Abstract
Introduction: Incubation of drug-craving refers to a time-dependent increase in drug cue-elicited craving that occurs during protracted withdrawal. Historically, rat models of incubated cocaine craving employed extended-access (typically 6 h/day) intravenous drug self-administration (IV-SA) procedures, although incubated cocaine craving is reported to occur following shorter-access IV-SA paradigms. The notoriously low-throughput of extended-access IV-SA prompted us to determine whether two different short-access IV-SA procedures akin to those in the literature result in qualitatively similar changes in glutamate receptor expression and the activation of downstream signaling molecules within prefrontal cortex (PFC) subregions as those reported previously by our group under 6h-access conditions. Methods: For this, adult, male Sprague-Dawley rats were trained to intravenously self-administer cocaine for 2 h/day for 10 consecutive days (2-h model) or for 6 h on day 1 and 2 h/day for the remaining 9 days of training (Mixed model). A sham control group was also included that did not self-administer cocaine. Results: On withdrawal day 3 or 30, rats were subjected to a 2-h test of cue-reinforced responding in the absence of cocaine and a time-dependent increase in drug-seeking was observed under both IV-SA procedures. Immunoblotting of brain tissue collected immediately following the cue test session indicated elevated phospho-Akt1, phospho-CaMKII and Homer2a/b expression within the prelimbic subregion of the PFC of cocaine-incubated rats. However, we failed to detect incubation-related changes in Group 1 metabotropic glutamate receptor or ionotropic glutamate receptor subunit expression in either subregion. Discussion: These results highlight further a role for Akt1-related signaling within the prelimbic cortex in driving incubated cocaine craving, and provide novel evidence supporting a potential role also for CaMKII-dependent signaling through glutamate receptors in this behavioral phenomenon.