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The Ventral Tegmental Area has calbindin neurons with the capability to co-release glutamate and dopamine into the nucleus accumbens.

A figure from this studyFeatured Paper of the Month – December 2019.

Unraveling the mystery of the glutamate-dopamine connection
The ventral tegmental area (VTA) is a brain structure that participates in the rewarding effects of drug use, but the role of specific neurons within the VTA is unclear. Scientists at NIDA’s Intramural Research Program conducted a set of studies to better understand the function of glutamate neurons in this addiction-relevant brain region. Glutamate is an excitatory neurotransmitter that plays an important role in brain development, normal brain processes, and pathological conditions like addiction.

Studying rat brain, the investigators discovered that the calcium binding protein calbindin is expressed in approximately 30% of all VTA glutamate neurons. They also found that approximately 20% of these VTA neurons express molecules for the production of dopamine, a neurotransmitter that plays a key role in the reinforcing effects of addictive drugs. The researchers then went on to show that 80% of the glutamate neurons expressing calbindin that project to the nucleus accumbens shell—another area of the brain involved in the rewarding effects of drugs—also express dopamine. These findings broaden our understanding of the diversity of VTA neurons, and identify a subpopulation of calbindin neurons with the capability to co-release glutamate and dopamine in the nucleus accumbens shell. Further studies are necessary to determine the role these neurons play in behavior.

Publication Information

Mongia, Smriti; Yamaguchi, Tsuyoshi; Liu, Bing; Zhang, Shiliang; Wang, Huiling; Morales, Marisela

The Ventral Tegmental Area has calbindin neurons with the capability to co-release glutamate and dopamine into the nucleus accumbens. Journal Article

In: Eur J Neurosci, 2019, ISSN: 1460-9568 (Electronic); 0953-816X (Linking).

Abstract | Links

@article{Mongia:2019aa,
title = {The Ventral Tegmental Area has calbindin neurons with the capability to co-release glutamate and dopamine into the nucleus accumbens.},
author = {Smriti Mongia and Tsuyoshi Yamaguchi and Bing Liu and Shiliang Zhang and Huiling Wang and Marisela Morales},
url = {https://www.ncbi.nlm.nih.gov/pubmed/31215698},
doi = {10.1111/ejn.14493},
issn = {1460-9568 (Electronic); 0953-816X (Linking)},
year = {2019},
date = {2019-06-19},
urldate = {2019-06-19},
journal = {Eur J Neurosci},
address = {National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA.},
abstract = {The ventral tegmental area (VTA) has three major classes of neurons: dopaminergic (expressing tyrosine hydroxylase; TH), GABAergic (expressing vesicular GABA transporter; VGaT) and glutamatergic (expressing vesicular glutamate transporter 2; VGluT2). While VTA dopaminergic and GABAergic neurons have been further characterized by expression of calcium-binding proteins (calbindin, CB; calretinin, CR or parvalbumin, PV), it is unclear whether these proteins are expressed in rat VTA glutamatergic neurons. Here, by a combination of in situ hybridization (for VGluT2 mRNA detection) and immunohistochemistry (for CB-, CR- or PV-detection), we found that among the total population of VGluT2 neurons, 30% coexpressed CB, 3% coexpressed PV and <1% coexpressed CR. Given that some VGluT2 neurons coexpress TH or VGaT, we examined whether these neurons coexpress CB, and found that about 20% of VGluT2-CB neurons coexpressed TH and about 13% coexpressed VGaT. Because VTA TH-CB neurons are known to target the nucleus accumbens (nAcc), we determined whether VGluT2-CB-TH neurons innervate nAcc, and found that about 80% of VGluT2-CB neurons innervating the nAcc shell coexpressed TH. In summary, (a) CB, PV and CR are detected in subpopulations of VTA-VGluT2 neurons; (b) CB is the main calcium-binding protein present in VTA-VGluT2 neurons; (c) one-third of VTA-VGluT2 neurons coexpress CB; (d) some VTA-VGluT2-CB neurons have the capability to co-release dopamine or GABA, and (e) a subpopulation of VTA glutamatergic-dopaminergic neurons innervates nAcc shell. These findings further provide evidence for molecular diversity among VTA-VGluT2 neurons, neurons that may play a role in specific circuitry and behaviours.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

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The ventral tegmental area (VTA) has three major classes of neurons: dopaminergic (expressing tyrosine hydroxylase; TH), GABAergic (expressing vesicular GABA transporter; VGaT) and glutamatergic (expressing vesicular glutamate transporter 2; VGluT2). While VTA dopaminergic and GABAergic neurons have been further characterized by expression of calcium-binding proteins (calbindin, CB; calretinin, CR or parvalbumin, PV), it is unclear whether these proteins are expressed in rat VTA glutamatergic neurons. Here, by a combination of in situ hybridization (for VGluT2 mRNA detection) and immunohistochemistry (for CB-, CR- or PV-detection), we found that among the total population of VGluT2 neurons, 30% coexpressed CB, 3% coexpressed PV and <1% coexpressed CR. Given that some VGluT2 neurons coexpress TH or VGaT, we examined whether these neurons coexpress CB, and found that about 20% of VGluT2-CB neurons coexpressed TH and about 13% coexpressed VGaT. Because VTA TH-CB neurons are known to target the nucleus accumbens (nAcc), we determined whether VGluT2-CB-TH neurons innervate nAcc, and found that about 80% of VGluT2-CB neurons innervating the nAcc shell coexpressed TH. In summary, (a) CB, PV and CR are detected in subpopulations of VTA-VGluT2 neurons; (b) CB is the main calcium-binding protein present in VTA-VGluT2 neurons; (c) one-third of VTA-VGluT2 neurons coexpress CB; (d) some VTA-VGluT2-CB neurons have the capability to co-release dopamine or GABA, and (e) a subpopulation of VTA glutamatergic-dopaminergic neurons innervates nAcc shell. These findings further provide evidence for molecular diversity among VTA-VGluT2 neurons, neurons that may play a role in specific circuitry and behaviours.

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  • https://www.ncbi.nlm.nih.gov/pubmed/31215698
  • doi:10.1111/ejn.14493

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