Stress-induced reinstatement of nicotine conditioned place preference in a rodent model of dopamine dysregulation: genetic, behavioral and molecular correlates of drug abuse vulnerability.

RATIONALE: Schizophrenia and related psychoses are accompanied by poor stress adaptation and a high prevalence of cigarette smoking, contributing to reduced treatment adherence and poor quality of life. The mechanistic contributions to stress-induced drug-seeking in psychosis remain poorly understood.

OBJECTIVES

The present study evaluated nicotine conditioned place preference (CPP) stress reinstatement in a heritable rodent model of dopamine dysregulation relevant to psychosis, alongside molecular and epigenetic alterations associated with drug use vulnerability.

METHODS

Adolescent offspring (F1) of Sprague-Dawley rats treated neonatally with saline (MSxFS) or quinpirole (MQxFQ) were assessed for nicotine CPP expression, extinction, and restraint stress-induced reinstatement. One hour following stress, nucleus accumbens (NAc) and amygdala tissue were analyzed for CREB and dynorphin expression, with complementary single-nucleus RNA sequencing used to identify cell-type-specific genetic adaptations in the medial prefrontal cortex (mPFC) of adolescent rats.

RESULTS

MQxFQ rats exhibited enhanced nicotine CPP, resistance to extinction, and robust stress-induced reinstatement relative to MSxFS controls. Following nicotine and stress exposure, MQxFQ rats showed reduced CREB in the NAc and increased CREB and dynorphin in the amygdala. Differential gene expression profiling in the mPFC revealed cell-type specific metabolic and plasticity-related neuroadaptations consistent with cortical vulnerability to psychosis and drug use.

CONCLUSIONS

These findings demonstrate significant expression of stress-induced reinstatement in a heritable model of dopamine dysregulation. Convergent molecular and genetic adaptations implicate dysregulated stress and reward circuitry, providing a mechanistic framework linking genetic risk for psychosis to maladaptive drug-seeking and vulnerability to stress.