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

Abstract

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 hr) 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 two weeks of cocaine SA or received yoked-saline infusions and were perfused either 2 hr or 7 days after the final SA session. Confocal microscopy and 3D reconstruction analyses were performed for Fos and p-CREB 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 hours after the end of cocaine SA whereas the opposite occurred following one 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.

Differential Effects of Dorsal and Ventral Medial Prefrontal Cortex Inactivation during Natural Reward Seeking, Extinction, and Cue-Induced Reinstatement

“…Cocaine may be a more salient reinforcer than sucrose, thereby differentially engaging mPFC subregions based on some motivational intensity gradient, although see Lenoir et al (2007). Another possible explanation is that repeated cocaine induces neuroplastic changes in the mPFC that results in differential regulation of seeking behavior relative to natural rewards (Robinson and Kolb, 1999; Robinson et al, 2001; McFarland et al, 2003; Muñoz-Cuevas et al, 2013; Radley et al, 2015; Siemsen et al, 2019). Cocaine also induces both appetitive and aversive behaviors (Ettenberg, 2004), whereas there are fewer aversive components to sucrose.…”

Amperometric measurements of cocaine cue and novel context‐evoked glutamate and nitric oxide release in the nucleus accumbens core

“…All animal use protocols were approved by the Institutional Animal Care and Use Committee of the Medical University of South Carolina (animal use protocol # 107,172) and were performed according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals (8th ed., 2011). On the day of surgery, rats were anesthetized with an intraperitoneal ketamine (66 mg/kg) and xylazine (1.33 mg/kg) injection (Siemsen, Giannotti, McFaddin, Scofield, & McGinty, ), and received ketorolac (Sigma Catalog number #K1136, 2 mg/kg, i.p.) for analgesia.…”

“…Rats in experiment 1 were secured in a stereotaxic apparatus (David Kopf Instruments, model 942) and received a bilateral intra‐prelimbic (PL) cortical (AP: +2.8 mm, ML: ±0.6 mm, DV: −3.8 mm relative to bregma) microinjection of either a chemogenetic or reporter‐only control vector (see materials). Rats in experiments 2 and 4 received a chronic indwelling jugular silastic catheter surgery as described previously (Siemsen, Giannotti, et al, ; Siemsen, Lombroso, & McGinty, ; Siemsen et al, ), and received a single intravenous infusion of Cefazolin to prevent bacterial infection. All rats received a unilateral intra‐NAcore guide cannula (BASi, Catalog number #7030; Pinnacle Technology) implantation following 4 weeks of virus expression (Experiment 1), immediately following catheterization (Experiment 2), in lieu of catheterization (Experiment 3), or 24 hr following the final cocaine SA session (Experiment 4, see below).…”

Heroin self-administration and extinction increases prelimbic cortical astroglia-synapse proximity and alters dendritic spine morphometrics that are reversed by N-acetylcysteine

“…Care was taken to ensure that the majority of each astrocyte in the Z-plane was imaged. In experiment 2, apical tuft dendrites of layer V PrL-NAcore neurons were imaged as previously described [30]. Briefly, dendritic spine segments were imaged only if they met the following criteria: 1: they could be traced back to the cell body of origin, 2: they were unobscured by neighboring dendritic segments, and 3: they were past the bifurcation of the proximal dendrite (terminating in layers I and II).…”