Dopamine transporter mRNA expression is intense in rat midbrain neurons and modest outside midbrain

Cerruti, Catherine; Walther, Donna; Kuhar, Michael J.; Uhl, George R.

doi:10.1016/0169-328x(93)90187-t

Cited by 115 publications

(53 citation statements)

References 22 publications

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“…These dopaminergic cells include those of the periventricular hypothalamic nuclei (Al4 cell group), the anteroventral periventricular hypothalamic nucleus and the suprachiasmatic preoptic nucleus (Al4 cell group), the anteroventral preoptic nucleus (A 15 cell group), and the posterior hypothalamus (Al 1 cell group). Although a previous study reported DAT mRNA expression in the region of the Al 1 cell group (Cerruti et al, 1993) using the combined immunohistochemistrylin situ hybridization method we were able to demonstrate directly specific labeling for DAT mRNA only in the adjacent dorsal A10 cell group and not in the Al 1 cell group.…”

Section: Discussionmentioning

confidence: 74%

“…Thus, DAT is likely to act at these terminal fields to regulate dopaminergic neurotransmission in accordance with the observation of highaffinity dopamine uptake in the hypothalamus (George and VanLoon, 1982). Although a previous study has reported very low levels of DAT mRNA expression in the region of the arcuate nucleus (Cerruti et al, 1993) labeling in the zona incerta, which contains much higher levels of DAT mRNA, has not been reported.…”

Section: Discussionmentioning

confidence: 85%

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Cell-type-specific expression of catecholamine transporters in the rat brain

1994

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The dopamine transporter (DAT) and norepinephrine transporter (NET) terminate catecholaminergic neurotransmission at synapses by high- affinity sodium-dependent reuptake into presynaptic terminals, and are the initial sites of action for drugs of abuse and antidepressants. In the present study, we used in situ hybridization combined with immunohistochemistry to study the distribution of DAT and NET mRNA in the adult rat brain. Cells were first immunolabeled with antisera directed against one of the catecholamine-synthetic enzymes, tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH), or phenylethanolamine-N-methyltransferase (PNMT), in order to identify dopaminergic, noradrenergic, or epinephrine-containing cells. The immunolabeled cells were subsequently assayed for their ability to express catecholamine transporter mRNAs by in situ hybridization using either a rat DAT or NET cRNA probe. All dopaminergic cell groups of the mesencephalon contained high levels of DAT mRNA but only the A12 and A13 dopaminergic cell groups of the diencephalon appear to express detectable levels of DAT. All norepinephrine-containing cell bodies in the brainstem (locus coeruleus and lateral tegmentum) appear to express NET mRNA. In contrast, epinephrine-containing cell bodies of the brainstem do not appear to express NET mRNA, which raises the possibility that epinephrine may utilize a transporter that is distinct from the other bioactive amines, or may act as an endocrine regulator that does not require rapid reuptake mechanisms. Moreover, the cell- type-specific expression of catecholamine transporters suggests that DAT and NET gene expression may be closely linked to cellular mechanisms that specify transmitter phenotype. The termination of neurotransmission is a critical component of neural signaling and depends on the rapid removal of neurotransmitters from the synaptic cleft. Pharmacological evidence indicates that the action of monoamines at the synapse is terminated predominantly by rapid reuptake into presynaptic nerve endings via neurotransmitter-specific, high-affinity, Na(+)-dependent membrane transporter proteins. The cDNAs encoding distinct transporter proteins for the monoamines dopamine, norepinephrine, and serotonin have been cloned, expressed, and characterized in a variety of heterologous systems (Blakely et al., 1991; Giros et al., 1991; Hoffman et al., 1991; Kilty et al., 1991; Pacholczyk et al., 1991; Shimada et al., 1991; Usdin et al., 1991). Although the monoamine transporters share a high degree of sequence homology, they are distinguished by their monoamine substrate specificities and by their differential sensitivities to a wide spectrum of transport antagonists. For example, pharmacological agents that potently inhibit norepinephrine and serotonin transport, such as desmethylimipramine and citalopram, have little effect on the activity of the dopamine transporter (Javitch et al., 1983).(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 85%

Cell-type-specific expression of catecholamine transporters in the rat brain

1994

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“…First, in situ (4) and immunohistochemical (3) analyses have failed to detect M1 expression in neurons of the substantia nigra. Therefore, it is unlikely that M1 receptors are present on the nerve terminals of dopaminergic cells, which express the dopamine transporter and comprise the major site of dopamine uptake (26,27). Thus, modulation of dopamine uptake by the M1 receptor appears unlikely.…”

Section: Discussionmentioning

confidence: 99%

Hyperactivity, elevated dopaminergic transmission, and response to amphetamine in M1 muscarinic acetylcholine receptor-deficient mice

Gerber

Sotnikova

Gainetdinov

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

239

181

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Acetylcholine serves an important modulatory role in the central nervous system. Pharmacological evidence has suggested that cholinergic activity can modulate central dopaminergic transmission; however, the nature of this interaction and the receptors involved remain undefined. In this study we have generated mice lacking the M1 muscarinic acetylcholine receptor and examined the effects of M1 deletion on dopaminergic transmission and locomotor behavior. We report that M1 deficiency leads to elevated dopaminergic transmission in the striatum and significantly increased locomotor activity. M1-deficient mice also have an increased response to the stimulatory effects of amphetamine. Our results provide direct evidence for regulation of dopaminergic transmission by the M1 receptor and are consistent with the idea that M1 dysfunction could be a contributing factor in psychiatric disorders in which altered dopaminergic transmission has been implicated. Muscarinic acetylcholine receptors are members of the family of G protein-coupled receptors and are widely expressed in the central nervous system and periphery (1, 2). Molecular cloning studies identified genes for five distinct muscarinic receptors, M1-M5, which are expressed in overlapping patterns in the brain. Of these, M1 is predominant in the cortex and hippocampus (3) and, together with M4, is the major muscarinic receptor in the striatum (4), where it is expressed on the majority of cell types (5, 6). M1 receptors couple with a G q type of G protein, and activation of this pathway leads to stimulation of phospholipase C-␤, mobilization of intracellular calcium, and increased neuronal excitability (2). Activation of pharmacologically defined M1 receptors has been shown to enhance the excitability of cortical (7) and striatal (8) neurons. Muscarinic receptors mediate many of the cholinergic effects described in the central nervous system and have been implicated in a variety of central processes, including locomotion, sleep, thermoregulation, generation of seizures, antinociception, and learning and memory (1, 2, 9).A large body of evidence suggests the existence of a complex balance between the cholinergic and dopaminergic systems in the basal ganglia and that disruption of this balance could contribute to movement disorders such as parkinsonism (10, 11). Dopamine can exert both positive and negative regulatory influences on striatal cholinergic transmission, with D1 and D2 receptors exerting facilitative and inhibitory actions, respectively (11). Cholinergic regulation of striatal dopaminergic transmission is less well defined and can occur at multiple levels of the nigrostriatal system. Although a number of pharmacological studies have addressed the effects of muscarinic function on striatal dopaminergic transmission, such studies are limited by the lack of highly subtype-specific muscarinic antagonists (2) and the expression of multiple muscarinic receptors affecting nigrostriatal function. Thus, evidence for both facilitative (12-15) and inhibitory (16-19) mu...

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“…This discrepancy could be the result of a heterogeneous DAT content in the thalamic dopaminergic axons. Indeed, dopaminergic neurons express heterogeneous DAT levels (e.g., high levels in the substantia nigra vs undetectable levels in the hypothalamus) in all species reported to date, including humans and macaque monkeys (Table 1) (Cerruti et al, 1993;Ciliax et al, 1995Ciliax et al, , 1999Haber et al, 1995). A different DAT expression among the dopaminergic neurons projecting to the midline and nonmidline thalamic nuclei would explain the differences in DAT-ir axonal density in the distinct thalamic regions.…”

Section: Dopaminergic Axons Profusely Target the Human And Monkey Thamentioning

confidence: 99%

The Primate Thalamus Is a Key Target for Brain Dopamine

Sánchez-González

García‐Cabezas²,

Rico³

et al. 2005

J. Neurosci.

283

187

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The thalamus relays information to the cerebral cortex from subcortical centers or other cortices; in addition, it projects to the striatum and amygdala. The thalamic relay function is subject to modulation, so the flow of information to the target regions may change depending on behavioral demands. Modulation of thalamic relay by dopamine is not currently acknowledged, perhaps because dopamine innervation is reportedly scant in the rodent thalamus. We show that dopaminergic axons profusely target the human and macaque monkey thalamus using immunolabeling with three markers of the dopaminergic phenotype (tyrosine hydroxylase, dopamine, and the dopamine transporter). The dopamine innervation is especially prominent in specific association, limbic, and motor thalamic nuclei, where the densities of dopaminergic axons are as high as or higher than in the cortical area with the densest dopamine innervation. We also identified the dopaminergic neurons projecting to the macaque thalamus using retrograde tract-tracing combined with immunohistochemistry. The origin of thalamic dopamine is multiple, and thus more complex, than in any other dopaminergic system defined to date: dopaminergic neurons of the hypothalamus, periaqueductal gray matter, ventral mesencephalon, and the lateral parabrachial nucleus project bilaterally to the monkey thalamus. We propose a novel dopaminergic system that targets the primate thalamus and is independent from the previously defined nigrostriatal, mesocortical, and mesolimbic dopaminergic systems. Investigating this "thalamic dopaminergic system" should further our understanding of higher brain functions and conditions such as Parkinson's disease, schizophrenia, and drug addiction.

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Dopamine transporter mRNA expression is intense in rat midbrain neurons and modest outside midbrain

Cited by 115 publications

References 22 publications

Cell-type-specific expression of catecholamine transporters in the rat brain

Cell-type-specific expression of catecholamine transporters in the rat brain

Hyperactivity, elevated dopaminergic transmission, and response to amphetamine in M1 muscarinic acetylcholine receptor-deficient mice

The Primate Thalamus Is a Key Target for Brain Dopamine

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