PRE-EXPOSURE TO DIAZEPAM ADMINISTRATION CONTEX DURING CHRONIC TREATMENT PREVENTS WITHDRAWAL EXPRESSION: CORRELATION WITH LOW nNOS LEVELS IN HIPPOCAMPUS

ARTUR DE LA VILLARMOIS, E; PÉREZ, MF

Mar del Plata

Congreso; Reunión Conjunta SAIC SAFE SAE; 2016

SAIC

Benzodiazepines are commonly prescribed for anxiety and sleep disorders. However, prolonged administration may lead to dependence with evident withdrawal syndrome. We previously demonstrated that a hippocampal (HP)-dependent associative learning process underlie diazepam (DZ) dependence. Also, nitric oxide (NO) participates in DZ dependence; and it is synthesized by neuronal NO synthase (nNOS) upon activation of glutamate NMDA receptors, which are crucial players in HP synaptic plasticity. The aim of the present work is to develop a therapeutic strategy to prevent withdrawal expression by interfering with the learning process underlying DZ dependence, and to reveal possible HP NO-dependent mechanisms underlying DZ dependence. For this purpose we administered DZ (5mg/kg/day i.p) to male wistar rats along 18 days, the last 5 days they were pre-exposed to DZ administration context and 48 hs after the last DZ administration animals were evaluated in the plus-maze test to evidence an "anxiety-like behavior" as a sign of the withdrawal syndrome. Animals where then sacrificed for assessment of HP synaptic plasticity and nNOS expression by extracellular multi-unitary recordings and western blot respectively. Our results show that animals without pre-exposure expressed anxiety, evidenced an increased HP plasticity (measured as a lower threshold to generate LTP) and HP NOS-1 expression comparable to control group. Contrary, animals pre-exposed to the DZ administration context did not show anxiety or enhanced HP synaptic transmission, but a significant reduction in nNOS expression was observed when compared to controls. In conclusion, we can hypothesize that manipulation of the contextual cues presented during DZ administration may be considered an effective non-pharmacological tool to prevent the withdrawal syndrome. The mechanisms underlying this effect could be related to reduction in HP glutamate transmission, principally associated to reduced NO levels.