Long lasting molecular changes underlying sensitization to cocaine are absent in nucleus accumbens and striatum from preproenkephalin knock out mice.

MONGI BRAGATO B.; ASSIS A; BARTOS M; ZIMMER A; CANCELA L

Mar del Plata

Congreso; LXII Reunión Científica Anual SAFE; 2010

Sociedad Argntina de Farmacología Experimental (SAFE)

Repeated administration of cocaine induces psychomotor sensitization, characterized by an augmented locomotor response to a subsequent cocaine challenge. Among the enduring neuronal changes responsible for the expression of cocaine sensitization, alterations in glutamate and dopamine signaling, as well as plasticity within the nucleus accumbens and striatum play a critical role. However, it has been described that not only the glutamatergic and dopaminergic system are involved in this phenomenon but also the enkephalinergic sytem. The main goal of this study was to demonstrate the involvement of the enkephalinergic system in cocaine-induced behavioral sensitization, and to determine long lasting associated molecular changes, such as the ERK activity and the surface AMPA receptor expression in mesocorticolimbic brain areas. Male C57B/6J wild type and preproenkephalin knockout (Penk -/-KO) 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. On day 21, mice were killed for biochemical analysis. The nucleus accumbens, striatum, hippocampus and prefrontal cortex were dissected and GluR1, dopamine transporter and ERK levels measured by western blot. Penk-/- KO mice did not show sensitization to the behavioral effects induced by cocaine and failed to show the cocaine-induced increases in ERK activity and AMPA cell surface expression evidenced in the wild type 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 wild-type mice. These results indicate that preproenkephalin-derived opioid peptides did not interfere with the primary action of cocaine on the dopaminergic system, although they seem to be strongly involved in the long-term plastic changes underlying behavioral sensitization to cocaine.