ENKEPHALINERGIC SYSTEM IS INVOLVED IN COCAINE INDUCED BEHAVIORAL SENSITIZATION AND THE ASSOCIATED INCREASE IN BRAIN-DERIVED NEUROTROPHIC FACTOR IN NUCLEUS ACCUMBENS.

AVALOS, M.P.; MONGI BRAGATO, B.; ZAMPONI, E.; MASCÓ, D.; CANCELA LM.

Córdoba

Encuentro; XIV Reunion Nacional y III Encuentro Internacional de la Asociacion Argentina de Ciencias del Comportamiento; 2013

Asociación Argentina de Ciencias del Comportamiento.

Repeated intermittent exposure to cocaine produces a progressively greater locomotor response to the drug (behavioral sensitization) which is generally coupled to a progressively greater drug-induced increases in dopamine efflux in the nucleus accumbens (NAc). The process underlying behavioral sensitization involves a complex interplay between dopamine (DA) and others neurotransmitters and neuropeptides such as glutamate, opioid peptides and brain-derived neurotrophic factor growth (BDNF). BDNF regulate drug-induced long-term neuroadaptations that encompass alterations in molecular components at the synapse and changes in gene expression. BDNF protein and its receptor (TrkB) are induced in the Prefrontal cortex (Pfc), NAc and Ventral Tegmental Area (VTA) after chronic cocaine treatment. BDNF is reported to alter glutamatergic and dopaminergic transmission in the brain areas associated with cocaine-induced sensitization. On the other hand, opioid receptors and endogenous opioid peptides, mainly enkephalin, are largely distributed in the mesocorticolimbic system. There is pharmacological evidence for a role of opioid receptors in the development and expression of psychostimulant induced sensitization. However, enkephalin contribution to the induction and expression of this phenomenon on behavioral and associated molecular parameters has been poorly studied. The main goal of this study was to demonstrate the involvement of the enkephalinergic system in cocaine-induced behavioral sensitization, and their association with changes in BDNF and its receptor. 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. On day 21 of the treatment the following experiments were done: 1) Immunofluorescence: BDNF and TrkB levels were determined in PfC, NAc, Dorsal Striatum and VTA in response to saline and cocaine challenge. 2) Western blot: to determinate pTrkB levels in these brain areas. We found that chronic cocaine administration increases BDNF and pTrkB levels in NAc and VTA compared to controls animals. These effects are absent in KO mice Penk (-/-).These results demonstrate that enkephalinergic system is involved in cocaine- induced alterations in neurotrophic factors in the NAc and indicate that preproenkephalin-derived opioid peptides are strongly involved in the long-term plastic changes underlying behavioral sensitization to cocaine. Grants: FONCyT, SECyT, CONICET.