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Early Life Stress, Chronic Drug Use and Neuroplasticity in Nonhuman Primate Models of Cocaine Abuse: Relevance to Treatment Strategies

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Abstract Despite the risks of adolescent initiation of drug use for lifelong addiction and its tremendous health and societal costs, the neurobiological factors leading to increased vulnerability to substance use disorders (SUDs), including cocaine (COC) use disorder (CUD), are poorly understood. Early life stress (ELS), including adverse experiences such as childhood maltreatment (MALT), is a major risk factor for psychopathologies like SUDs, anxiety and depression, which are often comorbid. Indeed, individuals with histories of childhood MALT are more vulnerable to COC addiction, and deficits in emotional regulation predisposes them to stress-induced relapse, contributing to spiraling of drug taking. Despite these risks, how ELS and COC abuse during adolescence interact to alter brain development, increasing vulnerability to CUD later in life, has not been elucidated. There are also strong sex differences in progression from initiation of drug use during adolescence (experimentation) to the onset of drug dependence, with women showing increased vulnerability, although the underlying neurobiological mechanisms are unclear. The goal of this proposal is to examine long-term ELS- related impact and neurobiological mechanisms of increased risk to CUD during adulthood. To accomplish this, we are using a unique and highly translational nonhuman primate (NHP) model of infant MALT with adolescence COC self-administration (SA) and addressing sex differences. The studies proposed here with a cohort of adult macaques that experienced infant MALT followed by COC SA during adolescence, and characterized longitudinally since birth, are unparalleled. They will provide information of critical relevance for the human HEALthy Brain and Child Development (HBCD) and Adolescent Brain Cognitive Development (ABCD) NIH studies by examining early risk factors and neurobiological mechanisms for SUDs. The studies leverage this unique cohort of animals during adulthood to examine the long-term impact of ELS and adolescence COC SA on neurobiology of reward and stress/emotion regulatory circuits following a year of COC abstinence (Aim 1), neurobiological changes in dopamine (DA) and serotonin (5-HT) receptors and functional connectivity (FC) of prefrontal cortex (PFC) with ventral striatum (nucleus accumbens) and amygdala following re-exposure to COC SA (Aim 2), and the rate of recovery of DA and 5-HT receptors and FC during abstinence from long-term COC, to investigate whether it predicts COC-induced relapse and responses to pharmacological interventions targeting DA and 5-HT receptors; PET data will inform personalized medicine approaches (Aim 3). We hypothesize differential effectiveness of DA and 5-HT receptor compounds (alone vs. mixtures) in MALT than Control animals, and in females versus males. We propose that ELS, in addition to adolescence COC exposure, leads to the dysregulation of reward and stress/emotional systems typically reported in human psychiatric conditions, resulting in increased risk to CUD in adulthood, in comparison to animals with COC adolescence exposure but no ELS history.
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