Vesicular Glutamate Transport Promotes Dopamine Storage and Glutamate Corelease In Vivo

Departments of Physiology and Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
Neuron (Impact Factor: 15.05). 03/2010; 65(5):643-56. DOI: 10.1016/j.neuron.2010.02.012
Source: PubMed


Dopamine neurons in the ventral tegmental area (VTA) play an important role in the motivational systems underlying drug addiction, and recent work has suggested that they also release the excitatory neurotransmitter glutamate. To assess a physiological role for glutamate corelease, we disrupted the expression of vesicular glutamate transporter 2 selectively in dopamine neurons. The conditional knockout abolishes glutamate release from midbrain dopamine neurons in culture and severely reduces their excitatory synaptic output in mesoaccumbens slices. Baseline motor behavior is not affected, but stimulation of locomotor activity by cocaine is impaired, apparently through a selective reduction of dopamine stores in the projection of VTA neurons to ventral striatum. Glutamate co-entry promotes monoamine storage by increasing the pH gradient that drives vesicular monoamine transport. Remarkably, low concentrations of glutamate acidify synaptic vesicles more slowly but to a greater extent than equimolar Cl(-), indicating a distinct, presynaptic mechanism to regulate quantal size.

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    • "One of them proposes that glutamate and DA coexist (and are co-released) from the same pool of vesicles (Hnasko et al., 2010;). This hypothesis has been based on the co-immunoprecipitation of VMAT2 and VGluT2 from nAcc preparations (Hnasko et al., 2010). In clear contrast, a recent study has shown lack of VMAT2 and VGluT2 co-immunoprecipitation when ultrastructurally confirmed pure nAcc synaptic vesicles were used (Zhang et al., 2015). "
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    • "DOI: 10.7554/eLife.11396 1 of 31 RESEARCH ARTICLE Although a clear role for ACh in volume transmission and for nAChRs in nicotine dependence has been established, several observations suggest that ACh may have additional functions in cholinergic neurons. For example, it has been demonstrated in several systems that neurotransmitters can be coreleased (El Mestikawy et al., 2011; Gras et al., 2008; Guzman et al., 2011; Hnasko et al., 2010; Hnasko and Edwards, 2012; Ren et al., 2011; Shabel et al., 2014), and that cooperation between vesicular neurotransmitter transporters located in the same synaptic vesicle (SV) can reciprocally increase the packaging of their respective neurotransmitters into SVs, a process termed vesicular synergy (El Mestikawy et al., 2011; Gras et al., 2008; Hnasko et al., 2010). Furthermore, infusion of glutamate receptor antagonists into the IPN results in decreased nicotine intake (Fowler et al., 2011) and withdrawal (Zhao-Shea et al., 2013) suggesting that glutamate-mediated fast synaptic transmission is also important in nicotine addiction. "
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    • "Studies in rodents provide evidence for this co-phenotype in relation to addiction. Mice lacking Vglut2 in midbrain dopamine neurons display enhanced cocaine administration and cue-induced drug-seeking (Alsiö et al. 2011), as well as attenuated locomotor response upon acute injections of amphetamine (Birgner et al. 2010) and cocaine (Hnasko et al. 2010). "
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