Pramit Jagtap

In humans, genetics have been implicated as a contributing factor in the predisposition of an individual to developing substance use disorder. The diverse genetic backgrounds of mice provide a tool for investigating the intersection of genetics with substance use disorder by using behavioral paradigms and whole-cell electrophysiology. Here, we explored whether there were mouse genetic strain differences in cocaine (15 mg/kg) conditioned place preference (CPP) and psychomotor sensitization between male B6129SF2/J (B129) and C57BL/6J (C57) mice. We further explored whether genetic background (B129 vs C57) differentially influenced neuronal plasticity in medium spiny neurons (MSNs) of the accumbens shell (NAcSh) following chronic cocaine and abstinence (10-14 days). Our data reveal robust mouse strain differences in cocaine psychomotor sensitization (C57 > B129) as well as in cocaine CPP (B129 > C57) which flips based on mouse strain. Ex vivo whole-cell electrophysiology recordings in MSNs of the NAcSh highlight a strain conserved drop in MSN excitability following chronic cocaine and abstinence. This was in contrast to strain dependent differences in glutamatergic physiology through analysis of miniature excitatory postsynaptic currents (mEPSCs). C57 mice displayed augmented mEPSC frequencies and amplitudes in cocaine treated animals compared to their saline counterparts whereas B129 animals displayed no difference between cocaine versus saline treatment. Convergent human to mouse gene expression studies have identified genetic differences in glutamate reuptake mechanisms which may predispose certain individuals to the development of cocaine use disorder. Our data mirrors the human condition of cocaine use in that the intersection of genetics with drug use produces differential effects on behavior and neuroplasticity in the NAcSh, a key node in the mammalian reward circuit which has been hypothesized to drive drug related relapse.