Withdrawal from adolescent cocaine exposure affects spa al memory and glutamate synapse homeostasis in the dorsal hippocampus

Cocaine is a highly addictive psychostimulant whose abuse induces long-lasting alterations in the brain, which are more profound and impactful for early-onset users, representing a widespread social and economic burden. However, the neurobiological mechanisms that underpin the different age-of-onset changes induced by cocaine intake and withdrawal are still poorly understood. Since chronic cocaine exposure is associated with broad cognitive deficits, we here investigated the consequences of withdrawal from developmental cocaine on spatial memory, one of the critical domains subserving essential memory processes during brain maturation. Moreover, we evaluated at a molecular level the cocaine-induced hippocampal glutamatergic adaptations that may contribute to altering the three-dimensional perceptions of adolescent rats. Adolescent male rats were treated subcutaneously with 5 mg/kg/day of cocaine or saline from post-natal day (PND) 28 to PND42. Following 2 weeks of drug withdrawal, rats were subjected to the spatial order object recognition (SOOR) test, a hippocampal-dependent cognitively demanding test. Immediately after the test rats were sacrificed, and brains were collected and frozen. Western blot analyses were performed on glutamatergic receptor subunits and scaffolding proteins in the dorsal hippocampus (dH). Statistical significance was assessed by two-way ANOVA multiple comparisons or unpaired t-test, as appropriate. 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-exposed rats. Interestingly, in the postsynaptic density (PSD) fraction of the dH of animals with a history of cocaine exposure, we found increased GluN1, GluN2A and GluN2B protein levels versus saline-treated rats. Conversely, the SOOR test considerably decreased NMDA receptor subunits and the scaffold protein SAP102 levels only in cocaine-exposed rats, suggesting increased lateral trafficking that might contribute to the maladaptive plasticity underlying vulnerability induced by psychostimulant use. Moreover, PSD95, an index of PSD integrity, was increased by cocaine and the behavioral test, while unaltered after the test performance in cocaine-treated rats. Our results demonstrated that animals exposed to cocaine during adolescence showed a spatial memory impairment. This deficit may be due to an overall increase of NMDA receptor subunit localization and retention in the PSD caused by cocaine, which, in turn, alters their capability to correctly process spatial information once exposed to the learning task. All these data highlight adolescence as a critical developmental window of vulnerability for psychostimulant-induced cognitive impairment, here emphasized by prolonged cocaine withdrawal that may have changed the fine-tuning mechanisms of memory formation. Sponsored by: MUR PRIN 20227HRFPJ