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Review
, 1216, 86-98

VMAT2: A Dynamic Regulator of Brain Monoaminergic Neuronal Function Interacting With Drugs of Abuse

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Review

VMAT2: A Dynamic Regulator of Brain Monoaminergic Neuronal Function Interacting With Drugs of Abuse

Lee E Eiden et al. Ann N Y Acad Sci.

Abstract

The monoaminergic neuron, in particular the dopaminergic neuron, is central to mediating the hedonic and addictive properties of drugs of abuse. The effects of amphetamine (AMPH) and cocaine (COC), for example, depend on the ability to increase dopamine in the synapse, by effects on either the plasma membrane transporter DAT or the vesicular transporter for monoamine storage, VMAT2. The potential role of DAT as a target for AMPH and COC has been reviewed extensively. Here, we present VMAT2 as a target that enables the rewarding and addictive actions of these drugs, based on imaging, neurochemical, biochemical, cell biological, genetic, and immunohistochemical evidence. The presence of VMAT2 in noradrenergic, serotoninergic, histaminergic, and potentially trace aminergic neurons invites consideration of a wider role for aminergic neurotransmission in AMPH and COC abuse and addiction.

Conflict of interest statement

Conflicts of interest

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Neurotransmitter accumulation in the synaptic vesicle.
Figure 2
Figure 2
Differential expression of hVMAT1 and hVMAT2 in the CNS and periphery. Staining for VMAT1 and VMAT2 in human substantia nigra (SN) and adrenal gland (AG). Adrenal gland data are taken from Erickson et al., and substantia nigra micrographs were discussed but not shown in that publication. Note the complete absence of specific staining for VMAT1 in human brain tissue, and corresponding expression of both VMAT1 and VMAT2 in human adrenal medulla under conditions of staining and incubation as described in Ref. .
Figure 3
Figure 3
Cellular aspects of VMAT2 trafficking, expression, and targeting by drugs of abuse. Dual site of action of AMPH at the synaptic vesicle and at DAT, and single site of action of COC at DAT, are depicted. VMAT2 trafficking to SSVs and LDCVs is regulated in part by phosphorylation, and VMAT2 transport by G- protein coupling, through signal transduction pathways that are not yet characterized. TBZ binds directly to VMAT2 independently of its cellular location. See text for details.
Figure 4
Figure 4
Chemical structure of dihydrotetrabenazine.

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