Cognitive Interference and NOS-1 inhibition Are Therapeutic Strategies to Prevent Benzodiazepine Withdrawal Expression

EMILCE ARTUR DE LA VILLARMOIS; MARIA FLORENCIA CONSTANTIN; MARIELA F. PEREZ

Córdoba

Congreso; XXXIII Reunión Anual de la Sociedad Argentina de Investigación en Neurociencias; 2018

Sociedad Argentina de Investigación en Neurociencia (SAN)

Prolonged diazepam (DZ) administration may lead to withdrawal expression after treatment discontinuation, induced by a context-dependent learning process. Drug abuse and learning phenomena are accompanied by alterations in synaptic plasticity in brain structures such as hippocampus (HP). Nitric oxide (NO), synthesized by neuronal NO synthase (NOS-1), is a crucial player in HP synaptic plasticity, learning process and participates in DZ withdrawal. The aim of this work is to develop therapeutic strategies to prevent DZ withdrawal expression by interfering with the learning process or NO synthesis, and evaluate how these strategies could alter HP functional plasticity or NOS-1 expression. Male Wistar rats received DZ along 18 days under 3 protocols: control, latent inhibition (LI) and NOS-1 inhibition (7NI). Forty eight hours after the last administration animals were evaluated in the plus-maze test to evidence an "anxiety-like behavior" as withdrawal sign. Animals where then sacrificed for assessment of synaptic plasticity and NOS-1 expression by extracellular multi-unitary recordings and western-blot respectively. Our results show that control protocol induces anxiety, increased HP plasticity and NOS-1 expression. Interestingly, LI and 7NI protocols reversed these effects. In conclusion, we can hypothesize that learning interference and NOS-1 inhibition during DZ administration may be considered as possible avenues for therapeutic interventions to prevent DZ withdrawal.