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 may therefore corelease glutamate. In the present study, we analyzed mice with a conditional deletion of Vglut2 in DA neurons (Vglut2 f/f;DAT-Cre ) to address the functional significance of the glutamate-DA cophenotype for responses to cocaine and food reinforcement. Biochemical parameters of striatal DA function were also examined by using DA receptor 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 basal mRNA levels 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.

Multiplexed neurochemical signaling by neurons of the ventral tegmental area

“…Furthermore, slow phasic pharmacologic and rapid phasic behavioral firing patterns are similarly processed in downstream accumbal targets (ventral pallidum and lateral preoptic area; Root et al, 2012, 2013; Barker et al, 2014). These dissociable fast and slow signaling patterns in the accumbens are consistent with findings suggesting that glutamate and dopamine each have specific roles in addiction-associated behaviors (Birgner et al, 2010; Alsiö et al, 2011). …”

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…Interestingly, cocaine CPP is unaffected by this intervention . In contrast with the behavioral effects observed in the sensitization models, dopamine transporter neuron-specific knockout of 858 VGlut2 increases motivation to obtain sucrose and low doses of cocaine, as well as cue-induced reinstatement of cocaine seeking (Alsiö et al, 2011). These effects can be reconciled by the fact that the specific VGlut2 deletion reduces dopaminergic signaling in the NAc.…”

An update on the connections of the ventral mesencephalic dopaminergic complex

“…However, numerous recent multidisciplinary studies have provided evidence for abundant functionally significant release of GLU and/or GABA from the axons of DA neurons, irrespective of the relative strength of the corresponding neuroanatomical evidence for co-localization (Joyce and Rayport, 2000; Chuhma et al, 2004; 2009; Hnasko et al, 2010; 2012; Stuber et al, 2010; Alsiö et al, 2011; Fortin et al, 2012; Tritsch et al, 2012; Stamatakis et al, 2013). Moreover, in the case of GLU, in vivo co-expression is reported to peak early and decline as rats mature (Mendez et al, 2008).…”