Neurobehavioral Consequences of Dopamine Dysregulation in a Heritable Rodent Model: Implications for Psychosis and Drug Abuse Vulnerability

Schizophrenia and related psychoses are often accompanied by significantly elevated rates of cigarette smoking, poor stress adaptations, and enhanced relapse vulnerability. These comorbid behaviors contribute to reduced treatment adherence and worsened clinical outcomes, yet the neurobiological mechanisms linking psychosis-related dopamine dysregulation to nicotine reward and relapse remain poorly understood. Identifying these mechanisms is critical for developing novel treatment targets and interventions that can improve both psychiatric and substance use outcomes. The experiments presented in this dissertation used the neonatal quinpirole model of dopamine dysregulation to investigate behavioral, molecular, and receptor-level mechanisms underlying psychosis-relevant phenotypes. This model is the first to demonstrate heritable dopamine D2 receptor sensitivity, a neurobiological marker considered to be a hallmark of psychosis. This sensitized dopamine system confers sensorimotor gating deficits and enhanced behavioral responses to nicotine, replicating core features of schizophrenia and its comorbidities. In this project we show that pharmacological modulation of metabotropic glutamate type 5 (mGlu5) or adenosine A(2A) receptor signaling normalized sensorimotor gating and restored cyclic-AMP-response element binding protein (CREB) levels in the nucleus accumbens, highlighting potential therapeutic avenues for mitigating dopamine-mediated circuit dysfunction. In addition animals with enhanced dopamine D2 receptor sensitivity demonstrated heightened vulnerability to nicotine-seeking, resistance to extinction, and robust stress-induced reinstatement. These behavioral adaptations were accompanied by region-specific molecular changes, including altered CREB and dynorphin expression, as well as prefrontal cortex cell-type specific genetic changes that are consistent with dysregulated stress and reward circuitry. Nicotine vapor exposure resulted in dose-dependent reward sensitivity mediated by α4β2 nicotinic acetylcholine receptor signaling. This occurred alongside increases in brain-derived neurotrophic factor (BDNF) in mesolimbic regions, suggesting plasticity mechanisms that may drive heightened vulnerability in a more translatable nicotine administration paradigm. Collectively, this work provides a comprehensive mechanistic framework linking heritable dopamine dysregulation to psychosis-relevant behavioral deficits and heightened vulnerability to nicotine reward. Through examining the molecular, circuit-level, and plasticity adaptations that underlie these behaviors, these findings advance our understanding of how genetic and epigenetic risk factors contribute to comorbid substance use in psychosis. These data may ultimately contribute to mechanism-focused treatment interventions that can improve both psychosis-related symptomology and associated drug use vulnerability.