ReviewGlutamate neurons within the midbrain dopamine regions
Section snippets
Anatomical identification of midbrain glutamatergic neurons
The analysis of glutamatergic neurons has been greatly advanced in the last decade due to the cloning of three distinct vesicular glutamate transporters (VGluT1, VGluT2 and VGluT3), which accumulate glutamate into vesicles for its synaptic release (Bellocchio et al., 1998, Takamori et al., 2000, Bai et al., 2001, Fremeau et al., 2001, Fujiyama et al., 2001, Hayashi et al., 2003, Herzog et al., 2001, Varoqui et al., 2002). VGluT1 and VGluT2 are restricted to known glutamatergic neurons, and
Glutamatergic neurons within the RRF and the SNC
By applying radioactive in situ hybridization in combination with TH immunolabeling, we have found that the vast majority of VGluT2-expressing neurons do not co-express TH within the RRF, SNC (Yamaguchi et al., 2013), or lateral PBP and lateral PN of the VTA (Yamaguchi et al., 2007, Yamaguchi et al., 2011, Li et al., 2013) (Fig. 1, Fig. 2). In contrast, some of the VGluT2 neurons located in the midline nuclei of the VTA (medial PBP, medial PN, RLi, IF, and CLi) co-express TH (VGluT2-TH neurons;
VGluT2 neurons within the VTA
In contrast to the apparent uniformity among the VGluT2 neurons within the RRF and the SNC, the VGluT2 neurons within the VTA are heterogeneous in their concentration, distribution and composition (Yamaguchi et al., 2007, Yamaguchi et al., 2011, Li et al., 2013, Root et al., 2013). Although some VGluT2 neurons expressing either TH or GABAergic markers are present within the medial aspects of the VTA (Yamaguchi et al., 2007, Root et al., 2013), most VGluT2 neurons lack both TH and GABAergic
Dual VGluT2-TH neurons
Evidence for the expression of VGluT2 mRNA in a subset of TH neurons observed by radioactive in situ hybridization procedures is supported by quantitative RT-PCR of individual laser micro-dissected VTA neurons (Yamaguchi et al., 2011, Li et al., 2013). These VGluT2-TH neurons express aromatic L-amino acid decarboxylase, and as such have the capability to synthesize DA. However, only a subset of VGluT2-TH neurons express vesicular monoamine transporter (VMAT2), dopamine transporter (DAT), or D2
Intrinsic and extrinsic inputs by VTA glutamatergic neurons
It is well known that VTA neurons receive extensive glutamatergic innervation (Geisler et al., 2007). A role for local VTA VGluT2 neurons in VTA neurotransmission has been suggested based on electrophysiological and anatomical findings showing that some VTA VGluT2 neurons establish local glutamatergic synapses on VTA DA and non-DA neurons (Dobi et al., 2010). These studies indicate that VTA VGluT2 neurons provide local glutamatergic neurotransmission. This novel model of local communication in
Conclusions and future directions
All glutamatergic neurons within the major midbrain DA subdivisions (RRF, SNc, and VTA) contain VGluT2 mRNA, and they may provide fast non-DA excitatory signaling. The VGluT2 neurons within the RRF and SNc do not co-express TH, and as such they are incapable of DA co-release. The VTA contains two major classes of VGluT2 neurons: VGluT2 neurons lacking TH (VGluT2-only neurons), which are present in all subdivisions of the VTA, and VGluT2 neurons co-expressing TH (VGluT2-TH neurons) that are
Acknowledgements
This research was supported by the NIDA Intramural Research Program.
References (76)
- et al.
Molecular and functional analysis of a novel neuronal vesicular glutamate transporter
J Biol Chem.
(2001) - et al.
A transgenic mouse line for molecular genetic analysis of excitatory glutamatergic neurons
Mol Cell Neurosci
(2010) - et al.
A subset of ventral tegmental area neurons is inhibited by dopamine, 5-hydroxytryptamine and opioids
Neuroscience
(1997) - et al.
Dopamine neurons control striatal cholinergic neurons via regionally heterogeneous dopamine and glutamate signaling
Neuron
(2014) - et al.
Dopamine neuron glutamate cotransmission: frequency-dependent modulation in the mesoventromedial projection
Neuroscience
(2009) The role of D2-autoreceptors in regulating dopamine neuron activity and transmission
Neuroscience
(2014)- et al.
The expression of vesicular glutamate transporters defines two classes of excitatory synapse
Neuron
(2001) - et al.
Secretory granule-mediated co-secretion of L-glutamate and glucagon triggers glutamatergic signal transmission in islets of Langerhans
J Biol Chem
(2003) - et al.
Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo
Neuron
(2010) - et al.
The role of nucleus accumbens dopamine in motivated behavior: a unifying interpretation with special reference to reward-seeking
Brain Res Brain Res Rev
(1999)
Mesoaccumbens dopamine neuron synapses reconstructed in vitro are glutamatergic
Neuroscience
Immunohistochemical demonstration of glutaminase in catecholaminergic and serotoninergic neurons of rat brain
Brain Res
Postembedding immunogold labelling reveals subcellular localization and pathway-specific enrichment of phosphate activated glutaminase in rat cerebellum
Neuroscience
Reward and aversion in a heterogeneous midbrain dopamine system
Neuropharmacology
Electrical stimulation of mesencephalic cell groups (A9–A10) produces monosynaptic excitatory potentials in rat frontal cortex
Brain Res
Stereological estimates of dopaminergic, GABAergic and glutamatergic neurons in the ventral tegmental area, substantia nigra and retrorubral field in the rat
Neuroscience
The mesolimbic dopamine reward circuit in depression
Biol Psychiatry
Mesolimbic dopaminergic pathways in fear conditioning
Prog Neurobiol
Motivational views of reinforcement: implications for understanding the behavioral functions of nucleus accumbens dopamine
Behav Brain Res
The projections of the ventral tegmental area and adjacent regions: a combined fluorescent retrograde tracer and immunofluorescence study in the rat
Brain Res Bull
Catecholamine theories of reward: a critical review
Brain Res
Dynamics of the dopaminergic system as a key component to the understanding of depression
Prog Brain Res.
An update on the connections of the ventral mesencephalic dopaminergic complex
Neuroscience
The role of dopamine in conditioning and latent inhibition: what, when, where and how?
Neurosci Biobehav Rev.
Glutamate and dopamine transmission from midbrain dopamine neurons share similar release properties but are differentially affected by cocaine
J Neurosci
Organization of the ascending projections from the ventral tegmental area: a multiple fluorescent retrograde tracer study in the rat
J Comp Neurol
Enhanced Sucrose and Cocaine Self-Administration and Cue-Induced Drug Seeking after Loss of VGLUT2 in Midbrain Dopamine Neurons in Mice
J Neurosci
The localization of the brain-specific inorganic phosphate transporter suggests a specific presynaptic role in glutamatergic neurotransmission
J Neurosci
The debate over dopamine’s role in reward: the case for incentive salience
Psychopharmacology (Berl).
The dual dopamine-glutamate phenotype of growing mesencephalic neurons regresses in mature rat brain
J Comp Neurol
Ultrastructural characterization of the mesostriatal dopamine innervation in mice, including two mouse lines of conditional VGLUT2 knockout in dopamine neurons
Eur J Neurosci
VGLUT2 in dopamine neurons is required for psychostimulant-induced behavioral activation
Proc Natl Acad SciU S A
GDNF enhances the synaptic efficacy of dopaminergic neurons in culture
Eur J Neurosci
Dopamine D1 receptors facilitate transmitter release
Nature.
Dopamine neurons mediate a fast excitatory signal via their glutamatergic synapses
J Neurosci
Glutamatergic and nonglutamatergic neurons of the ventral tegmental area establish local synaptic contacts with dopaminergic and nondopaminergic neurons
J Neurosci
Collateralization of monoamine neurons: mesotelencephalic dopamine projections to caudate, septum, and frontal cortex
J Neurosci
Properties and opioid inhibition of mesolimbic dopamine neurons vary according to target location
J Neurosci
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