Reinstatement of nicotine conditioned place preference in a transgenerational model of drug abuse vulnerability in psychosis: Impact of BDNF on the saliency of drug associations

RationalePsychotic disorders such as schizophrenia are often accompanied by high rates of cigarette smoking, reduced quit success, and high relapse rates, negatively affecting patient outcomes. However, the mechanisms underlying altered relapse-like behaviors in psychosis are poorly understood.ObjectivesThe present study analyzed changes in extinction and reinstatement of nicotine conditioned place preference (CPP) and resulting changes in brain-derived neurotrophic factor (BDNF) in a novel heritable rodent model of psychosis, demonstrating increased dopamine D-2 receptor sensitivity, to explore mechanisms contributing to changes in relapse-like behaviors.MethodsMale and female offspring of two neonatal quinpirole-treated (1 mg/kg quinpirole from postnatal day (P)1-21; QQ) and two neonatal saline-treated (SS) Sprague-Dawley rats (F1 generation) were tested on an extended CPP paradigm to analyze extinction and nicotine-primed reinstatement. Brain tissue was analyzed 60 min after the last nicotine injection for BDNF response in the ventral tegmental area (VTA), the infralimbic (IfL) and prelimbic (PrL) cortices.ResultsF1 generation QQ offspring demonstrated delayed extinction and more robust reinstatement compared to SS control animals. In addition, QQ animals demonstrated an enhanced BDNF response to nicotine in the VTA, IfL and Prl cortices compared to SS offspring.ConclusionsThis study is the first to demonstrate altered relapse-like behavior in a heritable rodent model with relevance to comorbid drug abuse and psychosis. This altered pattern of behavior is hypothesized to be related to elevated activity-dependent BDNF in brain areas associated with drug reinforcement during conditioning that persists through the extinction phase, rendering aberrantly salient drug associations resistant to extinction and enhancing relapse vulnerability.

Automated summary

This study analyzed changes in relapse-like behaviors and the underlying mechanisms in a novel heritable rodent model of psychosis. The results showed that the model exhibited delayed extinction and enhanced reinstatement compared to the control group, and also displayed an increased BDNF response. This study is the first to demonstrate altered relapse-like behavior in a heritable rodent model with relevance to drug abuse and psychosis, suggesting the involvement of elevated activity-dependent BDNF in drug-associated brain areas.