.“Enkephalinergic system and opioid receptors are strongly involved in cocaine induced behavioral sensitization and associated molecular changes in nucleus accumbens and striatum”

MONGI BRAGATO B; ASSIS A; BARTOS M; ZIMMER A; CANCELA LILIANA

Uspallata

Congreso; V Neurotoxicity Society Meeting; 2011

NTS

Opioid receptors and endogenous opioid peptides, mainly enkephalin, are largely distributed in the mesolimbic system. However, their contribution to cocaine - induced sensitization on behavioral and associated molecular parameters has been poorly studied. 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 was measured on days 15 and 21. In another set of experiments, male C57B/6J WT mice received the same treatment but 30min before each cocaine injection, the animals were administered with a naloxone injection (1mg/Kg s.c.). On day 21, mice were killed for biochemical analysis. The nucleus accumbens, striatum, hippocampus and prefrontal cortex were dissected and GluR1, dopamine transporter, ERK and CREB levels were measured by western blot. pEenk KO mice did not show sensitization to the behavioral effects induced by cocaine and failed to show the cocaine-induced increases in ERK and CREB activation as well as AMPA cell surface expression evidenced in the WT mice. However, the locomotor activity in response to an acute injection of the drug and the levels of dopamine transporter were similar in both KO and WT mice. Wild type mice pretreated with naloxone did not show the cocaine - induced increased in ERK and CREB phosphorilation. These results indicate that preproenkephalin-derived opioid peptides, possibly through the activation of opioid receptors in mesolimbic areas, are strongly involved in the long-term plasticity underlying behavioral sensitization to cocaine.