Differential expression of tyrosine hydroxylase and membrane dopamine transporter genes in subpopulations of dopaminergic neurons of the rat mesencephalon

doi:10.1016/0169-328X(94)90029-9

Molecular Brain Research

Volume 22, Issues 1–4, March 1994, Pages 29-38

https://doi.org/10.1016/0169-328X(94)90029-9 Get rights and content

Abstract

Dopaminergic (DA) cells of the substantia nigra pars compacta (SNC) and the ventral tegmental area (VTA) display differences in their topography, biochemistry and susceptibility to pathological processes. Neuronal dopamine concentration is regulated in large part by tyrosine hydroxylase (TH), the rate-limiting enzyme of dopamine synthesis, and by the dopamine reuptake system. In the present study, TH protein, TH mRNA and dopamine membrane transporter (DAT) mRNA were quantified at cellular level in 4 arbitràry subregions of the rat ventral mesencephalon (lateral, middle, medial SNC and VTA), using in situ hybridization and immunoautoradiography. The distribution of labelling for TH protein and TH mRNA was almost superimposable and close to that of DAT mRNA in mesencephalic neurons. Lower values of cellular expression in TH protein, TH mRNA and DAT mRNA were observed in the lateral part of the SNC compared to the other subregions. TH and DAT expression were correlated in SNC but not in VTA. Indeed DA cells in this region expressed low levels of DAT mRNA in comparison to the middle and medial SNC. These results suggest a heterogeneity of DA metabolism among populations of mesencephalic cells. The relative lower expression of the DAT gene in VTA neurons suggests a less efficient dopamine reuptake capacity, which may partly account for the relative sparing of the mesolimbic system reported in Parkinson's disease and MPTP-treated animals.

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Abuse of psychostimulants like cocaine that inhibit dopamine (DA) reuptake through the dopamine transporter (DAT) represents a major public health issue, however FDA-approved pharmacotherapies have yet to be developed. Recently a class of ligands termed “atypical DAT inhibitors” has gained attention due to their range of effectiveness in increasing extracellular DA levels without demonstrating significant abuse liability. These compounds not only hold promise as therapeutic agents to treat stimulant use disorders but also as experimental tools to improve our understanding of DAT function. Here we used patch clamp electrophysiology in mouse brain slices to explore the effects of two atypical DAT inhibitors (R-modafinil and JHW 007) on the physiology of single DA neurons in the substantia nigra and ventral tegmental area. Despite their commonalities of being DAT inhibitors that lack cocaine-like behavioral profiles, these compounds exhibited surprisingly divergent cellular effects. Similar to cocaine, R-modafinil slowed DA neuron firing in a D2 receptor-dependent manner and rapidly enhanced the amplitude and duration of D2 receptor-mediated currents in the midbrain. In contrast, JHW 007 exhibited little effect on firing, slow DAT blockade, and an unexpected inhibition of D2 receptor-mediated currents that may be due to direct D2 receptor antagonism. Furthermore, pretreatment with JHW 007 blunted the cellular effects of cocaine, suggesting that it may be valuable to investigate similar DAT inhibitors as potential therapeutic agents. Further exploration of these and other atypical DAT inhibitors may reveal important cellular effects of compounds that will have potential as pharmacotherapies for treating cocaine use disorders.
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This is probably due to transgenic over-expression of DAT in the VTA, which enhances the vulnerability of this region in DAT-tg mice. Physiologically, VTA neurons do not express as much DAT as SNc neurons and therefore, the VTA is relatively spared from damage in PD (Blanchard et al., 1994). The relationship between DAT expression and neurodegeneration is supported by a study in PD patients showing that brain regions containing the highest levels of DAT protein – the caudate and putamen – are also the most sensitive to damage (Miller et al., 1997).
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Research reportDifferential expression of tyrosine hydroxylase and membrane dopamine transporter genes in subpopulations of dopaminergic neurons of the rat mesencephalon

Abstract

Brain Res.

Neuroscience

Eur. J. Pharmacol.

Brain Res.

Neuroscience

Neuroscience

Mol. Brain Res.

Methods Neurosci.

Neuroscience

Neuroscience

Mol. Brain Res.

Brain Res.

Brain Res.

Mol. Brain Res.

Brain Res.

Brain Res. Bull.

Brain Res.

Neuroscience

Biochemistry of neurotransmitters in Parkinson's disease

Mesocortical dopamine neurons: rapid transmitter turnover compared to other brain catecholamine systems

Brain Res.

Analyse autoradiographique dans le système nerveux central par photométrie et cartographie combinées

C.R. Soc. Biol.

Dopamine-containing systems in the CNS

Cellular quantification of tyrosine hydroxylase in the rat brain by immunoautoradiography

J. Neurochem.

A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Evidence for the existence of monoamine-containing neurons in the central nervous system — I. Demonstration of monoamines in the cell bodies of brain stem neurons

Acta physiol. Scand.

Tyrosine hydroxylase gene expression in human ventral mesencephalon: detection of tyrosine hydroxylase messenger RNA in neurites

J. Neurosci. Res.

Research report
Differential expression of tyrosine hydroxylase and membrane dopamine transporter genes in subpopulations of dopaminergic neurons of the rat mesencephalon