Topiramate-chitosan nanoparticles prevent morphine reinstatement with no memory impairment: Dopaminergic and glutamatergic molecular aspects in rats.

Besides their clinical application, chronic misuse of opioids has often been associated to drug addiction due to their addictive properties, underlying neuroadaptations of AMPA glutamate-receptor-dependent synaptic plasticity. Topiramate (TPM), an AMPAR antagonist, has been used to treat psychostimulants addiction, despite its harmful effects on memory. This study aimed to evaluate the effects of a novel topiramate nanosystem on molecular changes related to morphine reinstatement. Rats were previously exposed to morphine in conditioned place preference (CPP) paradigm and treated with topiramate-chitosan nanoparticles (TPM-CS-NP) or non-encapsulated topiramate in solution (S-TPM) during CPP extinction; following memory performance evaluation, they were re-exposed to morphine reinstatement. While morphine-CPP extinction was comparable among all experimental groups, TPM-CS-NP treatment prevented morphine reinstatement, preserving memory performance, which was impaired by both morphine-conditioning and S-TPM treatment. In the NAc, morphine increased D1R, D2R, D3R, DAT, GluA1 and MOR immunoreactivity. It also increased D1R, DAT, GluA1 and MOR in the dorsal hippocampus. TPM-CS-NP treatment decreased D1R, D3R and GluA1 and increased DAT in the NAc, decreasing GluA1 and increasing D2 and DAT in the dorsal hippocampus. Taken together, we may infer that TPM-CS-NP treatment was able to prevent the morphine reinstatement without memory impairment. Therefore, TPM-CS-NP may be considered an innovative therapeutic tool due to its property to prevent opioid reinstatement because it acts modifying both dopaminergic and glutamatergic neurotransmission, which are commonly related to morphine addiction.