Elsevier

Neuroscience

Volume 282, 12 December 2014, Pages 60-68
Neuroscience

Review
Glutamate neurons within the midbrain dopamine regions

https://doi.org/10.1016/j.neuroscience.2014.05.032Get rights and content

Highlights

  • VGluT2-expressing glutamate neurons reside within RRF, SNC, and VTA.

  • Some VTA VGluT2 neurons, but not RRF or SNC VGluT2 neurons, co-express tyrosine hydroxylase.

  • Subsets of VGluT2-TH neurons co-express or lack VMAT2, DAT, or D2 receptor.

  • VTA VGluT2 neurons exhibit local VTA projections as well as and extrinsic projections.

  • Accumbens medial shell is a preferential target of VTA VGluT2-TH neurons.

Abstract

Midbrain dopamine systems play important roles in Parkinson’s disease, schizophrenia, addiction, and depression. The participation of midbrain dopamine systems in diverse clinical contexts suggests these systems are highly complex. Midbrain dopamine regions contain at least three neuronal phenotypes: dopaminergic, GABAergic, and glutamatergic. Here, we review the locations, subtypes, and functions of glutamatergic neurons within midbrain dopamine regions. Vesicular glutamate transporter 2 (VGluT2) mRNA-expressing neurons are observed within each midbrain dopamine system. Within rat retrorubral field (RRF), large populations of VGluT2 neurons are observed throughout its anteroposterior extent. Within rat substantia nigra pars compacta (SNC), VGluT2 neurons are observed centrally and caudally, and are most dense within the laterodorsal subdivision. RRF and SNC rat VGluT2 neurons lack tyrosine hydroxylase (TH), making them an entirely distinct population of neurons from dopaminergic neurons. The rat ventral tegmental area (VTA) contains the most heterogeneous populations of VGluT2 neurons. VGluT2 neurons are found in each VTA subnucleus but are most dense within the anterior midline subnuclei. Some subpopulations of rat VGluT2 neurons co-express TH or glutamic acid decarboxylase (GAD), but most of the VGluT2 neurons lack TH or GAD. Different subsets of rat VGluT2-TH neurons exist based on the presence or absence of vesicular monoamine transporter 2, dopamine transporter, or D2 dopamine receptor. Thus, the capacity by which VGluT2-TH neurons may release dopamine will differ based on their capacity to accumulate vesicular dopamine, uptake extracellular dopamine, or be autoregulated by dopamine. Rat VTA VGluT2 neurons exhibit intrinsic VTA projections and extrinsic projections to the accumbens and to the prefrontal cortex. Mouse VTA VGluT2 neurons project to accumbens shell, prefrontal cortex, ventral pallidum, amygdala, and lateral habenula. Given their molecular diversity and participation in circuits involved in addiction, we hypothesize that individual VGluT2 subpopulations of neurons play unique roles in addiction and other disorders.

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)

  • M.P. Joyce et al.

    Mesoaccumbens dopamine neuron synapses reconstructed in vitro are glutamatergic

    Neuroscience

    (2000)
  • T. Kaneko et al.

    Immunohistochemical demonstration of glutaminase in catecholaminergic and serotoninergic neurons of rat brain

    Brain Res

    (1990)
  • J.H. Laake et al.

    Postembedding immunogold labelling reveals subcellular localization and pathway-specific enrichment of phosphate activated glutaminase in rat cerebellum

    Neuroscience

    (1999)
  • S. Lammel et al.

    Reward and aversion in a heterogeneous midbrain dopamine system

    Neuropharmacology

    (2014)
  • N. Mercuri et al.

    Electrical stimulation of mesencephalic cell groups (A9–A10) produces monosynaptic excitatory potentials in rat frontal cortex

    Brain Res

    (1985)
  • R.G. Nair-Roberts et al.

    Stereological estimates of dopaminergic, GABAergic and glutamatergic neurons in the ventral tegmental area, substantia nigra and retrorubral field in the rat

    Neuroscience

    (2008)
  • E.J. Nestler et al.

    The mesolimbic dopamine reward circuit in depression

    Biol Psychiatry

    (2006)
  • M.A. Pezze et al.

    Mesolimbic dopaminergic pathways in fear conditioning

    Prog Neurobiol

    (2004)
  • J.D. Salamone et al.

    Motivational views of reinforcement: implications for understanding the behavioral functions of nucleus accumbens dopamine

    Behav Brain Res

    (2002)
  • L.W. Swanson

    The projections of the ventral tegmental area and adjacent regions: a combined fluorescent retrograde tracer and immunofluorescence study in the rat

    Brain Res Bull

    (1982)
  • R.A. Wise

    Catecholamine theories of reward: a critical review

    Brain Res

    (1978)
  • G. Yadid et al.

    Dynamics of the dopaminergic system as a key component to the understanding of depression

    Prog Brain Res.

    (2008)
  • L. Yetnikoff et al.

    An update on the connections of the ventral mesencephalic dopaminergic complex

    Neuroscience

    (2014)
  • A.M. Young et al.

    The role of dopamine in conditioning and latent inhibition: what, when, where and how?

    Neurosci Biobehav Rev.

    (2005)
  • M.F. Adrover et al.

    Glutamate and dopamine transmission from midbrain dopamine neurons share similar release properties but are differentially affected by cocaine

    J Neurosci

    (2014)
  • A. Albanese et al.

    Organization of the ascending projections from the ventral tegmental area: a multiple fluorescent retrograde tracer study in the rat

    J Comp Neurol

    (1983)
  • J. Alsiö et al.

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

    J Neurosci

    (2011)
  • E.E. Bellocchio et al.

    The localization of the brain-specific inorganic phosphate transporter suggests a specific presynaptic role in glutamatergic neurotransmission

    J Neurosci

    (1998)
  • K.C. Berridge

    The debate over dopamine’s role in reward: the case for incentive salience

    Psychopharmacology (Berl).

    (2007)
  • N. Bérube-Carriére et al.

    The dual dopamine-glutamate phenotype of growing mesencephalic neurons regresses in mature rat brain

    J Comp Neurol

    (2009)
  • N. Bérube-Carriére et al.

    Ultrastructural characterization of the mesostriatal dopamine innervation in mice, including two mouse lines of conditional VGLUT2 knockout in dopamine neurons

    Eur J Neurosci

    (2012)
  • C. Birgner et al.

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

    Proc Natl Acad SciU S A

    (2010)
  • M.J. Bourque et al.

    GDNF enhances the synaptic efficacy of dopaminergic neurons in culture

    Eur J Neurosci

    (2000)
  • D.L. Cameron et al.

    Dopamine D1 receptors facilitate transmitter release

    Nature.

    (1993)
  • N. Chuhma et al.

    Dopamine neurons mediate a fast excitatory signal via their glutamatergic synapses

    J Neurosci

    (2004)
  • A. Dobi et al.

    Glutamatergic and nonglutamatergic neurons of the ventral tegmental area establish local synaptic contacts with dopaminergic and nondopaminergic neurons

    J Neurosci

    (2010)
  • J.H. Fallon

    Collateralization of monoamine neurons: mesotelencephalic dopamine projections to caudate, septum, and frontal cortex

    J Neurosci

    (1981)
  • C.P. Ford et al.

    Properties and opioid inhibition of mesolimbic dopamine neurons vary according to target location

    J Neurosci

    (2006)
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