Repeated cocaine exposure and prolonged withdrawal induce spatial memory impairment and dysregulate the glutamatergic synapse composition in the dorsal hippocampus of male rats

Abstract

Adolescents are particularly susceptible to various forms of gratification, among which psychostimulants. 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. 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.

Towards 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. Next, we investigated subcellular specific expression of markers of the glutamate synapse in the dorsal hippocampus.

Our findings show that withdrawal from repeated cocaine exposure during adolescence is associated with spatial memory impairment. 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 Analysis of endocytosis markers (Rab family of monomeric GTPase) revealed that cocaine-withdrawn rats favor the degradative pathway (Rab7-Rab9) over the recycling pathway (Rab11).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, mislocalization of glutamatergic receptors together with sorting of NMDA receptor towards degradation, rather than recycling, may contribute to the understanding of the mechanisms underlying the spatial memory deficits in male rats with an adolescent history of cocaine.