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Two dopamine receptors: Biochemistry, physiology and pharmacology
Life Sciences, Vol. 35, pp. 2281-2296 Printed in the U.S.A.
Pergamon Press
MINIREVIHd
TWO DOPAMINE RECEL~fORS: BIOCHEMISTRY, PHYSIOLOGY AND PHARMACOLOGY. J.C. STOOF
and J.W. KEBABIAN
Department of Neurology, Medical Faculty, Free University, van der Boechorststraat 7, 1081 BT, Amsterdam, The Netherlands. Experimental Therapeutics Branch, National Institute of Neurological and Communicative Disorders and Stroke, National Institutes of Health, Bethesda, MD 20205, USA.
summarZ In 1979, two categories of dopamine (DA) receptors (designated as D-I and D-2) were identified on the basis of the ability of a limited number of agonists and antagonists to discriminate between these two entities. In the past 5 years agonists and antagonists selective for each category of receptor have been identified. Using these selective drugs it has been possible to attribute the effects of DA upon physiological and biochemical processes to the stimulation of either a D-I or a D-2 receptor. Thus, DA-induced enhancement of both hormone release from bovine parathyroid gland and firing of neurosecretory cells in the CNS of Lymnaea stagnalis has been attributed to stimulation of a D-I receptor. Likewise, the DA-induced inhibition of the release of prolactin and ~-MSH from the pituitary gland, as well as of acetylcholine, DA and 8-endorphin from brain, the DA-induced inhibition of chemo-sensory discharge in rabbit carotid body and the DA-induced hyperpolarization of neurosecretory cells in the CNS of Lymnaea stagnalis have been attributed to stimulation of a D-2 receptor. Independently two categories of DA receptors (designated as DA-I and DA-2) were identified in the cardiovascular system. Stimulation of a DA-I receptor increases the vascular cyclic AMP content and causes a relaxation of vascular smooth n~scle in renal blood vessels, whereas stimulation of a DA-2 receptor inhibits the release of norepinephrine from certain postganglionic sympathetic neurons. Recent studies with the newly developed drugs discriminating between D-I and D-2 receptors suggest however that the independently developed schemata for classification of dopamine receptors in either the central nervous and endocrine systems or the cardiovascular system are similar although maybe not completely identical. During the past 5 years, the existence of multiple categories of dopamine receptors has been debated by different research groups (1-7). Different investigators identified as few as one(2) or as many as four(l,5) distinct receptors for dopamine. A consensus about the number of dopamine receptors and their pharmacological properties is beginning to be reached (8,9); however, controversies still remain(10). In this review, we espouse the hypothesis currently accepted by most investigators that two distinct categories of dopamine receptors can be identified by biochemical as well as pharmacological criteria(4,7). Subsequently, we will discuss physiological processes regulated by either category of dopamine receptor. However, at the beginning of this discussion, it seems appropriate to review the biochemical and pharmacological 0024-3205/84 $3.00 + .00 Copyright (c) 1984 Pergamon Press Ltd.
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studies performed in neural, endocrine, renovascular and cardiovascular supporting the existence of two categories of dopamine receptors.
tissues
The concept that there are two categories of dopamine receptors arose from biochemical investigations. In the early 1970's, the ability of dopamine to stimulate adenylate cyclase activity in neural tissues was demonstrated in several laboratories(ll-13). Many dopaminergic agonists and antagonists displayed appropriate effects in this biochemical model of a dopamine receptor(14-16). However, several dopaminergic ergots displayed inappropriate activity in the biochemical assay system. Although these ergots stimulated dopamine receptors in the pituitary gland and were, therefore, anticipated to mimic the stimulatory effect of dopamine upon adenylate cyclase activity, these co~pounds blocked the ability of dopamine to increase adenylate cyclase activity in neural tissue(17,18). To account for this discrepancy, it was proposed that the dopamine receptor capable of stimulating adenylate cyclase (the D-I receptor) was a distinct entity from the dopamine receptor in the pituitary gland (the D-2 receptor) (4,7,19,20). FUrthermore, it was proposed that the physiological effect(s) of dopamine upon the D-I receptor were the consequence of increased cyclic AMP production while the physiological effects of dopamine upon the D-2 receptor were not associated with the stimulated formation of cyclic AMP(4). Subsequent studies with normal and pathologic pituitary tissue have shown that stimulation of the D-2 receptor inhibits adenylate cyclase activity(21-24). Biochemical and pharmacological studies oE the renovascular and cardiovascular system also suggested the existence of two dopamine receptors(6). Following extensive studies of the dopamine receptors in the renovascular and cardiovascular system, two dopamine receptors, designated as the DA-I and the DA-2 receptors were identified. Stimulation of the DA-I receptor causes an increase in vascular cyclic AMP content (for a review see 25) and a relaxation of vascular smooth muscle in renal blood vessels(6). Stimulation of the DA-2 receptor inhibits the stimulated release of norepinephrine from terminals of certain postganglionic sympathetic neurons ( f o r reviews see 26 and 27); stimulation of this receptor has not been reported to increase cyclic AMP formation. In their initial classification schema, Goldberg and Kohli noted differences between the pharmacology of the D-I and the DA-I receptor as well as the D-2 and the DA-2 receptor(6,28). Although these differences remain, the development of selective dopaminergic drugs (see below) and their application to the renovascular and the cardiovascular system has pointed to extensive similarities between the D-I and DA-I receptors as well as the D-2 and the DA-2 receptors(26,29,30). In view of the extensive discussion of the cardiovascular dopamine receptors in other minireviews and elsewhere(25-27,31,32), an elaborate discussion of these receptors will not be attempted.
Phar_maco_logical ~pro_0~rties- o ~ the two dopamine recejp_tors The existence of two dopamine receptors has been supported by the identification of agonists and antagonists selective for either of these receptors. The availability of these relatively selective con~pounds testifies to the progress which has occurred in the past five years. However, the con~oounds discussed in this section represent only the "first generation" of selective dopaminergic agonists and antagonists; future investigations will surely identify compounds combining higher affinity with greater selectivity. These second and third generation co~pounds may be useful as therapeutic agents. Likewise, it seems reasonable to anticipate that the insight obtained from the structure activity relationship at either the D-I or the D-2 receptor will lead to the development of novel research tools facilitating the scientific investigation of these receptors.
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Selective D-I Agonists At present the most selective D-I agonist is SKF 38393 (Figure I). In the dopamine-sensitive adenylate cyclase assay system, SKF 38393 mimicks the ability of dopamine to stimulate adenylate cyclase activity(33,34). In this biochemical model of the D-I receptor, SKF 38393 displays a higher affinity than does dopamine; however, unlike dopamine SKF 38393 is only a partial agonist. Likewise, SKF 38393 stimulates the renal DA-I receptor(6). Because SKF 38393 does not inhibit prolactin release, it is presumed not to stimulate the D-2 receptor(33). However, in biochemical models of the D-2 receptor, SKF 38393 in higher concentrations does interact with this receptor(35,36). The reason for this discrepancy between the [ physiological and biochemical data is not immediately evident. The D-I agonist activity of SKF 38393 resides in the Renantiomer; the S-enantiomer is significantly less potent as a D-I agonist(37). This observation complements previous demonstrations of the stereoselectivity of the D-I receptor(15,38).
CI
HOrN
H
2,3,4,5-tetrahydro-7,8dihydroxy-l-phenyl-IH-3benzazepine SKF 38393
HO'~~"~N
H
6-chloro-2,3,4,5-tetrahydro-7,8dihydroxy-l-(4-hydroxy phenyl)-IH3-benzazeplne SKF 82526
NH2
OH
8-amino-l,2,3,4-tetrahydro4-(3,4-dihydroxyphenyl)-2methyl-isoqu[noline Di hyd
roxynomi fen:~ i n e
7-chloro-2,3,4,5-tetrahydro-3-methyl 5-phenyl-IH-3-benzazepine-7-ol SCH 23390
FIG. I. Selective D-I receptor agonists and antagonist
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SKF 82526 (Figure i) is another agonist discriminating between the D-I and the D-2 dopamine receptors in physiological models(39). However,in biochemical models of the D-2 receptor, this conloound is also active (35). This compound, under the trade name fenoldopam, is currently undergoing clinical trials as an antihypertensive drug (40).
N-n-propyl di-~(3-hydroxy phenyl)ethylamine
N-n-propyl-N-phenylethy]-p(3hydroxy phenyl) ethylamine
RU 24926
RU 24213
OH
OH !
I
CIH2
5-hydroxy-2(N-n-propyl-N-2phenylethyl)-aminotetraline N 0434
~NCH2CH2CH3
4,4a,5,6,7,8,8a,9-octahydro5-n-propyl-2H-pyrazolo-3,4-g quinoline LY 141865 FIG. 2. Selective D-2 receptor agonists
~H2
5-hydroxy-2(N-n-propyl-N-2thienylethyl)-aminotetraline N 0437
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Dihydroxy nomifensine (Figure i) is another selective D-I agonist. This compound stimulates the dopamine-sensitive adenylate cyclase(41) and causes vasodilatation of renal blood vessels in the dog(42). The 8-deamino analogue of this compound is equipotent with the parent cor~pound as a DA-I agonist(43). The D-I agonist activity of dihydroxy nomifensine resides in the S-enantiomer. This compound also displays an extremely weak interaction with the D-2 receptor (as modeled by the spiroperidol binding); interestingly, the D-2 receptor recognizes both the R- and S-enantiomers with approximately the same affinity. A speculative model of the D-I dopamine receptor has been developed to account for the enantiomeric selectivity of SKF 38393 and dihydroxy nomifensine (44). Selective D-I Antagonist_s SCH 23390,the 3-methyl 7-chloro analogue of SKF 38393 (Figure I), is a selective antagonist of the D-I receptor(45,46) as well as on the DA-I receptor (29,30). Both the 3-methyl and the 7-chloro substituents impart antagonist activity to SCH 23390; however, the halogen is essential for the potent antagonist activity of the molecule (47). SCH 23390 does interact with the D-2 receptor; however, its affinity for this receptor is significantly less than its affinity for the D-I receptor(45-48). SKF 83566, the 7-bromo analogue of SCH 23390, is reported to also be a selective [3-1 antagonist(49). Selective D-2 Agon ists In the past five years, drugs from several different chemical families have been shown to stimulate the D-2 but not the D-I receptor (Figure 2). The di-Nsubstituted phenethylamines, RU 24926 and RU 24213, the di-N-substituted 5hydroxy-2-aminotetralins, N-0434 and N-0437 and the partial ergoline, LY 141865, stimulate the D-2 receptor but not the D-I receptor (50-53). LY 141865 also discriminates between the DA-2 and the DA-I receptors in the cardiovascular system(54). The ability of LY 141865 and LY 171555, the (-)-isomer oE LY 141865, to selectively activate peripheral presynaptic dopamine receptors, an example of the DA-2 receptor, suggests that the D-2 and the DA-2 receptors may be the same pharmacological entity (55, 56). Seleqtive D-2 _Antagonists The antagonists do~peridone, (-)-sulpiride and YM 09151-2 (Figure 3) each block the D-2 but not the D-I receptor(57-60). Dor~oeridone and (-)-sulpiride do have a much higher affinity as a blocker on the DA-2 receptor than on the DA-I receptor in the cardiovascular syst~n; this suggests the pharmacological similarity between the D-2 and the DA-2 receptors. Binding Studies Probably no area of dopamine receptor research has created more controversy than the identification of dopamine receptors in radioligand binding assays. As noted recently(65), '~oinding studies of dopamine receptors, although easy to perform, have yielded too many data, too many categories of dopamine receptors and too many controversies". On the basis of binding data, as many as 4 distinct dopamine receptors have been identified(l,5). Only now are the classification sch~nata for DA-receptors based on binding studies beginning to be brought into agreement with classification schemata based on more conventional pharmacological techniques. Thus, it has been proposed that the D-I receptor (i.e. the dopamine receptor which when stimulated increases adenylate cyclase activity) exists in two interconvertible states differing in their affinity for agonists. In particular, Leff and Creese have suggested that "the D-3 binding (site) may, at least in part, represent a high-affinity agonist binding state of the D-I receptor"(8,66). Likewise, the D-2 and the D-4 receptors (as defined by Seeman) may be interconvertible forms of the D-2 receptor (i.e. the dopamine receptor found in the pituitary gland) (9,67,68). Not all investigators accept the v i ~ that binding data support the existence of two categories of dopamine receptor each existing in two affinity
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CH30 H O . i CH 3 I OH O ,i ,
'----' / \ CH2CH3
SO2NH 2 N-(l-benzyl-2-methyl pyrrolidin-3-yl) -5-chloro-2-methoxy-4-methyl aminobe:~zamide YM 09151-2
N-~. °
N-(~-ethyl-2-pyrrolidiny[methyl) -2-methoxy-5-sulphamoyl benzamide Sulpiride
/---k ,H O
CI 5-chlor,~-l-(l-(3-(2,3-dihydro-2-oxo-IHbenzimi~ ~zol-l-yl)-n-propyl)-4-piperidinyl)-l,3-d[hydro-2H-benzimidazol-2-one Domperidone FIG.3. Selective D-2 receptor antagonists states. For example, Laduron argues for the existence of a single dopamine receptor(2). Similarly, Schwartz and his colleagues continue to consider the existence of 3 dopamine receptors(10). In the coming years, it may be anticipated that some consensus about the significance of the dopamine receptor binding data may emerge.
PhysiC°9 %ca! Xroc_esses ! ~ u ~ a A ~ - ~ the ~ A ~_~e~oto~ The dopamine receptor upon the parenchymal cells of the bovine parathyroid gland provides the best example of a D-I receptor because this cell type manifests both biochemical and physiological responses to dopamine. Dopamine elicits the biochemical signs characteristic of D-I receptor activation (i.e. enhanced adenylate cyclase activity, increased cyclic AMP production and activation of a cyclic AMP-dependent protein kinase) as well as a physiological sign of receptor activation, an increase in the rate of release of parathyroid hormone (38,69-71). The pharmacology of this dopamine receptor has been
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extensively characterized: the receptor is stimulated by dopamine and SKF 38393, the selective D-I agonist; conversely, the receptor is blocked by neuroleptics as well as by the ergots lergotrile and lisuride(38,72). (+)-Sulpiride (but not (-)-sulpiride) is a weak antagonist of this D-I receptor; this conlplements the report by Kohli et al. that (+)-sulpiride is a weak antagonist of the DA-I receptor in vitro(73,74). The ability of SCH 23390 to block this dopamine receptor has not been examined. Retina Dopamine-sensitive adenylate cyclase activity, and by inference the D-I receptor, occurs in the retina of several manmlalian species(ll,75). However, the cellular localization and physiological consequences of stimulating any of these D-I receptors is not known. In the teleost retina, the biochemical and physiological role of dopamine is better established. In fish retina, dopamine occurs in certain amacrine cells which synapse upon the external horizontal cells (70). The external horizontal cells possess an unusually responsive dopamine-sensitive adenylate cyclase: in isolated horizontal cells, the maximal effect of dopamine is a 450-fold increase in the content of cyclic AMP(77). In cell-free homogenates of the teleost retina, dopamine increases adenylate cyclase activity 5- to 7-fold: this effect of dopamine is mimicked by SKF 38393 and blocked by SCH 23390(34,47). Conversely, LY 141865 and (-)-sulpiride are without effect in this biochemical assay system(34,53). The physiological consequences of a dopamine-induced formation of cyclic AMP (and by inference stimulation of the D-I receptor) are only beginning to be identified in the carp retina(78). Application of dopamine to carp retina will potentiate 2.8-fold the hyperpolarizing L-type S-potentials recorded from external horizontal cells; dopamine also diminishes the area of the retina from which light can elicit such a response in a given cell. In addition, dopamine restricts the migration of intracellularly injected lucifer yellow between horizontal cells. These effects of dopamine as was noted recently (78) "can be explained on the basis of an uncoupling action of dopamine at gap junctions between horizontal cells". Cyclic AMP may participate in these responses to dopamine; dibutyryl cyclic AMP together with 3-isobutyl-l-methyl xanthine mimicks the effects of dopamine. To date, the drugs discriminating between the D-I and the D-2 dopamine receptors have not been tested on these physiological parameters. Mammalian CNS In contrast to the wealth of information about the dopamine D-I receptor in the parathyroid gland and retina, substantially less is known about the D-I receptor in the mammalian CNS. Although dopamine-sensitive adenylate cyclase occurs in dopamine-containing brain regions, the type of cell (neuron?) possessing this receptor was known only in one case. In the olfactory tubercle, the enzyme (and by inference the D-I receptor) occurs upon the pyramidal cells(79,80). Recently, a d_opamine and adenosine 3':5'-monophosphate regulated p_hosphoprotein with an apparent m~lecular weight of __32,000 Daltons (DARPP-32) has been associated with the D-I (and not the D-2) dopamine receptor by biochemical and anatomical criteria(81,82). DARPP-32 is not the D-I receptor; rather it is believed to be a protein occurring in cells possessing a D-I receptor. DARPP-32 inhibits protein phosphatase activity in vitro(83).Recently Nestler and Greengard(83a) postulated that phosphorylation of DARPP-32 leads indirectly to a physiological response by regulating the state of phosphorylation of other neuronal substrate proteins. Localization of DARPP-32 in the CNS by immunocytochemistry confirmed the location of the D-I receptor upon the pyramidal cells of the olfactory tubercle and also suggested that the D-I receptor has a discrete cellular location in other regions of the brain(82). The identification of DARPP-32 and its localization within the CNS may significantly advance our understanding of the role of the D-I receptor. Although the D-I receptor in the central nervous system has been described as a "receptor in search of a function", we feel that it is appropiate to distinguish between "no function" and "no known function".
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Phys iol og ical processes r_egu_fated b~ t h e D - 2 rece~qotor_ PituitarzG!and_ The dopamine receptor in the pituitary gland may be considered the prototype of the D-2 receptor. This D-2 receptor occurs upon both the ~trophs(23,50,59,67,68,84,85) as well as the melanotrophs (21,22, 36,53,60,86,87). When tested upon mammotrophs, selective D-2 agonists inhibit prolactin release and cyclic AMP production (50,88,89). D-2 receptor antagonists block the effects of dopaminergic agonists. The D-2 receptor associated with the melanotrophs in the intermediate lobe also regulates cyclic AMP formation as well as hormone release. D-2 receptor agonists inhibit basal and stimulated cyclic AMP formation as well as basal and stimulated hormone release (21,22,36,53,60,86). Selective D-2 receptor antagonists (e.g. (-)-sulpiride or YM 09151-2) can block the effects of agonists upon the intermediate lobe D-2 receptor. The intermediate lobe of the pituitary gland is innervated by dopaminergic fibers which form synapse-like connections with the melanotrophs(90). Therefore, the D-2 receptor in the intermediate lobe provides an example of a postsynaptic ;9-2 receptor. St r iatum { _Chol iqe
~umt Dqpamiqer~g i q Neuqqqs Dopamine is a major neurotransmitter in the neostriatum. The release of dopamine from the terminals of the nigro-neostriatal dopaminergic neurons can be modulated by many substances including dopamine and dopaminergic drugs (for a review see 98,99). Under carefully selected conditions, the release of dopamine in vitro can be inhibiteJ by dopamine and D-2 receptor agonists(100-103). LY 141865 inhibits the Kor electrically evoked release of dopamine; conversely, SKF 38393 is without effect. The inhibitory effect of LY 141865 can be antagonised by (-)-sulpiride and other benzamides (103,104). Dopamine "autoreceptors" located on either the terminals or the soma and dendrites of the nigro-neostriatal dopaminergic neurons also modulate the turnover of dopamine (I05-i07). The pharmacological properties of the autoreceptor resemble those of the D-2 receptor in the pituitary gland. LY 141865 stimulates the autoreceptor both in vivo and in vitro(108). In contrast, SKF 38393 has not been reported to be active in any experimental model of these autoreceptors. In several experimental models of these autoreceptors, sulpiride is active as an antagonist(109-111). The ability of the ergots to stimulate the autoreceptor in vivo has been well established(ll2). However, to demonstrate agonist activity of these cor~pounds in vitro, particular care must be taken in the preparation of synaptosomes(ll3). In preparing this review, we encountered no suggestion that the presynaptic autoreceptor differed pharmacologically from the autoreceptors located on the soma and dendrites; indeed, Roth has argued
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that the two receptors are pharmacologically similar(ll4). Autoreceptors also regulate the electrical activity of the dopaminergic nigro-neostriatal neurons. Stimulation of the autoreceptor depresses the spontaneous electrical activity of these neurons. Neuroleptics antagonize this effect of the agonists(llS-llT). The ability of sulpiride and YM 09151-2 to block the depressing effects is compatible with the hypothesis that the autoreceptor regulating electrical activity (like the autoreceptor regulating dopamine release) is a D-2 dopamine receptor(llS-120). Dopam!ner_gi c r e g u l a t i o n _ o f b r a i q ~ t i d e ~le~s ~ I n the medio-basal hypothalamus, dopamine i n h i b i t s beth the spontaneous and the K+- evoked release of ~-endorphin(121). LY 141865 i n h i b i t s the release of ~-endorphin whereas SKF 38393 does not. This e f f e c t of LY 141865 i s blocked by (-)-sulpiride. Although these data support the conclusion that dopamine inhibits the release of 8-endorphin by stimulating a D-2 receptor, they do not clarify the location of this receptor. In the neostriatum, dopamine and the D-2 agonists RU 24926 and LY 141865 potentiate the enhanced release of cholecystokinin (CCK)-like immunoreactivity(122,123). This effect of the D-2 agonists was blocked by (-)sulpiride and domperidone. It is not clear if this D-2 effect is direct or indirect; likewise, the location of the D-2 receptor is unknown. Carotid bod Z A D-2 dopamine receptor occurs in the rabbit carotid body(124). The spontaneous chemosensory discharge from the carotid body is depressed by the D-2 agonist LY 141865, but unaffected by SKF 38393, a D-I receptor agonist. The depressant effects of either dopamine or LY 141865 were reduced by the selective D-2 antagonists don~peridone and (-)-sulpiride. These data provide strong evidence for the presence of a D-2 receptor in the rabbit carotid body.
Ce i I s [/ossessi n~[~ t h _ _D-1 And _D-2- d_o~a_mi_ne _r_ecep~qrs Striatum Dopamine can both stimulate and inhibit the formation of cyclic AMP in the neostriatum. Dopamine stimulates the efflux of cyclic AMP from slices of rat neostriatum; this is in accord with its ability to stimulate the adenylate cyclase activity in cell-free homogenates of this tissue. (-)-Sulpiride potentiates the dopamine-stimulated efflux of cyclic AMP but did not appreciably change the molar potency of dopamine(90,125). In addition, SKF 38393 also stimulates the efflux of cyclic AMP from this preparation of neostriatal tissue. (-)-Sulpiride does not potentiate this effect of SKF 38393; however, LY 141865 reduces the response to SKF 38393. These findings indicate the occurrence in the neostriatum of a D-2 receptor inhibiting cyclic AMP formation brought about by the stimulation of a D-I receptor. The D-2 receptor mediated inhibition of cyclic AMP formation can be demonstrated in the presence as well as the absence of calcium ions in the incubation medium. Since calcium ions are obligatory for the release of neurotransmitter(126), this observation suggests that neurotransmitter release does not participate in the D-2 receptor-mediated inhibition of cyclic AMP formation. Consequently, it is possible that a population of neurons in the rat neostriatum possesses both a D-I and a D-2 dopamine receptor. Invertebrates Dopamine occurs in the nervous system of many invertebrate species (for a review see 127). Physiological studies of invertebrate nervous systems indicate a multiplicity of dopamine receptors. Dopamine can excite as well as inhibit the firing of neurons in Helix aspersa(128,129) , Planorbis(130) and Aplysia
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californica(131) by stimulating pharmacologically distinct receptors. However, the drugs used in these studies were not the ones used to define the vertebrate [3-1 and D-2 receptors. A dopamine-sensitive adenylate cyclase has been demonstrated in neural tissue of Helix (132), Mytilus edulis (133) and Aplysia(134). Many neuroleptics inhibit the stimulatory effect of dopamine on cyclic AMP production. Pharmacological studies, performed with drugs discriminating between vertebrate D-I and D-2 receptors, indicate the occurrence of a D-2 receptor on the growth hormone-producing cells in the CNS of the snail Lymnaea stagnalis. Dopamine instantaneously hyperpolarizes these cells. This effect of dopamine is mimicked by LY 141865 and is markedly attenuated by (-)-sulpiride as well as by YM 09151-2. SKF 38393 fails to mimick this effect of dopamine. The hyperpolarizing effect of dopamine can be demonstrated in individually isolated growth hormone producing cells. Interestingly, a D-I receptor also occurs in the CNS of this snail. SKF 38393 (but not LY 141865) increases the excitability of the growth hormone producing cells. The stimulatory effect of SKF 38393 can be abolished by the selective D-I antagonist SCH 23390 and can be mimicked by intracellular injections of cyclic AMP(135). Dopamine (in the presence of (-)sulpiride) also increases the excitability of these cells.
Concl_qd ing_ r_e_n_n_n_nks_ ~r The intracellular events initiated by stimulation of either the D-I or the D-2 dopamine receptor are now better understood than in 1979 when the two dopamine receptor hypothesis was first put forward (see Table i). It is now clear that also the D-2 receptor can regulate adenylate cyclase: stimulation of the D-2 receptor inhibits this enzyme activity. In contrast stimulation of the D-I receptor enhances the activity of this enzyme. Likewise, the past 5 years have witnessed the development of the "first generation" of drugs selective for either the D-I or the D-2 dopamine receptors. The availability of these drugs has enabled us and many others to identify cellular processes associated with stimulation of either category of receptor. In preparing this review, it was especially interesting to note that the dopamine receptors in either the central nervous and endocrine systems or the cardiovascular system display many similarities. In addition it is interesting to observe that even (certain) invertebrate dopamine receptors appear to fall into either the D-I or the D-2 category. This observation might suggest that dopamine receptors have been preserved during the course of evolution. In this minireview, we have discussed only those cellular processes for which an association with either a D-I or a D-2 receptor has been made. We have not mentioned the effects of dopamine for which such an association has not (as yet) been made. It is tempting to anticipate that also these physiological effects of DA can be associated with the D-I(DA-I) or the D-2(DA-2) receptor. However, this might be an oversimplification since there are some reasons to believe that a further subclassification of DA-receptors cannot be ruled out completely (136). We note that the progres made in analyzing some of the consequences of stimulation of either the D-I or the D-2 receptor in the CNS could assist in understanding the behavioral effects of dopamine. The development of selective agonists and antagonists of the D-I and the D-2 dopamine receptors may facilitate such an analysis of dopaminergic behavior. It is worth noting that using these selective drugs recently, dopaminergic behaviors, like grooming and certain forms of stereotypy, have been attributed to D-I receptor stimulation (137, 138). In addition it has been reported that not only D-2 receptor
SKF 38393; SKF 82526 Dihydroxy nomifensine
- SCH 23390
-
relaxation of vascular smooth muscle in renal vessels
repetitive firing of growth hormone producing cells in CNS of Lymnaea stagnalis
bovine PTH release
.
(142)
- (-)-sulpiride; YM 09151-2; Domperidone
- RU 24926; RU 24213; N 0434; N 0437 LY 141865
- inhibition of NE release (certain peripheral sympathetic neurons)
hyperpolarization of growth hormone producing cells in CNS of Lynanaea stagnalis
inhibition of chemosensory discharge (rabbit carotid body)
inhibition of firing rate of DA-ergic neurons
inhibition of 8-endorphin release (rat hypothalamus)
- inhibition of prolactin and ~-MSH release (rat pituitary gland) - inhibition of ACh- and DA release (rat neostriatum)
- decrease in cAMP formation
D-2(=DA 2 ?) RECEPTORS
* Recently also the occurrence of D-2 receptors not linked to an adenylate cyclase has been reported
Selective antagonists
Pharmacology Selective agonists:
Physiological manifestations Receptor stimulation induces:
increase in cAMP formation
- phosphorylation of DARPP-32
-
D-I(=DA 1 ?) RECEPTORS
DOPAMINE RECEPTORS: BIOCHEMISTRY, PHYSIOLOGY AND PHARMACOLOGY
Biochemical manifestations Receptor stimulation induces:
T W O
TABLE I
ho hO
u~
rf O
CD
O
O
oo 4~
Z O
on
< o
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stimulation but also D-I receptor stimulation induces rotation in rats unilaterally injected with 6-OH-DA into the nigrostriatal pathway (139-141). It does not seem irrational to anticipate that more conloonents of dopaminergic behavior will be associated with either the D-I or the D-2 receptor or with a functional interaction between the D-I and the D-2 receptor.
References I. 2.
3. 4. 5. 6. 7.
8. 9. i0. ii. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.
23. 24. 25. 26. 27.
28. 29.
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Pergamon Press
MINIREVIHd
TWO DOPAMINE RECEL~fORS: BIOCHEMISTRY, PHYSIOLOGY AND PHARMACOLOGY. J.C. STOOF
and J.W. KEBABIAN
Department of Neurology, Medical Faculty, Free University, van der Boechorststraat 7, 1081 BT, Amsterdam, The Netherlands. Experimental Therapeutics Branch, National Institute of Neurological and Communicative Disorders and Stroke, National Institutes of Health, Bethesda, MD 20205, USA.
summarZ In 1979, two categories of dopamine (DA) receptors (designated as D-I and D-2) were identified on the basis of the ability of a limited number of agonists and antagonists to discriminate between these two entities. In the past 5 years agonists and antagonists selective for each category of receptor have been identified. Using these selective drugs it has been possible to attribute the effects of DA upon physiological and biochemical processes to the stimulation of either a D-I or a D-2 receptor. Thus, DA-induced enhancement of both hormone release from bovine parathyroid gland and firing of neurosecretory cells in the CNS of Lymnaea stagnalis has been attributed to stimulation of a D-I receptor. Likewise, the DA-induced inhibition of the release of prolactin and ~-MSH from the pituitary gland, as well as of acetylcholine, DA and 8-endorphin from brain, the DA-induced inhibition of chemo-sensory discharge in rabbit carotid body and the DA-induced hyperpolarization of neurosecretory cells in the CNS of Lymnaea stagnalis have been attributed to stimulation of a D-2 receptor. Independently two categories of DA receptors (designated as DA-I and DA-2) were identified in the cardiovascular system. Stimulation of a DA-I receptor increases the vascular cyclic AMP content and causes a relaxation of vascular smooth n~scle in renal blood vessels, whereas stimulation of a DA-2 receptor inhibits the release of norepinephrine from certain postganglionic sympathetic neurons. Recent studies with the newly developed drugs discriminating between D-I and D-2 receptors suggest however that the independently developed schemata for classification of dopamine receptors in either the central nervous and endocrine systems or the cardiovascular system are similar although maybe not completely identical. During the past 5 years, the existence of multiple categories of dopamine receptors has been debated by different research groups (1-7). Different investigators identified as few as one(2) or as many as four(l,5) distinct receptors for dopamine. A consensus about the number of dopamine receptors and their pharmacological properties is beginning to be reached (8,9); however, controversies still remain(10). In this review, we espouse the hypothesis currently accepted by most investigators that two distinct categories of dopamine receptors can be identified by biochemical as well as pharmacological criteria(4,7). Subsequently, we will discuss physiological processes regulated by either category of dopamine receptor. However, at the beginning of this discussion, it seems appropriate to review the biochemical and pharmacological 0024-3205/84 $3.00 + .00 Copyright (c) 1984 Pergamon Press Ltd.
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studies performed in neural, endocrine, renovascular and cardiovascular supporting the existence of two categories of dopamine receptors.
tissues
The concept that there are two categories of dopamine receptors arose from biochemical investigations. In the early 1970's, the ability of dopamine to stimulate adenylate cyclase activity in neural tissues was demonstrated in several laboratories(ll-13). Many dopaminergic agonists and antagonists displayed appropriate effects in this biochemical model of a dopamine receptor(14-16). However, several dopaminergic ergots displayed inappropriate activity in the biochemical assay system. Although these ergots stimulated dopamine receptors in the pituitary gland and were, therefore, anticipated to mimic the stimulatory effect of dopamine upon adenylate cyclase activity, these co~pounds blocked the ability of dopamine to increase adenylate cyclase activity in neural tissue(17,18). To account for this discrepancy, it was proposed that the dopamine receptor capable of stimulating adenylate cyclase (the D-I receptor) was a distinct entity from the dopamine receptor in the pituitary gland (the D-2 receptor) (4,7,19,20). FUrthermore, it was proposed that the physiological effect(s) of dopamine upon the D-I receptor were the consequence of increased cyclic AMP production while the physiological effects of dopamine upon the D-2 receptor were not associated with the stimulated formation of cyclic AMP(4). Subsequent studies with normal and pathologic pituitary tissue have shown that stimulation of the D-2 receptor inhibits adenylate cyclase activity(21-24). Biochemical and pharmacological studies oE the renovascular and cardiovascular system also suggested the existence of two dopamine receptors(6). Following extensive studies of the dopamine receptors in the renovascular and cardiovascular system, two dopamine receptors, designated as the DA-I and the DA-2 receptors were identified. Stimulation of the DA-I receptor causes an increase in vascular cyclic AMP content (for a review see 25) and a relaxation of vascular smooth muscle in renal blood vessels(6). Stimulation of the DA-2 receptor inhibits the stimulated release of norepinephrine from terminals of certain postganglionic sympathetic neurons ( f o r reviews see 26 and 27); stimulation of this receptor has not been reported to increase cyclic AMP formation. In their initial classification schema, Goldberg and Kohli noted differences between the pharmacology of the D-I and the DA-I receptor as well as the D-2 and the DA-2 receptor(6,28). Although these differences remain, the development of selective dopaminergic drugs (see below) and their application to the renovascular and the cardiovascular system has pointed to extensive similarities between the D-I and DA-I receptors as well as the D-2 and the DA-2 receptors(26,29,30). In view of the extensive discussion of the cardiovascular dopamine receptors in other minireviews and elsewhere(25-27,31,32), an elaborate discussion of these receptors will not be attempted.
Phar_maco_logical ~pro_0~rties- o ~ the two dopamine recejp_tors The existence of two dopamine receptors has been supported by the identification of agonists and antagonists selective for either of these receptors. The availability of these relatively selective con~pounds testifies to the progress which has occurred in the past five years. However, the con~oounds discussed in this section represent only the "first generation" of selective dopaminergic agonists and antagonists; future investigations will surely identify compounds combining higher affinity with greater selectivity. These second and third generation co~pounds may be useful as therapeutic agents. Likewise, it seems reasonable to anticipate that the insight obtained from the structure activity relationship at either the D-I or the D-2 receptor will lead to the development of novel research tools facilitating the scientific investigation of these receptors.
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Selective D-I Agonists At present the most selective D-I agonist is SKF 38393 (Figure I). In the dopamine-sensitive adenylate cyclase assay system, SKF 38393 mimicks the ability of dopamine to stimulate adenylate cyclase activity(33,34). In this biochemical model of the D-I receptor, SKF 38393 displays a higher affinity than does dopamine; however, unlike dopamine SKF 38393 is only a partial agonist. Likewise, SKF 38393 stimulates the renal DA-I receptor(6). Because SKF 38393 does not inhibit prolactin release, it is presumed not to stimulate the D-2 receptor(33). However, in biochemical models of the D-2 receptor, SKF 38393 in higher concentrations does interact with this receptor(35,36). The reason for this discrepancy between the [ physiological and biochemical data is not immediately evident. The D-I agonist activity of SKF 38393 resides in the Renantiomer; the S-enantiomer is significantly less potent as a D-I agonist(37). This observation complements previous demonstrations of the stereoselectivity of the D-I receptor(15,38).
CI
HOrN
H
2,3,4,5-tetrahydro-7,8dihydroxy-l-phenyl-IH-3benzazepine SKF 38393
HO'~~"~N
H
6-chloro-2,3,4,5-tetrahydro-7,8dihydroxy-l-(4-hydroxy phenyl)-IH3-benzazeplne SKF 82526
NH2
OH
8-amino-l,2,3,4-tetrahydro4-(3,4-dihydroxyphenyl)-2methyl-isoqu[noline Di hyd
roxynomi fen:~ i n e
7-chloro-2,3,4,5-tetrahydro-3-methyl 5-phenyl-IH-3-benzazepine-7-ol SCH 23390
FIG. I. Selective D-I receptor agonists and antagonist
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SKF 82526 (Figure i) is another agonist discriminating between the D-I and the D-2 dopamine receptors in physiological models(39). However,in biochemical models of the D-2 receptor, this conloound is also active (35). This compound, under the trade name fenoldopam, is currently undergoing clinical trials as an antihypertensive drug (40).
N-n-propyl di-~(3-hydroxy phenyl)ethylamine
N-n-propyl-N-phenylethy]-p(3hydroxy phenyl) ethylamine
RU 24926
RU 24213
OH
OH !
I
CIH2
5-hydroxy-2(N-n-propyl-N-2phenylethyl)-aminotetraline N 0434
~NCH2CH2CH3
4,4a,5,6,7,8,8a,9-octahydro5-n-propyl-2H-pyrazolo-3,4-g quinoline LY 141865 FIG. 2. Selective D-2 receptor agonists
~H2
5-hydroxy-2(N-n-propyl-N-2thienylethyl)-aminotetraline N 0437
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Two Dopamine Receptors
2285
Dihydroxy nomifensine (Figure i) is another selective D-I agonist. This compound stimulates the dopamine-sensitive adenylate cyclase(41) and causes vasodilatation of renal blood vessels in the dog(42). The 8-deamino analogue of this compound is equipotent with the parent cor~pound as a DA-I agonist(43). The D-I agonist activity of dihydroxy nomifensine resides in the S-enantiomer. This compound also displays an extremely weak interaction with the D-2 receptor (as modeled by the spiroperidol binding); interestingly, the D-2 receptor recognizes both the R- and S-enantiomers with approximately the same affinity. A speculative model of the D-I dopamine receptor has been developed to account for the enantiomeric selectivity of SKF 38393 and dihydroxy nomifensine (44). Selective D-I Antagonist_s SCH 23390,the 3-methyl 7-chloro analogue of SKF 38393 (Figure I), is a selective antagonist of the D-I receptor(45,46) as well as on the DA-I receptor (29,30). Both the 3-methyl and the 7-chloro substituents impart antagonist activity to SCH 23390; however, the halogen is essential for the potent antagonist activity of the molecule (47). SCH 23390 does interact with the D-2 receptor; however, its affinity for this receptor is significantly less than its affinity for the D-I receptor(45-48). SKF 83566, the 7-bromo analogue of SCH 23390, is reported to also be a selective [3-1 antagonist(49). Selective D-2 Agon ists In the past five years, drugs from several different chemical families have been shown to stimulate the D-2 but not the D-I receptor (Figure 2). The di-Nsubstituted phenethylamines, RU 24926 and RU 24213, the di-N-substituted 5hydroxy-2-aminotetralins, N-0434 and N-0437 and the partial ergoline, LY 141865, stimulate the D-2 receptor but not the D-I receptor (50-53). LY 141865 also discriminates between the DA-2 and the DA-I receptors in the cardiovascular system(54). The ability of LY 141865 and LY 171555, the (-)-isomer oE LY 141865, to selectively activate peripheral presynaptic dopamine receptors, an example of the DA-2 receptor, suggests that the D-2 and the DA-2 receptors may be the same pharmacological entity (55, 56). Seleqtive D-2 _Antagonists The antagonists do~peridone, (-)-sulpiride and YM 09151-2 (Figure 3) each block the D-2 but not the D-I receptor(57-60). Dor~oeridone and (-)-sulpiride do have a much higher affinity as a blocker on the DA-2 receptor than on the DA-I receptor in the cardiovascular syst~n; this suggests the pharmacological similarity between the D-2 and the DA-2 receptors. Binding Studies Probably no area of dopamine receptor research has created more controversy than the identification of dopamine receptors in radioligand binding assays. As noted recently(65), '~oinding studies of dopamine receptors, although easy to perform, have yielded too many data, too many categories of dopamine receptors and too many controversies". On the basis of binding data, as many as 4 distinct dopamine receptors have been identified(l,5). Only now are the classification sch~nata for DA-receptors based on binding studies beginning to be brought into agreement with classification schemata based on more conventional pharmacological techniques. Thus, it has been proposed that the D-I receptor (i.e. the dopamine receptor which when stimulated increases adenylate cyclase activity) exists in two interconvertible states differing in their affinity for agonists. In particular, Leff and Creese have suggested that "the D-3 binding (site) may, at least in part, represent a high-affinity agonist binding state of the D-I receptor"(8,66). Likewise, the D-2 and the D-4 receptors (as defined by Seeman) may be interconvertible forms of the D-2 receptor (i.e. the dopamine receptor found in the pituitary gland) (9,67,68). Not all investigators accept the v i ~ that binding data support the existence of two categories of dopamine receptor each existing in two affinity
2286
Two Dopamine Receptors
Vol. 35, No. 23, 1984
CH30 H O . i CH 3 I OH O ,i ,
'----' / \ CH2CH3
SO2NH 2 N-(l-benzyl-2-methyl pyrrolidin-3-yl) -5-chloro-2-methoxy-4-methyl aminobe:~zamide YM 09151-2
N-~. °
N-(~-ethyl-2-pyrrolidiny[methyl) -2-methoxy-5-sulphamoyl benzamide Sulpiride
/---k ,H O
CI 5-chlor,~-l-(l-(3-(2,3-dihydro-2-oxo-IHbenzimi~ ~zol-l-yl)-n-propyl)-4-piperidinyl)-l,3-d[hydro-2H-benzimidazol-2-one Domperidone FIG.3. Selective D-2 receptor antagonists states. For example, Laduron argues for the existence of a single dopamine receptor(2). Similarly, Schwartz and his colleagues continue to consider the existence of 3 dopamine receptors(10). In the coming years, it may be anticipated that some consensus about the significance of the dopamine receptor binding data may emerge.
PhysiC°9 %ca! Xroc_esses ! ~ u ~ a A ~ - ~ the ~ A ~_~e~oto~ The dopamine receptor upon the parenchymal cells of the bovine parathyroid gland provides the best example of a D-I receptor because this cell type manifests both biochemical and physiological responses to dopamine. Dopamine elicits the biochemical signs characteristic of D-I receptor activation (i.e. enhanced adenylate cyclase activity, increased cyclic AMP production and activation of a cyclic AMP-dependent protein kinase) as well as a physiological sign of receptor activation, an increase in the rate of release of parathyroid hormone (38,69-71). The pharmacology of this dopamine receptor has been
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Two Dopamine Receptors
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extensively characterized: the receptor is stimulated by dopamine and SKF 38393, the selective D-I agonist; conversely, the receptor is blocked by neuroleptics as well as by the ergots lergotrile and lisuride(38,72). (+)-Sulpiride (but not (-)-sulpiride) is a weak antagonist of this D-I receptor; this conlplements the report by Kohli et al. that (+)-sulpiride is a weak antagonist of the DA-I receptor in vitro(73,74). The ability of SCH 23390 to block this dopamine receptor has not been examined. Retina Dopamine-sensitive adenylate cyclase activity, and by inference the D-I receptor, occurs in the retina of several manmlalian species(ll,75). However, the cellular localization and physiological consequences of stimulating any of these D-I receptors is not known. In the teleost retina, the biochemical and physiological role of dopamine is better established. In fish retina, dopamine occurs in certain amacrine cells which synapse upon the external horizontal cells (70). The external horizontal cells possess an unusually responsive dopamine-sensitive adenylate cyclase: in isolated horizontal cells, the maximal effect of dopamine is a 450-fold increase in the content of cyclic AMP(77). In cell-free homogenates of the teleost retina, dopamine increases adenylate cyclase activity 5- to 7-fold: this effect of dopamine is mimicked by SKF 38393 and blocked by SCH 23390(34,47). Conversely, LY 141865 and (-)-sulpiride are without effect in this biochemical assay system(34,53). The physiological consequences of a dopamine-induced formation of cyclic AMP (and by inference stimulation of the D-I receptor) are only beginning to be identified in the carp retina(78). Application of dopamine to carp retina will potentiate 2.8-fold the hyperpolarizing L-type S-potentials recorded from external horizontal cells; dopamine also diminishes the area of the retina from which light can elicit such a response in a given cell. In addition, dopamine restricts the migration of intracellularly injected lucifer yellow between horizontal cells. These effects of dopamine as was noted recently (78) "can be explained on the basis of an uncoupling action of dopamine at gap junctions between horizontal cells". Cyclic AMP may participate in these responses to dopamine; dibutyryl cyclic AMP together with 3-isobutyl-l-methyl xanthine mimicks the effects of dopamine. To date, the drugs discriminating between the D-I and the D-2 dopamine receptors have not been tested on these physiological parameters. Mammalian CNS In contrast to the wealth of information about the dopamine D-I receptor in the parathyroid gland and retina, substantially less is known about the D-I receptor in the mammalian CNS. Although dopamine-sensitive adenylate cyclase occurs in dopamine-containing brain regions, the type of cell (neuron?) possessing this receptor was known only in one case. In the olfactory tubercle, the enzyme (and by inference the D-I receptor) occurs upon the pyramidal cells(79,80). Recently, a d_opamine and adenosine 3':5'-monophosphate regulated p_hosphoprotein with an apparent m~lecular weight of __32,000 Daltons (DARPP-32) has been associated with the D-I (and not the D-2) dopamine receptor by biochemical and anatomical criteria(81,82). DARPP-32 is not the D-I receptor; rather it is believed to be a protein occurring in cells possessing a D-I receptor. DARPP-32 inhibits protein phosphatase activity in vitro(83).Recently Nestler and Greengard(83a) postulated that phosphorylation of DARPP-32 leads indirectly to a physiological response by regulating the state of phosphorylation of other neuronal substrate proteins. Localization of DARPP-32 in the CNS by immunocytochemistry confirmed the location of the D-I receptor upon the pyramidal cells of the olfactory tubercle and also suggested that the D-I receptor has a discrete cellular location in other regions of the brain(82). The identification of DARPP-32 and its localization within the CNS may significantly advance our understanding of the role of the D-I receptor. Although the D-I receptor in the central nervous system has been described as a "receptor in search of a function", we feel that it is appropiate to distinguish between "no function" and "no known function".
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Phys iol og ical processes r_egu_fated b~ t h e D - 2 rece~qotor_ PituitarzG!and_ The dopamine receptor in the pituitary gland may be considered the prototype of the D-2 receptor. This D-2 receptor occurs upon both the ~trophs(23,50,59,67,68,84,85) as well as the melanotrophs (21,22, 36,53,60,86,87). When tested upon mammotrophs, selective D-2 agonists inhibit prolactin release and cyclic AMP production (50,88,89). D-2 receptor antagonists block the effects of dopaminergic agonists. The D-2 receptor associated with the melanotrophs in the intermediate lobe also regulates cyclic AMP formation as well as hormone release. D-2 receptor agonists inhibit basal and stimulated cyclic AMP formation as well as basal and stimulated hormone release (21,22,36,53,60,86). Selective D-2 receptor antagonists (e.g. (-)-sulpiride or YM 09151-2) can block the effects of agonists upon the intermediate lobe D-2 receptor. The intermediate lobe of the pituitary gland is innervated by dopaminergic fibers which form synapse-like connections with the melanotrophs(90). Therefore, the D-2 receptor in the intermediate lobe provides an example of a postsynaptic ;9-2 receptor. St r iatum { _Chol iqe
~umt Dqpamiqer~g i q Neuqqqs Dopamine is a major neurotransmitter in the neostriatum. The release of dopamine from the terminals of the nigro-neostriatal dopaminergic neurons can be modulated by many substances including dopamine and dopaminergic drugs (for a review see 98,99). Under carefully selected conditions, the release of dopamine in vitro can be inhibiteJ by dopamine and D-2 receptor agonists(100-103). LY 141865 inhibits the Kor electrically evoked release of dopamine; conversely, SKF 38393 is without effect. The inhibitory effect of LY 141865 can be antagonised by (-)-sulpiride and other benzamides (103,104). Dopamine "autoreceptors" located on either the terminals or the soma and dendrites of the nigro-neostriatal dopaminergic neurons also modulate the turnover of dopamine (I05-i07). The pharmacological properties of the autoreceptor resemble those of the D-2 receptor in the pituitary gland. LY 141865 stimulates the autoreceptor both in vivo and in vitro(108). In contrast, SKF 38393 has not been reported to be active in any experimental model of these autoreceptors. In several experimental models of these autoreceptors, sulpiride is active as an antagonist(109-111). The ability of the ergots to stimulate the autoreceptor in vivo has been well established(ll2). However, to demonstrate agonist activity of these cor~pounds in vitro, particular care must be taken in the preparation of synaptosomes(ll3). In preparing this review, we encountered no suggestion that the presynaptic autoreceptor differed pharmacologically from the autoreceptors located on the soma and dendrites; indeed, Roth has argued
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that the two receptors are pharmacologically similar(ll4). Autoreceptors also regulate the electrical activity of the dopaminergic nigro-neostriatal neurons. Stimulation of the autoreceptor depresses the spontaneous electrical activity of these neurons. Neuroleptics antagonize this effect of the agonists(llS-llT). The ability of sulpiride and YM 09151-2 to block the depressing effects is compatible with the hypothesis that the autoreceptor regulating electrical activity (like the autoreceptor regulating dopamine release) is a D-2 dopamine receptor(llS-120). Dopam!ner_gi c r e g u l a t i o n _ o f b r a i q ~ t i d e ~le~s ~ I n the medio-basal hypothalamus, dopamine i n h i b i t s beth the spontaneous and the K+- evoked release of ~-endorphin(121). LY 141865 i n h i b i t s the release of ~-endorphin whereas SKF 38393 does not. This e f f e c t of LY 141865 i s blocked by (-)-sulpiride. Although these data support the conclusion that dopamine inhibits the release of 8-endorphin by stimulating a D-2 receptor, they do not clarify the location of this receptor. In the neostriatum, dopamine and the D-2 agonists RU 24926 and LY 141865 potentiate the enhanced release of cholecystokinin (CCK)-like immunoreactivity(122,123). This effect of the D-2 agonists was blocked by (-)sulpiride and domperidone. It is not clear if this D-2 effect is direct or indirect; likewise, the location of the D-2 receptor is unknown. Carotid bod Z A D-2 dopamine receptor occurs in the rabbit carotid body(124). The spontaneous chemosensory discharge from the carotid body is depressed by the D-2 agonist LY 141865, but unaffected by SKF 38393, a D-I receptor agonist. The depressant effects of either dopamine or LY 141865 were reduced by the selective D-2 antagonists don~peridone and (-)-sulpiride. These data provide strong evidence for the presence of a D-2 receptor in the rabbit carotid body.
Ce i I s [/ossessi n~[~ t h _ _D-1 And _D-2- d_o~a_mi_ne _r_ecep~qrs Striatum Dopamine can both stimulate and inhibit the formation of cyclic AMP in the neostriatum. Dopamine stimulates the efflux of cyclic AMP from slices of rat neostriatum; this is in accord with its ability to stimulate the adenylate cyclase activity in cell-free homogenates of this tissue. (-)-Sulpiride potentiates the dopamine-stimulated efflux of cyclic AMP but did not appreciably change the molar potency of dopamine(90,125). In addition, SKF 38393 also stimulates the efflux of cyclic AMP from this preparation of neostriatal tissue. (-)-Sulpiride does not potentiate this effect of SKF 38393; however, LY 141865 reduces the response to SKF 38393. These findings indicate the occurrence in the neostriatum of a D-2 receptor inhibiting cyclic AMP formation brought about by the stimulation of a D-I receptor. The D-2 receptor mediated inhibition of cyclic AMP formation can be demonstrated in the presence as well as the absence of calcium ions in the incubation medium. Since calcium ions are obligatory for the release of neurotransmitter(126), this observation suggests that neurotransmitter release does not participate in the D-2 receptor-mediated inhibition of cyclic AMP formation. Consequently, it is possible that a population of neurons in the rat neostriatum possesses both a D-I and a D-2 dopamine receptor. Invertebrates Dopamine occurs in the nervous system of many invertebrate species (for a review see 127). Physiological studies of invertebrate nervous systems indicate a multiplicity of dopamine receptors. Dopamine can excite as well as inhibit the firing of neurons in Helix aspersa(128,129) , Planorbis(130) and Aplysia
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Vol. 35, No. 23, 1984
californica(131) by stimulating pharmacologically distinct receptors. However, the drugs used in these studies were not the ones used to define the vertebrate [3-1 and D-2 receptors. A dopamine-sensitive adenylate cyclase has been demonstrated in neural tissue of Helix (132), Mytilus edulis (133) and Aplysia(134). Many neuroleptics inhibit the stimulatory effect of dopamine on cyclic AMP production. Pharmacological studies, performed with drugs discriminating between vertebrate D-I and D-2 receptors, indicate the occurrence of a D-2 receptor on the growth hormone-producing cells in the CNS of the snail Lymnaea stagnalis. Dopamine instantaneously hyperpolarizes these cells. This effect of dopamine is mimicked by LY 141865 and is markedly attenuated by (-)-sulpiride as well as by YM 09151-2. SKF 38393 fails to mimick this effect of dopamine. The hyperpolarizing effect of dopamine can be demonstrated in individually isolated growth hormone producing cells. Interestingly, a D-I receptor also occurs in the CNS of this snail. SKF 38393 (but not LY 141865) increases the excitability of the growth hormone producing cells. The stimulatory effect of SKF 38393 can be abolished by the selective D-I antagonist SCH 23390 and can be mimicked by intracellular injections of cyclic AMP(135). Dopamine (in the presence of (-)sulpiride) also increases the excitability of these cells.
Concl_qd ing_ r_e_n_n_n_nks_ ~r The intracellular events initiated by stimulation of either the D-I or the D-2 dopamine receptor are now better understood than in 1979 when the two dopamine receptor hypothesis was first put forward (see Table i). It is now clear that also the D-2 receptor can regulate adenylate cyclase: stimulation of the D-2 receptor inhibits this enzyme activity. In contrast stimulation of the D-I receptor enhances the activity of this enzyme. Likewise, the past 5 years have witnessed the development of the "first generation" of drugs selective for either the D-I or the D-2 dopamine receptors. The availability of these drugs has enabled us and many others to identify cellular processes associated with stimulation of either category of receptor. In preparing this review, it was especially interesting to note that the dopamine receptors in either the central nervous and endocrine systems or the cardiovascular system display many similarities. In addition it is interesting to observe that even (certain) invertebrate dopamine receptors appear to fall into either the D-I or the D-2 category. This observation might suggest that dopamine receptors have been preserved during the course of evolution. In this minireview, we have discussed only those cellular processes for which an association with either a D-I or a D-2 receptor has been made. We have not mentioned the effects of dopamine for which such an association has not (as yet) been made. It is tempting to anticipate that also these physiological effects of DA can be associated with the D-I(DA-I) or the D-2(DA-2) receptor. However, this might be an oversimplification since there are some reasons to believe that a further subclassification of DA-receptors cannot be ruled out completely (136). We note that the progres made in analyzing some of the consequences of stimulation of either the D-I or the D-2 receptor in the CNS could assist in understanding the behavioral effects of dopamine. The development of selective agonists and antagonists of the D-I and the D-2 dopamine receptors may facilitate such an analysis of dopaminergic behavior. It is worth noting that using these selective drugs recently, dopaminergic behaviors, like grooming and certain forms of stereotypy, have been attributed to D-I receptor stimulation (137, 138). In addition it has been reported that not only D-2 receptor
SKF 38393; SKF 82526 Dihydroxy nomifensine
- SCH 23390
-
relaxation of vascular smooth muscle in renal vessels
repetitive firing of growth hormone producing cells in CNS of Lymnaea stagnalis
bovine PTH release
.
(142)
- (-)-sulpiride; YM 09151-2; Domperidone
- RU 24926; RU 24213; N 0434; N 0437 LY 141865
- inhibition of NE release (certain peripheral sympathetic neurons)
hyperpolarization of growth hormone producing cells in CNS of Lynanaea stagnalis
inhibition of chemosensory discharge (rabbit carotid body)
inhibition of firing rate of DA-ergic neurons
inhibition of 8-endorphin release (rat hypothalamus)
- inhibition of prolactin and ~-MSH release (rat pituitary gland) - inhibition of ACh- and DA release (rat neostriatum)
- decrease in cAMP formation
D-2(=DA 2 ?) RECEPTORS
* Recently also the occurrence of D-2 receptors not linked to an adenylate cyclase has been reported
Selective antagonists
Pharmacology Selective agonists:
Physiological manifestations Receptor stimulation induces:
increase in cAMP formation
- phosphorylation of DARPP-32
-
D-I(=DA 1 ?) RECEPTORS
DOPAMINE RECEPTORS: BIOCHEMISTRY, PHYSIOLOGY AND PHARMACOLOGY
Biochemical manifestations Receptor stimulation induces:
T W O
TABLE I
ho hO
u~
rf O
CD
O
O
oo 4~
Z O
on
< o
2292
Two Dopamine Receptors
Vol. 35, No. 23, 1984
stimulation but also D-I receptor stimulation induces rotation in rats unilaterally injected with 6-OH-DA into the nigrostriatal pathway (139-141). It does not seem irrational to anticipate that more conloonents of dopaminergic behavior will be associated with either the D-I or the D-2 receptor or with a functional interaction between the D-I and the D-2 receptor.
References I. 2.
3. 4. 5. 6. 7.
8. 9. i0. ii. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.
23. 24. 25. 26. 27.
28. 29.
P. SEEMAN, Pharmacol. Rev. 32 229-313 (1980). P.M. LADURON, Dopamine Rece]~tors, J.W. Kebabian and C. Kaiser (Eds.), Amer. Chem. Soc. Synlo. Series 224, American Chemical Society Press, Washington D.C., pp. 22-28 (1983). I. CREESE, D.R. SIBLEY, M.W. HAMBLIN and S.E. LEFF, Annu. Rev. Neurosci. 6 43-71 (1983). J.W. KEBABIAN and D.B. CALNE, Nature 277 93-96 (1979). P. SOKOLOFF, M.P. MARTRES and J.C. SCHWARTZ, Naunyn-Schmiedberg's Arch. Pharmacol. 315 89-102 (1980). L.I. GOLDBERG and J.D. KOHLI, Trends Pharmacol. Sci. 4 64-66 (1983). P.F. SPANO, L. FRATTOLA, S. GOVONI, G.C. TONON- and M. TRABUCCHI, Dopaminergic Ergot Derivatives and Motor Function, Wenner-Gren Center International Symposium Series, 31, K. Fuxe and D.B. Calne (Eds.), Pergamon Press, Oxford, pp. 159-171 (1979). S.E. LEFF and I. CREESE, Trends Pharmacol. Sci. 4 463-467 (1983). D. GRIGORIADIS and P. SEEMAN, Can. J. Neurol.-Sci. ii (Suppl. i) 108-113 (1984). M.P. MARTRES, P. SOKOLOFF and J.C. SCHWARTZ, Naunyn-Schmiedberg's Arch. Pharmacol. 325 116-123 (1984). J.H. BROWN and M. MAKMAN, Proc. Natl. Acad. Sci. (USA) 69 539-543 (1972). J.W. KEBABIAN and P. GREENGARD, Science 174 1346-1349 (1971). J.W. KEBABIAN, G.L. PETZOLD and P. GREENGARD, Proc. Natl. Acad. Sci. (USA) 69 2145-2149 (1972). Y.C. CLEMENT-CORMIER, J.W. KEBABIAN, G.L. PETZOLD and P. GREENGARD, Proc. Natl. Acad. Sci. (USA) 71 1113-1117 (1974). R.J. MILLER, A.S. HORN and L.L. IVERSEN, Molec. Pharmacol. i0 759-766 (1974). L.L. IVERSEN, Science 188 1084-1089 (1975). J.W. KEBABIAN, D.B. CALNE and P.R. KEBABIAN, Com,~/n. Psychopharmacol. 1 311-318 (1977). L. PIERI, H.H. KELLER, W. BURKARD and M. DA PRADA, Nature 272 278-280 (1978). J.W. KEBABIAN, Adv. Biochem. Psychopharmacol. 19 131-154 (1978). P.F. SPANO, S. GOVONI and M. TRABUCCHI, Adv. Biochem. Psychopharmacol. 19 155-165 (1978). T.E. COTE, R.L. ESKAY, E.A. FREY, C.W. GREWE, M. MUNEMURA, J.C. STOOF and K. TSURUTA, Neuroendocrinology 35 217-224 (1982). F. LABRIE, H. MEUNIER, M. GODBOUT, R. VEILLEUX, V. GIGUERE, L. PROULXFERLAND, T. DIPAOLO and V. RAYMOND, Dopamine Receptors, J.W. Kebabian and C. Kaiser (Eds.), Amer. Chem. Soc. Synp. Series 224, American Chemical Society Press, Washington D.C. pp. 53-72 (1983). P. ONALI, J.P. SCHWARTZ and E. COSTA, Proc. Natl. Acad. Sci. (USA) 78 65316534 (1981). P. DECAMILLI, D. MACCONI and A. SPADA, Nature 278 252-254 (1979). O.E. BRODDE, Life Sci. 31 289-306 (1982). I. CAVERO, R. MASSINGHAM and F. LEFEVRE-BORG, Life Sci. 31 939-948 (1982). S.Z. LANGER and M.L. DUBOCOVICH, Peripheral Dopaminergic Rece]~tors, Adv. Biosci. 20 J.L. Imbs and J. Schwartz (Eds.), Pergamon Press, Oxford, pp. 223-245 (1979). L.I. GOLDBERG and J.D. KOHLI, Cor~un. Psychopharmacol. 3 447-456 (1979). L. I. GOLDBERG, D. GLOCK, J.D. KOHL I and A. BARNETT, Hyper tens ion 6
Vol. 35, No. 23, 1984
30.
31. 32. 33. 34. 35. 36. 37.
38.
39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58.
59.
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