Abstract
The ventral tegmental area (VTA) is widely implicated in drug addiction and other psychiatric disorders. This brain region is densely populated by dopaminergic (DA) neurons and also contains a sparse population of γ-aminobutyric acid (GABA)ergic cells that regulate the activity of the principal neurons. Therefore, an in-depth knowledge of the organization of VTA GABAergic circuits and of the plasticity induced by drug consumption is essential for understanding the mechanisms by which drugs induce stable changes in brain reward circuits. Using immunohistochemistry, we provide a detailed description of the localization of major GABAA and GABAB receptor subunits in the rat VTA. We show that DA and GABAergic cells express both GABAA and GABAB receptors. However VTA neurons differ considerably in the expression of GABAA receptor subunits, as the α1 subunit is associated predominantly with non-DA cells, whereas the α3 subunit is present at low levels in both types of VTA neurons. Using an unbiased stereological method, we then demonstrate that α1-positive elements represent only a fraction of non-DA neurons and that the ratio of DA and non-DA cells is quite variable throughout the rostro-caudal extent of the VTA. Interestingly, DA and non-DA cells receive a similar density of perisomatic synapses, whereas axo-dendritic synapses are significantly more abundant in non-DA cells, indicating that local interneurons receive prominent GABAergic inhibition. These findings reveal a differential expression of GABA receptor subtypes in the two major categories of VTA neurons and provide an anatomical basis for interpreting the plasticity of inhibitory circuits induced by drug exposure.
Highlights
The ventral tegmental area (VTA) is a midbrain region critically involved in natural reward and drug addiction [1,2]
We observed prominent labeling for the GABAAR a1 subunit and moderate labeling for GABAAR a3, whereas the other subunits were undetectable or expressed at very low levels. These observations are in good agreement with previous immunohistochemical reports [37,38,39], and indicate that GABAARs containing the a1 and/or a3 subunits are predominant in the VTA
Using triple immunofluorescence for Tyrosine hydroxilase (TH), GABAAR a1 and the neuronal marker NeuN in perfused tissue, we found that the a1 subunit was mainly expressed by non-DA cells (Fig. 1A,B), occasionally we observed TH-positive elements that were labeled for GABAAR a1
Summary
The ventral tegmental area (VTA) is a midbrain region critically involved in natural reward and drug addiction [1,2]. A population of GABAergic cells appears to be concentrated in the caudalmost tier of the VTA, the so-called tail of the VTA [14] These neurons are activated by exposure to psychostimulants and to other drugs [14,15,16,17], and send GABAergic projections to the VTA and the substantia nigra pars compacta [18,19]. A recent optogenetic study demonstrated that a significant number of GABAergic, medium spiny neurons of the nucleus accumbens project back to the VTA, where they target non-DA neurons [20]. It appears that different types of VTA and non-VTA neurons provide GABAergic inhibition of DA cells
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