research he French weekly magazine Le ouvel Observateur normally specializes in politics and the arts, so imagine my surprise when I opened the edition for 13/19 September 1990 and found a detailed article about dopamine, dopamine receptors and psychosis. The recent discovery of a novel, pharmacologically distinct dopamine receptor (termed the D3 receptor) had prompted the writhag of this article. The D3 receptor was discovered, by the use of molecular biology techniques, by the group in Paris led by JeanCharles Schwartz and Pierre Sokoloff1. The most exciting facet of this work was the preferential localization of the D3 dopamine receptor in certain limbic areas of brain; this might be important for antipsychotic (neuroleptic) drug action. This publication followed closely behind four reports of the isolation and expression of clones for human and rat D1 dopamine receptors 2-5. These discoveries have important implications for both basic and clinical neuroscience. In the 1980s, biochemical, physiological and pharmacological studies had virtually reached a consensus that there were two classes of dopamine receptor (D1 and De). However, in 1988 and 1989, two forms of the Dz dopamine receptor (D2(short) and D2dong)) were identified by gene cloning and shown to be derived from alternative splicing of a common gene (reviewed in Ref. 6). The new D3 receptor clone was isolated by the screening of rat brain cDNA and genomic libraries, and a combination of reverse transcription and use of the polymerase chain reaction (PCR) 1. The D1 receptor clones were isolated by the use of library screening and PCR analysis 2-5.
Interestingtimesfor dopaminereceptors tors. Each receptor shows consensus sites for glycosylation in the amino-terminal region (predicted extracellular), a potential palmitoylation site in the predicted intracellular carboxy-terminal section and consensus sequences for phosphorylation by protein kinases in the third predicted intracellular loop. Certain amino acids, highly conserved in cationic amine receptors 6, and thought to be important for ligand binding, are found in each doparnine receptor. These include an aspartic acid residue in the third predicted transmembrane region and two serine residues in the frith predicted transmembrane region with the aspartate probably forming an electrostatic interaction with the cationic amine group, and the serines hydrogen-bonding to the catechol moiety. The overall organization of the receptors and their genes groups the De and D3 receptors closer together and separates them from the D1 receptor. The De and D3 receptor proteins have long third intracellular loops and short carboxy-terminal tails, whereas in the D1 receptor the third intraceIlular loop is short and the carboxy-terminal tail is long. This latter arrangement is very similar to that for the 132adrenergic receptor and might reflect interaction with the G protein Gs. These are some of the key points that emerge from a comparison of the different dopamine receptors. Next, the D~ and D3 dopamine receptors will be considered separately.
used in reading the nucleic acid sequence; this is because there are two potential translational start sites in the human gene and three in the rat gene. Therefore, the different sizes reported result from the use of different translational start sites so that the precise size of the expressed D1 receptor protein is not clear. An intriguing possibility is that receptor isoforms of different sizes might be produced using the different start codons (D. Sibley, pers. commun.). In Table I a 446 an~no acid protein has been assumed for clarity, but this needs to be defined rigorously. In support of the identity of the different cloned receptor sequences, they exhibit essentially identical pharmacological properties consistent with a D1 receptor when they are expressed in animal cells, and also show dopamine stimulation of adenylate cyclasez-5. There are, however, some indications that this might not be the only D1 receptor, since D] dopamine receptors have been shown to stimulate phospholipase C rather than adenylate cyclase in some systems - suggesting the existence of another receptor subtype 7. In the present cloning reports, extra bands were seen on Southern blots that were hybridized at low stringency; this suggests the presence of additional D] receptor genes. Also, mRNA corresponding to the present D~ receptor gene was not detected in heart and kidney, which are tissues known functionally to contain D1 receptors. Therefore, additional D1 receptor clones are expected to be identified and might provide D1 dopamine receptor important targets for drug design. Whereas three of the reports of It is worthwhile remembering that, the cloning of the D1 dopamine although at one time the dopaminereceptor suggest a 446 amino acid sensitive adenylate cyclase (Dl Comparison of D1, D2 and D3 dopamine receptors protein z-4, one report suggests a dopamine receptor) was dismissed Table I summarizes some of the 487 amino acid protein s. Com- as an enzyme of no relevance to key properties of the different parison of the rat sequences 3'5 receptors s, it has now been cloned receptors. The proteins are all shows that, apart from a 41 amino and a D~ receptor selective comquite similar in size with D2(shom acid amino-terminal extension in pound, SCH 39166, is in clinical being the smallest, and the amino the 487 amino acid sequence, the trials as an antipsychotic9. acid sequences, when subjected to two proteins are virtually identical. hydropathy analysis, show the It seems that the two sequences D3 dopamine receptor motif of seven hydrophobic (pre- are derived from the same gene The characteristics of the D3 sumed transmembrane) regions but that there is some uncertainty dopamine receptor are quite novel. typical of G protein-linked recep- over which start codon should be It has a different anatomical TINS, Vol. 14, No, 2, 1991
news
© 1991, Elsevier Science PublishersLtd. (UK) 0166-
2236/91/$02.00
Philip G. Strange BiologicalLaboratory, TheUniversity, CanterburyCT27NJ, UK.
43
TABLE I. Comparison of dopamine receptor subtypes
receptor failed to inhibit adenylate cyclase under circumstances in which the D2 receptor did inhibit it. Amino acids Although these results might point Rat 446 415 444 446 to different transduction mechanHuman 446 414 443 isms at D3 receptors compared to Introns in gene No Yes Yes Yes D2 receptors, the lack of GTP sensitivity of agonlst binding Amino acid sequence homology in should not be stressed too much, transmembrane domains: as it might simply reflect the lack of 44% 100% 100% 75% (1) Versus D2(long) receptor appropriate G proteins in the cell (2) Versus 132adrenergic receptor 42% 39% 39% line used for expression. Third intracellular loop Short Long Long Long What are the functional impliCarboxy-terminal Long Short Short Short cations of these discoveries? First, for any tissue that contains both D2 C/P C/P C/P OT Brain regions enriched and D3 dopamine receptors, preOT OT OT NA NA NA NA IC vious biochemical, pharmacological, behavioural and clinical studies will Pituitary Absent Present Present Absent need to be re-evaluated to take Abbreviations: C/P, caudate/putamen; OT, olfactory tubercle; NA, nucleus accumbens; account of the effects of existing IC, islandsof Calleja. compounds on the two receptor species. This might provide resdistribution from that of the D2 tion of this circuit is not known, the olutions of some paradoxes in the dopamine receptor, as assessed by brain areas involved are associated literature. For example, GTPin situ hybridization, northern blot- with motivation, evaluation of con- insensitive agonist binding at D2ring and PCR analysis. Whereas sequences, mood and emotion. like dopamine receptors has been the D2 receptor is found in the The preferential localization of D3 described 12-14, and might reflect majority of tissues innervated with dopamine receptors in the striatal the existence of a D3 receptor dopamine, the D3 receptor is found part of the 'anterior cingulate cir- component. Purification studies of at high levels only in certain limbic cuit' could reflect the structural D2 receptors6 might indicate the brain regions, such as the olfactory and functional segregation of these existence of D2 and D3 comtubercle, nucleus accumbens, pathways - the D3 receptor pro- ponents and will need to be careislands of Calleja and hypothala- viding an interesting marker for fully reinterpreted. In the original paper I and the mus. Low, but significant, levels of them. D3 receptor mRNA are found in The pharmacological profile in accompanying commentary15, it is the caudate/putamen and the cingu- ligand-binding assays of the D3 proposed that the existence of the late, frontal and prefrontal cor- dopamine receptor expressed in D3 receptor might account for the tices, but not in the pituitary. If we animal cells is similar to, but differ- lower incidence of extrapyramidal assume that mRNA levels are ent from, that of the D2 dopamine side-effects shown by atypical related to the levels of expressed receptor. Although dopamine neuroleptics. It has been assumed proteins in these areas, then the antagonists display high affinities that neuroleptics exert their antiD2:D3 ratio is infinite in pituitary for both receptors, antagonist affin- psychotic effects via D2 dopamine lactotrophs (no D3), very high in ities are generally higher at D2 receptors in limbic and cortical caudate/putamen, greater than than D3 receptors, with antagon- regions, whereas the extrapyraone in the olfactory tubercle, ists that would be considered midal side-effects reflect D2 reapproaches unity in the nucleus 'typical neuroleptics' (such as ceptor blockade in the striatum accumbens, is less than one in haloperidol and spiperone) having a especially the putamen. In the some cortical regions and much 10-20-fold preference for D2 over past, it has been suggested that less than one in the islands of D3, but 'atypical neuroleptics' (such the difference between the two Calleja. More detailed comparative as clozapine, thiofidazine and sulpir- groups of neuroleptics results from studies will be required at both the ide) showing only a 2-3-fold pref- atypical neuroleptics having mRNA and protein level in order to erence. 'Atypical neuroleptics' are greater affinities for limbic/cortical verify these relationships. How- those that show good antipsychotic receptors, penetrating differenever, it is of some interest that, activity, but a lower propensity for tially into different parts 16 of the within the striatal complex, D3 extrapyramidal (parkinsonian) side- brain, or having greater anticholindopamine receptors are confined effects compared with 'typical ergic potenciesl7 (suppressing the to the ventral striatum (nucleus neuroleptics 11. Some agonists, side-effects). None of these explaaccumbens, olfactory tubercle), e.g. apomorphine and bromocryp- nations is entirely satisfactory and which forms part of the 'anterior fine, show equal affinities for the different factors might contribute cingulate circuit '1°. Within this cir- two receptors, whereas some, differentially for each drug. From cuit, anterior cingulate, temporal, e.g. dopamine, quinpirole and the present study it also seems entorhinal, perirhinal cortices, the pergolide, show a higher affinity that the atypical drugs have more amygdala and the hippocampal (20-100-fold) for D3 receptors. similar affinities for D~ and D3 formation project to the ventral The binding of agonlsts to D3 receptors than do typical antistriatum, which projects via the receptors is not sensitive to guan- psychotics. This difference is clearly thalamus back to the anterior cingu- ine nucleotides; this is in contrast interesting, but whether it reflects late cortex. Although the func- with D2 receptors. Also, the D3 atypical neuroleptic behaviour is Receptor isoform
44
D1
D2(short) D2(Iong) D3
TINS, VoL 14, No. 2, 1991
not clear, as all neuroleptics have higher affinities for D2 dopamine receptors, which are found at high levels in typical dopamine motor areas such as the putamen, where receptor blockade is thought to occur and lead to the side-effects. Perhaps it is the particular mixture of D2 and D3 blockade that results in the 'atypical' profile. The discovery of the D3 dopamine receptor has significant implications for drug design because it is a receptor that is related to the D2 dopamine receptor, but is pharmacologically different and has a different localization. It is worth pointing out that studies of the D3 receptor are possible only through the use of molecular biology techniques and we are able to contemplate the design of selective drugs because of the ability to express the cloned receptor sequence in animal cells. The availability of assay systems that are based on expression of cloned receptor genes will allow the design of D3 selective compounds as well as compounds active at D: and D2 receptors that have reduced D3 activity. What might be the pharmacological use of compounds that show greater selectivity for D3 receptors relative to D1/D2 receptors or vice versa? It has been assumed that the antipsychotic activity of drugs like haloperidol depends on blockade of dopamine receptors in limbic/cortical brain regions, and it is now known that this could be due to blockade of D3 as well as D2 receptors. D3 receptors are present at high levels in the ventral striatum and are also found in several other limbic and cortical regions. The ventral striatum participates in the basal ganglia 'anterior cingulate circuit', which is associated with parts of the brain important for motivation, evaluation, mood and emotion. The other brain regions containing D3 receptors are involved in many higher functions including regulation of behaviour and mood and emotion. Some of these functions are disturbed in the positive psychotic symptoms of schizophrenia, and the antipsychotic effect of drugs that act at dopamine receptors is probably to alter the effects of dopamine control over limbic/ cortical brain regions. Therefore, a drug that selectively blocks D3 dopamine receptors might be benTINS, Vol. 14, No. 2, 1991
eficial for psychosis but, because it lacks D2 receptor blockade, would have fewer extrapyramidal side-effects and also would not alter prolactin secretion, since the pituitary lactotroph cells lack D3 receptors. Alternatively, some D2 receptor blockade might be required in addition to D3 receptor blockade to achieve an antipsychotic effect; it might be the mixture of DJD3 blockade that generates the 'atypical' neuroleptic profile. Whatever the outcome, both preclinical and clinical studies with these compounds are likely to be highly illuminating with respect to the mechanism of the antipsychotic effect. By contrast, a D:/D2 receptor agonist with reduced D3 receptor activity might be of use for treating Parkinson's disease. It should preferentially restore dopamine control over basal ganglia motor function and might have a lower incidence of psychotomimetic sideeffects, if these are due to interaction at D3 receptors. A D~ receptor agonist lacking D: and D3 receptor activity might be useful for controlling excess prolactin secretion from the pituitary gland or for therapy of prolactin-secreting tumours. I can almost feel the stirrings of interest in the pharmaceutical industry.
Selected references 1 Sokoloff, P., Giros, B., Martres, M. P., Bouthenet, M. L. and Schwartz, J. C. (1990) Nature 347, 146-151 2 Dearry, A. et al. (1990) Nature 347, 72-76 3 Zhou, Q. Y. eta/. (1990) Nature 347, 76-80 4 Sunahara, R. K. et al. (1990) Nature 347, 80-83 5 Monsma, F. J., Mahan, L. C., McVittie, L. D., Gerfen, C. R. and Sibley, D. R. (1990) Proc. Natl Acad. Sci. USA 87, 6723-6727 6 Strange, P, G. (1990) Trends Neurosci. 13, 373-378 7 Andersen, P. H. et al. (1990) Trends Pharmacol, Sci. 1I, 231-236 8 Laduron, P. (1980) Trends Pharmacol. Sci. 1,471-474 9 Chipkin, R, E. (1990) Trends Pharmacol. Sci. 11, 185 10 Alexander, G. E., Delong, M. R. and Strick, P. L. (1986)Annu. Rev. Neurosci. 9, 357-381 11 Gilman, A. G., Goodman, L. S., Rail, T. W. and Murad, F., eds (1985) The Pharmacological Basis of Therapeutics
(7th edn), Macmillan 12 Leonard, M. N., Macey, C. A. and Strange, P. G. (1987) Biochem. J. 248, 595-602 13 Sokoloff, P., Redouane, K., Brann, M., Martres, M. P. and Schwartz, J. C. (1985) Naunyn Schmiedeberg's Arch. Pharmacol. 329, 236-243 14 Creese, I., Usdin, T. and Snyder, S. H. (1979) Nature 278, 577-578 15 Snyder, S. H. (1990) Nature 347, 121-122 16 Strange, P. G. (1990) Trends Pharmacol 5ci. 11,357 17 Miller, R. J, and Hiley, C. R. (1974) Nature 248, 596-597
TINS Editorial
Policy
Trends in Neurosciences is the leading neuroscience review journal, publishing timely news, reviews and other feature articles to enable researchers and teachers to keep up to date with current developments. The journal publishes articles in the format of different 'sections' which each month give readers the opportunity to read around their own field. Reviews form the foundations of each issue and are written by leading researchers to offer concise and authoritative articles of important areas of neuroscientific research. Research N e w s articles cover recent developments within a particular field and are generally written from the objective perspective of one of a specially-selected pool of correspondents. Perspectives and V i e w p o i n t articles complement the Reviews. The former often present and discuss areas of historical, social or more oblique interest but which can offer interesting insights into neuroscience research. The latter include more controversial or synthetic ideas. Perspectives on Disease is a section which discusses how basic research can offer useful approaches to neurological disease and Techniques articles describe and discuss new methods and their application.
Articles in TINS are usually commissioned by the Editor, in consultation with the Editorial Board. All articles are subject to peer and editorial review and may be rejected: commissioning does not guarantee publication.
45
Interestingtimesfor dopaminereceptors tors. Each receptor shows consensus sites for glycosylation in the amino-terminal region (predicted extracellular), a potential palmitoylation site in the predicted intracellular carboxy-terminal section and consensus sequences for phosphorylation by protein kinases in the third predicted intracellular loop. Certain amino acids, highly conserved in cationic amine receptors 6, and thought to be important for ligand binding, are found in each doparnine receptor. These include an aspartic acid residue in the third predicted transmembrane region and two serine residues in the frith predicted transmembrane region with the aspartate probably forming an electrostatic interaction with the cationic amine group, and the serines hydrogen-bonding to the catechol moiety. The overall organization of the receptors and their genes groups the De and D3 receptors closer together and separates them from the D1 receptor. The De and D3 receptor proteins have long third intracellular loops and short carboxy-terminal tails, whereas in the D1 receptor the third intraceIlular loop is short and the carboxy-terminal tail is long. This latter arrangement is very similar to that for the 132adrenergic receptor and might reflect interaction with the G protein Gs. These are some of the key points that emerge from a comparison of the different dopamine receptors. Next, the D~ and D3 dopamine receptors will be considered separately.
used in reading the nucleic acid sequence; this is because there are two potential translational start sites in the human gene and three in the rat gene. Therefore, the different sizes reported result from the use of different translational start sites so that the precise size of the expressed D1 receptor protein is not clear. An intriguing possibility is that receptor isoforms of different sizes might be produced using the different start codons (D. Sibley, pers. commun.). In Table I a 446 an~no acid protein has been assumed for clarity, but this needs to be defined rigorously. In support of the identity of the different cloned receptor sequences, they exhibit essentially identical pharmacological properties consistent with a D1 receptor when they are expressed in animal cells, and also show dopamine stimulation of adenylate cyclasez-5. There are, however, some indications that this might not be the only D1 receptor, since D] dopamine receptors have been shown to stimulate phospholipase C rather than adenylate cyclase in some systems - suggesting the existence of another receptor subtype 7. In the present cloning reports, extra bands were seen on Southern blots that were hybridized at low stringency; this suggests the presence of additional D] receptor genes. Also, mRNA corresponding to the present D~ receptor gene was not detected in heart and kidney, which are tissues known functionally to contain D1 receptors. Therefore, additional D1 receptor clones are expected to be identified and might provide D1 dopamine receptor important targets for drug design. Whereas three of the reports of It is worthwhile remembering that, the cloning of the D1 dopamine although at one time the dopaminereceptor suggest a 446 amino acid sensitive adenylate cyclase (Dl Comparison of D1, D2 and D3 dopamine receptors protein z-4, one report suggests a dopamine receptor) was dismissed Table I summarizes some of the 487 amino acid protein s. Com- as an enzyme of no relevance to key properties of the different parison of the rat sequences 3'5 receptors s, it has now been cloned receptors. The proteins are all shows that, apart from a 41 amino and a D~ receptor selective comquite similar in size with D2(shom acid amino-terminal extension in pound, SCH 39166, is in clinical being the smallest, and the amino the 487 amino acid sequence, the trials as an antipsychotic9. acid sequences, when subjected to two proteins are virtually identical. hydropathy analysis, show the It seems that the two sequences D3 dopamine receptor motif of seven hydrophobic (pre- are derived from the same gene The characteristics of the D3 sumed transmembrane) regions but that there is some uncertainty dopamine receptor are quite novel. typical of G protein-linked recep- over which start codon should be It has a different anatomical TINS, Vol. 14, No, 2, 1991
news
© 1991, Elsevier Science PublishersLtd. (UK) 0166-
2236/91/$02.00
Philip G. Strange BiologicalLaboratory, TheUniversity, CanterburyCT27NJ, UK.
43
TABLE I. Comparison of dopamine receptor subtypes
receptor failed to inhibit adenylate cyclase under circumstances in which the D2 receptor did inhibit it. Amino acids Although these results might point Rat 446 415 444 446 to different transduction mechanHuman 446 414 443 isms at D3 receptors compared to Introns in gene No Yes Yes Yes D2 receptors, the lack of GTP sensitivity of agonlst binding Amino acid sequence homology in should not be stressed too much, transmembrane domains: as it might simply reflect the lack of 44% 100% 100% 75% (1) Versus D2(long) receptor appropriate G proteins in the cell (2) Versus 132adrenergic receptor 42% 39% 39% line used for expression. Third intracellular loop Short Long Long Long What are the functional impliCarboxy-terminal Long Short Short Short cations of these discoveries? First, for any tissue that contains both D2 C/P C/P C/P OT Brain regions enriched and D3 dopamine receptors, preOT OT OT NA NA NA NA IC vious biochemical, pharmacological, behavioural and clinical studies will Pituitary Absent Present Present Absent need to be re-evaluated to take Abbreviations: C/P, caudate/putamen; OT, olfactory tubercle; NA, nucleus accumbens; account of the effects of existing IC, islandsof Calleja. compounds on the two receptor species. This might provide resdistribution from that of the D2 tion of this circuit is not known, the olutions of some paradoxes in the dopamine receptor, as assessed by brain areas involved are associated literature. For example, GTPin situ hybridization, northern blot- with motivation, evaluation of con- insensitive agonist binding at D2ring and PCR analysis. Whereas sequences, mood and emotion. like dopamine receptors has been the D2 receptor is found in the The preferential localization of D3 described 12-14, and might reflect majority of tissues innervated with dopamine receptors in the striatal the existence of a D3 receptor dopamine, the D3 receptor is found part of the 'anterior cingulate cir- component. Purification studies of at high levels only in certain limbic cuit' could reflect the structural D2 receptors6 might indicate the brain regions, such as the olfactory and functional segregation of these existence of D2 and D3 comtubercle, nucleus accumbens, pathways - the D3 receptor pro- ponents and will need to be careislands of Calleja and hypothala- viding an interesting marker for fully reinterpreted. In the original paper I and the mus. Low, but significant, levels of them. D3 receptor mRNA are found in The pharmacological profile in accompanying commentary15, it is the caudate/putamen and the cingu- ligand-binding assays of the D3 proposed that the existence of the late, frontal and prefrontal cor- dopamine receptor expressed in D3 receptor might account for the tices, but not in the pituitary. If we animal cells is similar to, but differ- lower incidence of extrapyramidal assume that mRNA levels are ent from, that of the D2 dopamine side-effects shown by atypical related to the levels of expressed receptor. Although dopamine neuroleptics. It has been assumed proteins in these areas, then the antagonists display high affinities that neuroleptics exert their antiD2:D3 ratio is infinite in pituitary for both receptors, antagonist affin- psychotic effects via D2 dopamine lactotrophs (no D3), very high in ities are generally higher at D2 receptors in limbic and cortical caudate/putamen, greater than than D3 receptors, with antagon- regions, whereas the extrapyraone in the olfactory tubercle, ists that would be considered midal side-effects reflect D2 reapproaches unity in the nucleus 'typical neuroleptics' (such as ceptor blockade in the striatum accumbens, is less than one in haloperidol and spiperone) having a especially the putamen. In the some cortical regions and much 10-20-fold preference for D2 over past, it has been suggested that less than one in the islands of D3, but 'atypical neuroleptics' (such the difference between the two Calleja. More detailed comparative as clozapine, thiofidazine and sulpir- groups of neuroleptics results from studies will be required at both the ide) showing only a 2-3-fold pref- atypical neuroleptics having mRNA and protein level in order to erence. 'Atypical neuroleptics' are greater affinities for limbic/cortical verify these relationships. How- those that show good antipsychotic receptors, penetrating differenever, it is of some interest that, activity, but a lower propensity for tially into different parts 16 of the within the striatal complex, D3 extrapyramidal (parkinsonian) side- brain, or having greater anticholindopamine receptors are confined effects compared with 'typical ergic potenciesl7 (suppressing the to the ventral striatum (nucleus neuroleptics 11. Some agonists, side-effects). None of these explaaccumbens, olfactory tubercle), e.g. apomorphine and bromocryp- nations is entirely satisfactory and which forms part of the 'anterior fine, show equal affinities for the different factors might contribute cingulate circuit '1°. Within this cir- two receptors, whereas some, differentially for each drug. From cuit, anterior cingulate, temporal, e.g. dopamine, quinpirole and the present study it also seems entorhinal, perirhinal cortices, the pergolide, show a higher affinity that the atypical drugs have more amygdala and the hippocampal (20-100-fold) for D3 receptors. similar affinities for D~ and D3 formation project to the ventral The binding of agonlsts to D3 receptors than do typical antistriatum, which projects via the receptors is not sensitive to guan- psychotics. This difference is clearly thalamus back to the anterior cingu- ine nucleotides; this is in contrast interesting, but whether it reflects late cortex. Although the func- with D2 receptors. Also, the D3 atypical neuroleptic behaviour is Receptor isoform
44
D1
D2(short) D2(Iong) D3
TINS, VoL 14, No. 2, 1991
not clear, as all neuroleptics have higher affinities for D2 dopamine receptors, which are found at high levels in typical dopamine motor areas such as the putamen, where receptor blockade is thought to occur and lead to the side-effects. Perhaps it is the particular mixture of D2 and D3 blockade that results in the 'atypical' profile. The discovery of the D3 dopamine receptor has significant implications for drug design because it is a receptor that is related to the D2 dopamine receptor, but is pharmacologically different and has a different localization. It is worth pointing out that studies of the D3 receptor are possible only through the use of molecular biology techniques and we are able to contemplate the design of selective drugs because of the ability to express the cloned receptor sequence in animal cells. The availability of assay systems that are based on expression of cloned receptor genes will allow the design of D3 selective compounds as well as compounds active at D: and D2 receptors that have reduced D3 activity. What might be the pharmacological use of compounds that show greater selectivity for D3 receptors relative to D1/D2 receptors or vice versa? It has been assumed that the antipsychotic activity of drugs like haloperidol depends on blockade of dopamine receptors in limbic/cortical brain regions, and it is now known that this could be due to blockade of D3 as well as D2 receptors. D3 receptors are present at high levels in the ventral striatum and are also found in several other limbic and cortical regions. The ventral striatum participates in the basal ganglia 'anterior cingulate circuit', which is associated with parts of the brain important for motivation, evaluation, mood and emotion. The other brain regions containing D3 receptors are involved in many higher functions including regulation of behaviour and mood and emotion. Some of these functions are disturbed in the positive psychotic symptoms of schizophrenia, and the antipsychotic effect of drugs that act at dopamine receptors is probably to alter the effects of dopamine control over limbic/ cortical brain regions. Therefore, a drug that selectively blocks D3 dopamine receptors might be benTINS, Vol. 14, No. 2, 1991
eficial for psychosis but, because it lacks D2 receptor blockade, would have fewer extrapyramidal side-effects and also would not alter prolactin secretion, since the pituitary lactotroph cells lack D3 receptors. Alternatively, some D2 receptor blockade might be required in addition to D3 receptor blockade to achieve an antipsychotic effect; it might be the mixture of DJD3 blockade that generates the 'atypical' neuroleptic profile. Whatever the outcome, both preclinical and clinical studies with these compounds are likely to be highly illuminating with respect to the mechanism of the antipsychotic effect. By contrast, a D:/D2 receptor agonist with reduced D3 receptor activity might be of use for treating Parkinson's disease. It should preferentially restore dopamine control over basal ganglia motor function and might have a lower incidence of psychotomimetic sideeffects, if these are due to interaction at D3 receptors. A D~ receptor agonist lacking D: and D3 receptor activity might be useful for controlling excess prolactin secretion from the pituitary gland or for therapy of prolactin-secreting tumours. I can almost feel the stirrings of interest in the pharmaceutical industry.
Selected references 1 Sokoloff, P., Giros, B., Martres, M. P., Bouthenet, M. L. and Schwartz, J. C. (1990) Nature 347, 146-151 2 Dearry, A. et al. (1990) Nature 347, 72-76 3 Zhou, Q. Y. eta/. (1990) Nature 347, 76-80 4 Sunahara, R. K. et al. (1990) Nature 347, 80-83 5 Monsma, F. J., Mahan, L. C., McVittie, L. D., Gerfen, C. R. and Sibley, D. R. (1990) Proc. Natl Acad. Sci. USA 87, 6723-6727 6 Strange, P, G. (1990) Trends Neurosci. 13, 373-378 7 Andersen, P. H. et al. (1990) Trends Pharmacol, Sci. 1I, 231-236 8 Laduron, P. (1980) Trends Pharmacol. Sci. 1,471-474 9 Chipkin, R, E. (1990) Trends Pharmacol. Sci. 11, 185 10 Alexander, G. E., Delong, M. R. and Strick, P. L. (1986)Annu. Rev. Neurosci. 9, 357-381 11 Gilman, A. G., Goodman, L. S., Rail, T. W. and Murad, F., eds (1985) The Pharmacological Basis of Therapeutics
(7th edn), Macmillan 12 Leonard, M. N., Macey, C. A. and Strange, P. G. (1987) Biochem. J. 248, 595-602 13 Sokoloff, P., Redouane, K., Brann, M., Martres, M. P. and Schwartz, J. C. (1985) Naunyn Schmiedeberg's Arch. Pharmacol. 329, 236-243 14 Creese, I., Usdin, T. and Snyder, S. H. (1979) Nature 278, 577-578 15 Snyder, S. H. (1990) Nature 347, 121-122 16 Strange, P. G. (1990) Trends Pharmacol 5ci. 11,357 17 Miller, R. J, and Hiley, C. R. (1974) Nature 248, 596-597
TINS Editorial
Policy
Trends in Neurosciences is the leading neuroscience review journal, publishing timely news, reviews and other feature articles to enable researchers and teachers to keep up to date with current developments. The journal publishes articles in the format of different 'sections' which each month give readers the opportunity to read around their own field. Reviews form the foundations of each issue and are written by leading researchers to offer concise and authoritative articles of important areas of neuroscientific research. Research N e w s articles cover recent developments within a particular field and are generally written from the objective perspective of one of a specially-selected pool of correspondents. Perspectives and V i e w p o i n t articles complement the Reviews. The former often present and discuss areas of historical, social or more oblique interest but which can offer interesting insights into neuroscience research. The latter include more controversial or synthetic ideas. Perspectives on Disease is a section which discusses how basic research can offer useful approaches to neurological disease and Techniques articles describe and discuss new methods and their application.
Articles in TINS are usually commissioned by the Editor, in consultation with the Editorial Board. All articles are subject to peer and editorial review and may be rejected: commissioning does not guarantee publication.
45
