Opioid receptorsand endogenous opioid peptides, mainly enkephalin, are largely distributed inthe mesolimbic system. However, their contribution to cocaine - inducedsensitization on behavioral and associated molecular parameters has been poorlystudied. Male C57B/6J wild type (WT)and preproenkephalin knockout (KO pENK) mice were daily treated with cocaine(15mg/Kg i.p.) and vehicle for 9 days followed by a cocaine challenge(7,5mg/Kg) on days 15 and 21 of the treatment. The locomotor activity wasmeasured on days 15 and 21. In another set of experiments, male C57B/6J WT micereceived the same treatment but 30 min. before each cocaine injection, theanimals were administered with a naloxone injection (1mg/Kg s.c.). Thelocomotor activity was measured on days 1, 15 and 21. On this day, mice werekilled for biochemical analysis. The nucleus accumbens, striatum, hippocampusand prefrontal cortex were dissected and GluR1, dopamine transporter, ERK andCREB levels were measured by western blot. Penk KO mice did not showsensitization to the behavioral effects induced by cocaine and failed to show the cocaine-induced increases in ERK activation and AMPA cell surface expression evidencedin the WT mice. However, the locomotor activity in response to an acuteinjection of the drug and the levels of dopamine transporter were similar inboth KO and WT mice. Wild type mice pretreated with naloxone did not show thecocaine - induced increased in ERK and CREB phosphorilation. These resultsindicate that preproenkephalin-derivedopioid peptides, possibly through the activation of opioid receptors inmesolimbic areas, are strongly involved in the long-term plasticity underlyingbehavioral sensitization to cocaine.

FinancialSupport: FONCYT, Ministerio de Ciencia y Tecnología, CONICET