Behavioral and dopamine sensitization to cocaine is absent in Proenkephalin Knockout mice: lack of neuroadaptations in AMPA receptor surface expression and BDNF/TrkB signaling in nucleus accumbens

BETHANIA MONGI-BRAGATO ; EMILIANO ZAMPONI; MARIA A ESPARZA, FLAVIA BOLLATI, CONSTANZA GARCIA-KELLER, MIRIAM B VIRGOLINI, PH.D., LIDIA M LOPEZ, ALICIA BRUSCO, PH., HAO-WEI SHEN, PH.D. PETER W KALIVAS, PH.D. AND LILIANA M CANCELA, PH.D.; MARIA AMPARO ASSIS; MIRIAM B VIRGOLINI; DANIEL MASCÓ; ANDREAS ZIMMER; LILIANA CANCELA

ADDICTION BIOLOGY

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2014

1355-6215

Behavioral sensitization to cocaine is associated to neuroadaptations that contribute to addiction. Enkephalin is highlyexpressed in mesocorticolimbic areas associated with cocaine-induced sensitization; however, their influence oncocaine-dependent behavioral and neuronal plasticity has not been explained. In this study, we employed a knockout(KO) model to investigate the contribution of enkephalin in cocaine-induced behavioral sensitization.Wild-type (WT)and proenkephalin KO mice were treated with cocaine once daily for 9 days to induce sensitization. Additionally, toclarify the observations in KO mice, the same procedure was applied in C57BL/6 mice, except that naloxone wasadministered before each cocaine injection. All animals received a cocaine challenge on days 15 and 21 of thetreatment to evaluate the expression of locomotor sensitization. On day 21, microdialysis measures of accumbalextracellular dopamine, Western blotting for GluR1 AMPA receptor (AMPAR), phosphorylated ERK2 (pERK2), CREB(pCREB), TrKB (pTrkB) were performed in brain areas relevant for sensitization from KO and WT and/or naloxone- andvehicle pre-treated animals.We found that KO mice do not develop sensitization to the stimulating properties of cocaineon locomotor activity and on dopamine release in the nucleus accumbens (NAc). Furthermore, pivotalneuroadaptations such as the increase in pTrkB receptor, pERK/CREB and AMPAR related to sensitized responses wereabsent in the NAc from KO mice. Consistently, full abrogation of cocaine-induced behavioral and neuronal plasticityafter naloxone pre-treatment was observed. We show for first time that the proenkephalin system is essential inregulating long-lasting pivotal neuroadaptations in the NAc underlying behavioral sensitization to cocaine.