Cocaine-withdrawn rats show memory deficits and altered hippocampal glutamatergic system

Adolescents are particularly susceptible to various forms of gratification, among which psychostimulants, such as cocaine. During adolescence the hippocampus, a brain area relevant to spatial memory domain, undergoes maturational processes, such as structural and molecular reorganization of the excitatory synapses. However, the neurobiological mechanisms that underpin the changes induced by cocaine intake and withdrawal are still poorly understood. Our goal was to reveal putatively enduring spatial memory deficits and molecular correlates in male rats exposed to repeated cocaine after a period of withdrawal during adolescence. To pursue this goal, adolescent Sprague-Dawley male rats were exposed to chronic cocaine treatment (5 mg/kg/day, subcutaneously) for 15 days and, after 2 weeks of withdrawal, were subjected to spatial order object recognition (SOOR) test, a memory task based on the rat's ability to recognize objects displacement. At molecular level, we investigated the subcellular specific expression of markers of the glutamate synapse in the dorsal hippocampus, a critical hub for the processing of spatial learning information. At the behavioral level, we found that withdrawal from developmental cocaine exposure affected the performance in the SOOR test as shown by the altered discrimination index, thus indicating a spatial memory domain impairment in cocaine-withdrawn rats. Such deficit was correlated to a reduced expression and retention of NMDA receptor subunits, GluN1, GluN2A and GluN2B, at both synaptic and extra-synaptic sites, an effect indicative of impaired NMDA receptor trafficking. Analysis of endocytosis markers (Rab family of monomeric GTPase) revealed that cocaine-withdrawn rats favor the degradative pathway (Rab7-Rab9) over the recycling pathway (Rab11). In contrast, saline-treated rats primarily activate the recycling pathway. Our findings may contribute to the understanding of the mechanisms underlying the spatial memory deficits in male rats with an adolescent history of cocaine. Sponsored by: PRIN 2022 cod. 20227HRFPJ