Biphasic effect of abstinence duration following cocaine self-administration on spine morphology and plasticity-related proteins in prelimbic cortical neurons projecting to the nucleus accumbens core

Cocaine self-administration (SA) in rats dysregulates glutamatergic signaling in the prelimbic (PrL) cortex and glutamate release in the nucleus accumbens (NA) core, promoting cocaine seeking. PrL adaptations that affect relapse to drug seeking emerge during the first week of abstinence, switching from an early (2 h) hypoglutamatergic state to a later (7 days) hyperglutamatergic state. Different interventions that normalize glutamatergic signaling in PrL cortex at each timepoint are necessary to suppress relapse. We hypothesized that plasticity-related proteins that regulate glutamatergic neurotransmission as well as dendritic spine morphology would be biphasically regulated during these two phases of abstinence in PrL cortical neurons projecting to the NA core (PrL–NA core). A combinatorial viral approach was used to selectively label PrL–NA core neurons with an mCherry fluorescent reporter. Male rats underwent 2 weeks of cocaine SA or received yoked-saline infusions and were perfused either 2 h or 7 days after the final SA session. Confocal microscopy and 3D reconstruction analyses were performed for Fos and pCREB immunoreactivity (IR) in the nucleus of layer V PrL–NA core neurons and GluA1–IR and GluA2–IR in apical dendritic spines of the same neurons. Here, we show that cocaine SA decreased PrL–NA core spine head diameter, nuclear Fos–IR and pCREB–IR, and GluA1–IR and GluA2–IR in putative mushroom-type spines 2 h after the end of cocaine SA, whereas the opposite occurred following 1 week of abstinence. Our findings reveal biphasic, abstinence duration-dependent alterations in structural plasticity and relapse-related proteins in the PrL–NA core pathway after cocaine SA.