Importance of administration context in benzodiazepines dependence expression: Molecular mechanism involved

MARIELA F. PÉREZ

Córdoba

Congreso; 3rd International Meeting on Pharmaceutical Sciences, 18-19 September, 2014 Córdoba, Argentina?; 2014

Benzodiazepines are commonly prescribed for therapy of disorders such as anxiety and sleepdisturbances, among others. However,prolonged treatment may lead to dependence and/or addiction, withevident withdrawal syndromein many patients. It is generally accepted that long-lasting neuroadaptationsresulting from repeated drug exposure involve an associative learning process. These learning and cognitiveaspects of addiction suggest the existence of common neurobiological mechanisms mediating drug addictionand memory. It is known that contextual memories recruit the hippocampus, an important structure forprocessing the associations between the environmental context and unconditioned stimuli, such as drugs ofabuse. Moreover, at cellular level, protein kinase M zeta (PKM) is critical for the maintenance ofhippocampal long-term potentiation (LTP) and spatial conditioned long-term memories. Also, a link betweenactivity-regulated cytoskeleton-associated protein (Arc), PKM and LTP maintenance has been proposed. Inour laboratory, we have evaluated an anxiety-like behavior as expression of a mild discontinuation symptomof chronic (18 days) diazepam (DZ) administration in rats. The anxiety-like behavior and an increasedhippocampal LTP were present only up to five days of withdrawal. After fifteen days of withdrawal, reexposureto the withdrawal environment was able to evoke anxiety, without drug exposure, and the increasedhippocampal LTP was restored. Furthermore, changes in contextual cues during re-exposure to thewithdrawal environment as well as intrahippocampal administration of PKM inhibitor, previous to reexposure,not only prevented the expression of the anxiety-like behavior, but also the associated enhancedhippocampal LTP and the increase in Arc expression. These results support the relevance of hippocampalsynaptic plasticity in the maintenance of the memory trace during DZ withdrawal, adding new evidences forcommon mechanisms between memory and drug addiction that can be therapeutic target for treatment orprevention of DZ dependence and/or abuse.