Physiological neuroadaptations in prefrontal cortical regulation of abstinence and cue-induced relapse to cocaine seeking
Year: 2025
Type: article
Abstract: • D1 and D2 dopamine receptors are differentially distributed in prelimbic cortex • Prelimbic neurons that project to nucleus accumbens express D1 or D2 receptors • Cocaine abstinence increases excitability of D1+prelimbic to acumbens neurons • Increased excitability of D1+prelimbic neurons is normalized by relapse in male rats • Relapse normalizes increased synaptic responses in female D1+ prelimbic neurons • Protein kinase A differentially alters synaptic plasticity in prelimbic neurons 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, ex vivo 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.
Source: Addiction Neuroscience
Institutions: Marquette University, Medical University of South Carolina
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,660
OpenAlex ID: W4414475598