Project Summary Relapse to cocaine use in postpartum women is a serious health problem that impacts the mother’s ability to care for her child, with life-long consequences for both the mother and child. There is a window of opportunity for treatment in the early postpartum period, as cocaine use in new mothers is significantly reduced by the competing motivation related to child rearing. Unfortunately, few women maintain abstinence and relapse to cocaine use beyond the first 6 months following their child’s birth. To date, little is known regarding the neurobiological mechanisms by which maternal motivation can prevent relapse to cocaine seeking in new mothers. The current proposal builds logically on my work from the past several years. Our prior work in rats demonstrates that during the unique early postpartum period, new mothers also reduce cocaine seeking, and that pharmacological inactivation of the medial preoptic area (mPOA), a critical structure orchestrating maternal behavior, results in increased maternal choice of cocaine-conditioned incentives in a concurrent pup/cocaine choice conditioned place preference (CPP) task. The objective of this proposal is to delineate the neural processes underlying the transient resistance to cocaine relapse in new mothers. To accomplish this goal, we will use a novel adaptation of the extinction-reinstatement CPP animal model of drug relapse and a pathway- specific chemogenetic approach to determine the role of mPOA neurons projecting to the infralimbic cortex (IL) and the ventral tegmental area (VTA) in preventing reinstatement of cocaine seeking in abstinent new mother rats. Both structures receive direct input from the mPOA and are critical nodes of the circuitry that mediates reward and response allocation, with the IL contributing to stimulus recognition and executive functions, and the VTA modulating the behavioral strategy via dopamine projections to the nucleus accumbens. The experiments in AIM 1 will use combined injections of a Cre-dependent inhibitory (hM4Di) or excitatory (hM3Dq) designer receptors exclusively activated by designer drugs (DREADD) AAV into the mPOA, with a retrograde transducing CAV2-Cre virus into the IL to assess the functional necessity and sufficiency of the mPOA à IL pathway on reinstatement of cocaine seeking in new mothers. Experiments in AIM 2 will determine the role of monosynaptic mPOA projections to the VTA (mPOAàVTA) in preventing reinstatement of previously extinguished cocaine seeking behavior in new mothers. This AIM will also use Gi- or Gq-DREADDs combined with CAV2-Cre to selectively manipulate mPOAàVTA pathway during reinstatement of cocaine CPP. The impact of these mPOAàIL and mPOAàVTA chemogenetic manipulations on maternal behavior will be also studied. Considering the consequences of maternal cocaine use on both mother and child health, it is of major clinical significance to understand the neurobiology contributing to this relapse-resistant state. This p...