Pharmacological NOS-1 Inhibition Within the Hippocampus Prevented Expression of Cocaine Sensitization: Correlation with Reduced Synaptic Transmission

ARTUR DE LA VILLARMOIS, EMILCE; PORETTI, MARIA BELEN; CARLINI, VALERIA P.; GABACH, LAURA A.; OCCHIEPPO, VICTORIA; PÉREZ, MARIELA FERNANDA; GABACH, LAURA A.; OCCHIEPPO, VICTORIA; PÉREZ, MARIELA FERNANDA; BIANCONI, SANTIAGO; SCHIÖTH, HELGI B.; BIANCONI, SANTIAGO; SCHIÖTH, HELGI B.; ARTUR DE LA VILLARMOIS, EMILCE; PORETTI, MARIA BELEN; CARLINI, VALERIA P.

MOLECULAR NEUROBIOLOGY

HUMANA PRESS INC

Año: 2019

0893-7648

Behavioral sensitization to psychostimulants hyperlocomotor effect is a useful model of addiction and craving. Particularly,cocaine sensitization in rats enhanced synaptic plasticity within the hippocampus, an important brain region for the associativelearning processes underlying drug addiction. Nitric oxide (NO) is a neurotransmitter involved in both, hippocampal synapticplasticity and cocaine sensitization. It has been previously demonstrated a key role of NOS-1/NO/sGC/cGMP signaling pathwayin the development of cocaine sensitization and in the associated enhancement of hippocampal synaptic plasticity. The aim of thepresent investigation was to determine whether NOS-1 inhibition after development of cocaine sensitization was able to reverseit, and to characterize the involvement of the hippocampus in this phenomenon. Male Wistar rats were administered only withcocaine (15 mg/kg/day i.p.) for 5 days. Then, animals received 7-nitroindazole (NOS-1 inhibitor) either systemically for the next5 days or a single intra-hippocampal administration. Development of sensitization and its expression after withdrawal weretested, as well as threshold for long-term potentiation in hippocampus, NOS-1, and CREB protein levels and gene expression.The results showed that NOS-1 protein levels and gene expression were increased only in sensitized animals as well as CREBgene expression. NOS-1 inhibition after sensitization reversed behavioral expression and the highest level of hippocampalsynaptic plasticity. In conclusion, NO signaling within the hippocampus is critical for the development and expression of cocainesensitization. Therefore, NOS-1 inhibition or NO signaling pathways interferences during short-term withdrawal after repeatedcocaine administration may represent plausible pharmacological targets to prevent or reduce susceptibility to relapse.