Paternal Cocaine-Seeking Motivation Defines Offspring's Vulnerability to Addiction by Down-Regulation of GABAergic GABRG3 in the Ventral Tegmental Area

Abstract

Abstract Epidemiological investigations indicate that parental drug abuse experiences significantly influenced addiction vulnerability of offspring. In studies using animal models, paternal cocaine-highly motivated drug-seeking behavior has been found to be an important determinant of offspring addiction susceptibility, but the key molecules contributing to offspring addiction susceptibility are currently unclear. We used the cocaine self-administration model and compared SA rat with paired yoke rat to differentiate paternal cocaine-seeking motivation, and the ventral tegmental area (VTA) transcriptomes of rat offspring in the natural state and after self-administration training were analyzed. Paternal cocaine-seeking experience, but not cocaine exposure, could increase lever-pressing behavior in male F1 offspring, without significantly altering cocaine drug sensitivity. RNA-seq of the ventral tegmental area in male F1 under drug-free state and after cocaine-self administration unveil that paternal cocaine self-administration, but not cocaine exposure alone, induced specific gene expression changes in specific modules. Gabrg3 was at the core position of the drug-seeking motivation related module network and highly correlated with parental drug-seeking motivation score. The downregulation of Gabrg3 expression caused by paternal experience of motivational cocaine-seeking mainly occurred in GABAergic neurons in VTA, potentially regulating synaptic and transmitter transmission in VTA. Paternal experience of motivational cocaine seeking can reshape the transcriptional network in the VTA of male offspring rats, possibly by downregulating Gabrg3 in GABAergic neurons. Gabrg3 perturbation may affect the processes related to synapse formation and transmitter transmission, which may be the possible neurobiological mechanism that enhances cocaine-seeking motivation in male offspring rats.