Transcriptomic Effects of Paternal Cocaine-seeking on the Reward Circuitry of Male Offspring

Abstract

Abstract In previous research, it has been established that a strong incentive motivation for cocaine, rather than the drug itself, can contribute to the intergenerational inheritance of cocaine addiction susceptibility in descendants. However, the precise impact of paternal cocaine-seeking on the reward circuitry of offspring remains not fully elucidated. To differentiate between cocaine-exposure and cocaine-seeking factors, we employed two distinct paternal cocaine acquisition paradigms: cocaine self-administration and yoked administration. These paradigms were used to generate the F1 generation, along with a control group receiving saline treatment. We conducted a comprehensive transcriptomic analysis of the male F1 offspring across seven relevant brain regions, both under drug-naive conditions and after cocaine self-administration. Our study revealed that the orbitofrontal cortex (OFC) exhibited more pronounced transcriptomic changes in response to cocaine-exposure. Conversely, the dorsal hippocampus (dHip), dorsal striatum (dStr), and ventral tegmental area (VTA) showed alterations that were more closely linked to the paternal voluntary cocaine-seeking experience. Based on transcriptomic analysis, measurements of dopamine levels (DOPA), and cellular activation analysis, we propose that the VTA-dStr pathway plays a pivotal role in mediating the effects of paternal voluntary cocaine-seeking on offspring. Furthermore, we identified potential transcriptomic regulatory mechanisms mediated by key transcriptional factors. Our findings provide a comprehensive overview of the transcriptional changes resulting from paternal highly-motivated cocaine-seeking. Importantly, our data highlight vulnerable neurocircuitry and novel gene candidates with therapeutic potential for disrupting the transgenerational inheritance of vulnerability to cocaine addiction.