARCH FELLOW, ULTIMATELY LEADING TO A FRUITFUL CAREER AS AN INDEPENDENT NEUROSCIENTIST COMMITTED TO IDENTIFYING EFFECTIVE CLINICAL MANAGEMENT STRATEGIES FOR PREGNANT WOMEN WITH SUBSTANCE USE AND MENTAL HEALTH COMORBIDITIES.