Enhanced sucrose and cocaine self-administration and cue-induced drug seeking after loss of VGLUT2 in midbrain dopamine neurons in mice

Abstract

Themesostriataldopamine(DA)systemcontributestoseveralaspectsofresponsestorewardingsubstancesandisimplicatedinconditionssuch asdrugaddictionandeatingdisorders.AsubsetofDAneuronshasbeenshowntoexpressthetype2Vesicularglutamatetransporter(Vglut2)and maytherefore corelease glutamate. In the present study, we analyzed mice with a conditional deletion of Vglut2 inDAneurons (Vglut2f/f;DAT-Cre) to address the functional significance of the glutamate-DA cophenotype for responses to cocaine and food reinforcement. Biochemical parameters of striatalDAfunction were also examined by usingDAreceptor autoradiography, immediate-early gene quantitative in situ hybridization after cocaine challenge, and DA-selective in vivo chronoamperometry. Mice in which Vglut2 expression had been abrogated in DA neurons displayed enhanced operant self-administration of both high-sucrose food and intravenous cocaine. Furthermore, cocaine seeking maintained by drug-paired cues was increased by 76%, showing that reward-dependent plasticity is perturbed in these mice. In addition, several lines of evidence suggest that adaptive changes occurred in both the ventral and dorsal striatum in the absence of VGLUT2: DA receptor binding was increased, and basalmRNAlevels of the DA-induced early genes Nur77 and c-fos were elevated as after cocaine induction. Furthermore, in vivo challenge of the DA system by potassium-evoked depolarization revealed less DA release in both striatal areas. This study demonstrates that absence of VGLUT2 in DA neurons leads to perturbations of reward consumption as well as reward-associated memory, features of particular relevance for addictive-like behavior. © 2011 the authors.