Review
Dopamine receptors and brain function

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Abstract

In the central nervous system (CNS), dopamine is involved in the control of locomotion, cognition, affect and neuroendocrine secretion. These actions of dopamine are mediated by five different receptor subtypes, which are members of the large G-protein coupled receptor superfamily. The dopamine receptor subtypes are divided into two major subclasses: the D1-like and D2-like receptors, which typically couple to Gs and Gi mediated transduction systems. In the CNS, the various receptor subtypes display specific anatomical distributions, with D1-like receptors being mainly post-synaptic and D2-like receptors being both pre- and post-synaptic. D1 and D2 dopamine receptors, the most abundant subtypes in the CNS, appear to be expressed largely in distinct neurons. Substance P and dynorphin, which are expressed in D1 receptor-containing neurons, as well as preproenkephalin in D2 receptor-containing neurons, have been used as monitors of dopaminergic activity in the CNS. Expression of immediate early genes, in particular fos, has also been found to correlate with dopaminergic transmission. Dopamine released from the hypothalamus controls the synthesis and secretion of prolactin from the anterior pituitary via D2 dopamine receptors. As yet, none of the dopamine receptor subtypes have been associated with the etiology of psychotic disorders, such as schizophrenia. However, the recent characterization of D3 and D4 receptors which are, interestingly, expressed in areas of the CNS mediating cognition and affect or show increased affinity for certain neuroleptics, have renewed the interest and hope of finding effective neuroleptics devoid of side effects. Finally, the recent production of genetically-derived animals lacking several of these receptor genes should help elucidate which specific physiological paradigms the recptors mediate.

Section snippets

The molecular biology of dopamine receptors: from D1 to D5

The introduction of gene cloning procedures to the neurotransmitter receptor field (for a review see Caron et al., 1990) resulted in a major shift in the understanding of the dopamine receptor system, and their previously unappreciated diversity was revealed. Bunzow et al. (1988)opened a new area in dopamine receptor research by cloning the first dopamine receptor cDNA, that of the D2 receptor. It was demonstrated that dopamine receptors belong to the large G protein-coupled receptor family.

Signal transduction of the dopamine receptors

The co-expression of various subtypes of dopamine receptors in the same brain region (such as the D1 and D2 in the striatum) and the inability to specifically target a dopamine receptor subtype by completely selective ligands makes it difficult to study the signal transduction associated with their activation in an intact tissue. The molecular cloning of the dopamine receptors has allowed the study of the properties of individual receptors in cultured cell lines. This has made it possible to

Distribution of the dopamine receptors in the central nervous system

Dopaminergic neurons are localized mainly in the substantia nigra pars compacta, the ventral tegmental area and the hypothalamus. They define three main pathways, the nigrostriatal, the mesolimbic and the tuberoinfundibular. Since selective radioligands capable of discriminating each member of the dopamine receptor family are unavailable, the study of dopamine receptor distribution in the brain by classic autoradiography binding techniques has been difficult. Thus, in situ hybridization has

Dopamine receptors and regulation of gene expression in the nigro-striatal pathway

The study of receptor and peptide levels in the striatum following perturbation of dopamine transmission is useful in better understanding the consequences of blockade of dopamine receptors (as occurring following neuroleptic treatment), interruption of dopaminergic transmission (as occurring in Parkinson's disease) or following the hyperactivation of the dopamine system (observed following abuse of psychostimulants such as cocaine and amphetamine).

Striatal efferent neurons are known to be

Dopamine receptors in the pituitary

The first direct evidence for the presence of dopamine receptors in the pituitary came from binding studies showing that high affinity, saturable and stereoselective binding sites for dopamine were detectable in the anterior (Creese et al., 1977; Caron et al., 1978; Bethea et al., 1982) and intermediate (Munemura et al., 1980; Lightman et al., 1982; Kohler and Fahlberg, 1985) lobes of the gland. On the basis of biochemical and pharmacological criteria, pituitary dopamine receptors were

Dopamine receptors and schizophrenia

The hypothesis that the dopaminergic system is overactive in schizophrenia is based on the finding that neuroleptics, which are used in the successful management of some symptoms of this disorder, selectively block dopamine receptors (Matthysse, 1974; Seeman, 1980; Kane and Freeman, 1994; Sigmundson, 1994). The dopamine hypothesis was further strengthened by the fact that psychostimulants, such as amphetamine, that increase dopaminergic transmission mainly by increasing the release of dopamine,

Transgenic animals: new frontiers for studying dopaminergic neurotransmission

The ability to make genetic changes in a predetermined way has provided an invaluable new tool to study individual players of dopaminergic transmission. In our laboratory, we have produced transgenic animals that express β galactosidase under the control of the D1 promoter to study the pattern of expression of the D1 receptor gene in the central nervous system (Severynse et al., 1995). β Galactosidase expression in the brain was found to closely match that of the D1 receptor mRNA previously

Perspectives

The last 30 years of research on the dopamine system have produced a wealth of information about the structure, function and regulation of the dopamine receptors. However, many unanswered questions remain. These include the functional role of the newest members of the dopamine receptor family (D3, D4 and D5), the significance of splice variants of the D2-like receptors, the relevance of the allelic variants found in the D4 receptor and whether a specific dopamine receptor is involved in the

Acknowledgements

M.J. was a recipient of an EMBO long term fellowship. C.M. was on sabbatical leave from the University of Brescia, Italy. M.G.C. is the beneficiary of a Bristol-Myers Squibb Unrestricted Neuroscience Award. We would like to thank Drs C. Le Moine and B. Bloch for helpful comments.

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