Physiological neuroadaptations in prefrontal cortical regulation of abstinence and cue-induced relapse to cocaine seeking

Biphasic molecular adaptations in pyramidal neurons (PNs) projecting from prelimbic (PL) cortex to the nucleus accumbens (NAc) (PL→NAc PNs) are hallmarks of early withdrawal vs. later abstinence from cocaine. However, whether biphasic electrophysiological changes accompany these molecular adaptations is unknown. Here we investigated sex-specific, <i>ex vivo</i> physiological neuroadaptations in Drd1 (PL^D1)- and Drd2 (PL^D2)-expressing PL→NAc PNs 2 hr or 7 days after cessation of cocaine self administration. Drd1- and Drd2-Cre⁺ transgenic male and female rats with virally labeled PL→NAc neurons were trained to self administer cocaine followed by two hours of withdrawal or one week of forced abstinence with or without a cue-induced cocaine- seeking test. Intrinsic excitability was increased selectively in PL^D1→NAc PNs of males, but not females, after 2 hr of withdrawal and 7d of abstinence that was normalized by cue-induced relapse. Increased sEPSC frequency (measure of presynaptic glutamate release) in PL^D1→NAc PNs and decreased AMPA/NMDA ratio (measurement of excitatory synaptic strength) in PL^D2→NAc PNs in males, not females, was present during early withdrawal but normalized as abstinence progressed. In females, not males, an increased AMPA/NMDA ratio occurred after 7d of abstinence that was normalized by cue-induced relapse to cocaine seeking. In contrast to findings in heroin-abstinent rats, PKA inhibition using Rp-cAMPs had no effect on augmented intrinsic excitability of PL→NAc PNs after 7d abstinence. However, RP-cAMPs reversed cocaine-augmented AMPA/NMDA ratio exclusively in PL^D1→NAc PNs of females. These data reveal that cocaine abstinence-induced physiological neuroadaptations in PL^D1→NAc PNs are normalized by cue-induced cocaine seeking in a sex-specific manner.