VGLUT2 in dopamine neurons is required for psychostimulant-induced behavioral activation

Abstract

The "One neuron-one neurotransmitter" concept has been challenged frequently during the last three decades, and the coexistence of neurotransmitters in individual neurons is now regarded as a common phenomenon. The functional significance of neurotransmitter coexistence is, however, less well understood. Several studies have shown that a subpopulation of dopamine (DA) neurons in the ventral tegmental area (VTA) expresses the vesicular glutamate transporter 2 (VGLUT2) and has been suggested to use glutamate as a cotransmitter. The VTA dopamine neurons project to limbic structures including the nucleus accumbens, and are involved in mediating the motivational and locomotor activating effects of psychostimulants. To determine the functional role of glutamate cotransmission by these neurons, we deleted VGLUT2 in DA neurons by using a conditional gene-targeting approach in mice. A DAT-Cre/Vglut2Lox mouse line (Vglut2 f/f;DAT-Cre mice) was produced and analyzed by in vivo amperometry as well as by several behavioral paradigms. Although basal motor function was normal in the Vglut2 f/f;DAT-Cre mice, their risk-taking behavior was altered. Interestingly, in both home-cage and novel environments, the gene targeted mice showed a greatly blunted locomotor response to the psychostimulant amphetamine, which acts via the midbrain DA system. Our results show that VGLUT2 expression in DA neurons is required for normal emotional reactivity as well as for psychostimulant-mediated behavioral activation.amphetamine | midbrain | neurotransmission | reward | striatum

Enhanced Sucrose and Cocaine Self-Administration and Cue-Induced Drug Seeking after Loss of VGLUT2 in Midbrain Dopamine Neurons in Mice

“…Elevated self-administration of high-sucrose, but not low-sucrose, food To test the functional implications for VGLUT2 in DA neurons (hereafter referred to as VGLUT2/DA), we studied voluntary consumption of rewarding substances in our previously described conditional Vglut2 f/f;DAT-Cre mouse line (Birgner et al, 2010).…”

“…By crossing Vglut2 f/f mice (Wallén-Mackenzie et al, 2006;Wallén-Mackenzie et al, 2009) with DAT-Cre mice (Ekstrand et al, 2007), as described previously (Birgner et al, 2010), both Vglut2 f/f;DAT-Cre cKO and Vglut2 f/f control (Ctrl) mice (which do not express the DAT-Cre transgene and therefore have normal Vglut2 expression) were produced in the same litters. Thus, cKO and Ctrl mice were of the same genetic background, a hybrid of C57/BL6 and Sv129.…”

“…First, DA neurons in the adult mouse ventral tegmental area (VTA) possess the ability to release glutamate in the NAc under physiological conditions (Stuber et al, 2010;Tecuapetla et al, 2010) in a VGLUT2-dependent manner (Stuber et al, 2010), and in response to stimulation mimicking reward-related activation of these neurons (Tecuapetla et al, 2010). Second, conditional knockout (cKO) mice lacking VGLUT2 specifically in DA neurons display altered locomotor responsiveness to the psychostimulants amphetamine (Birgner et al, 2010) and cocaine . Third, slices obtained from such cKO mice show decreased DA release in the NAc .…”

“…To explore this issue, we analyzed the recently described cKO mice (Birgner et al, 2010) in procedures of operant self-administration of both natural reward (i.e., sweet food) and cocaine. We report that the cKO mice showed elevated self-administration of both high-sugar food and cocaine and also displayed enhanced cocaine seeking in response to cocaine-associated cues.…”

Somatodendritic dopamine release: recent mechanistic insights

“…Long-standing evidence, primarily from cultured DA neurons, had indicated that glutamate could be synthesized and released by DA neurons [147,148]. Using optogenetic methods with selective expression of channelrhodopsin (ChR2) in DA neurons, several groups have now shown that glutamate released from DA axons produces glutamate receptor-dependent excitatory postsynaptic currents in striatal neurons in ex vivo slices [149][150][151][152][153][154] and mediates behavioural consequences in vivo [155]. Similar methods have shown that co-release of GABA from DA axons produces GABA A receptor-dependent IPSCs in striatal neurons, although DA neurons do not synthesize GABA but rather obtain it via plasma membrane uptake [152,156].…”