Dopamine receptors have been historically classified into two major subtypes, termed D1 and D2(1) . Operationally, native D1 receptors are defined by their ability to promote adenylate cyclase activity and bind agonists (e.g. fenoldopam, SKF-38393) ()and antagonists (SCH-23390) of the benzazepine and benzonapthazine class of compounds with high affinity(2, 3) . Dopamine D2 receptors inhibit adenylate cyclase activity and bind selectively to agonists (e.g. quinpirole) and antagonists (haloperidol, spiperone, emonopride) of numerous structural classes. The mammalian dopamine receptor family is comprised of five distinct genes, two of which encode D1 like receptors, termed D1/D1A and D5/D1B, and three genes encoding dopamine D2 like receptors, termed D2, D3, and D4, which in addition yield numerous functional splice and polymorphic forms of these receptors(4, 5, 6, 7, 8) .

Based on pharmacological, biochemical, and behavioral observations, it has been postulated that additional members of the dopamine D1 receptor gene subfamily exist(7, 9) . Thus, in native mammalian systems, selective D1 receptor stimulation has been linked to the activation of phospholipase C leading to phosphoinositide hydrolysis in both the brain and periphery all independent of adenylate cyclase activity (10, 11, 12, 13, 14, 15, 16) and inhibition of Na/H exchange (17) . Moreover, distinct behavioral effects mediated by selective D1 receptor stimulation also suggest the existence of D1-like subpopulations that either display unique pharmacological profiles for some D1 selective compounds or are not classically defined as adenylate cyclase-coupled D1 receptors(18, 19, 20, 21, 22) . Cloned D1/D1A and D5 D1B receptors are found only to stimulate adenylate cyclase activity in numerous cells lines(23, 24, 25) , and the weak D1 receptor-mediated alteration in Ca efflux observed in some cells also appears to be cAMP-dependent(26, 27, 28) . Thus, the proposed dissociation of dopamine D1-like receptor-mediated events from the stimulation of adenylate cyclase activity or in known responsivity to various structural classes of agonist/antagonist ligands are disparate with the observed pharmacological and signal transduction profiles of the cloned D1A/D1B receptors. Although there has been some molecular evidence for the existence of additional mammalian D1 like receptors(12) , the gene encoding this protein has yet to be identified.

Localization studies have thoroughly mapped the neuroanatomical distribution pattern of dopamine-containing cells in the avian brain, and dopamine D1-like receptors have been identified by both autoradiographic and ligand binding techniques.(29, 30, 31, 32, 33) . As with mammalian systems(34) , developmental discrepancies have been observed to exist between the number of D1 like receptors, as indexed by [H]SCH-23390 binding sites and the magnitude of D1 receptor-mediated cAMP accumulation in the avian retina(35, 36) . Similarly, selective D-1 receptor stimulation of avian retinal cells mediates K efflux, which has been shown to act independently of adenylate cyclase activity(37) .

The existence of genes encoding for additional D1-like receptor subtypes, at least in vertebrates, has recently received direct support. Thus, a gene encoding a unique D1 receptor subtype, termed D1C, has been isolated from Xenopus laevis, which is distinguishable from cloned Xenopus D1A and D1B receptors on the basis of its primary structure, receptor mRNA distribution, and expressed pharmacological profile(38) . Using a strategy based on low stringency homology screening, we report here on the isolation and characterization of an additional member of the vertebrate D1 receptor subfamily, termed D1D, from the avian species Gallus domesticus (chicken).

EXPERIMENTAL PROCEDURES

Cloning of Dopamine Receptor Genes

Transfection and Ligand Binding Analysis

cAMP Accumulation Assay

Northern Blot Analysis of Receptor RNA

RT-PCR Analysis of D1B Receptor mRNA

RESULTS AND DISCUSSION

The recent isolation and characterization of a novel D1-like receptor gene from Xenopus laevis, termed D1C(38) , has provided direct molecular evidence for the heterogeneity of the D1A and D1B receptor subfamily. In preliminary experiments, the generality of this observation was further strengthened by Southern blot analysis of avian genomic DNA probed with P-labeled dopamine D1 and D5 receptor fragments encoding trans-membrane domains 2-5, which revealed the presence of more than two distinct hybridizing bands (data not shown). Selective stringency screening of an avian genomic library was therefore initiated, and positives were isolated according to their distinctive hybridization patterns. Three types of signals were observed: 1) positives that strongly hybridized to D1 but not D5, 2) positives that strongly hybridized to D5 and weakly to D1, and 3) positives that hybridized moderately to both D1 and D5. Twenty-four selections from these differential hybridization patterns resulted in the isolation of three genomic fragments (LDChi-1, LDChi-2, and LDChi-6).

Sequence analysis indicated that all three clones shared strong deduced amino acid sequence homology to the mammalian dopamine D1-receptor family. Like their mammalian counterparts, all three genes were intronless within their putative coding sequence. Consensus nucleotide sequences for putative initiating methionines (40) were found in all three clones. The first two clones (LDChi-2 and LDChi-6) contained open reading frames of 1353 and 1464 nucleotides encoding 451- and 488-amino acid proteins with estimated molecular masses of 49,142 and 53,110 Da, respectively. The third genomic clone (LDChi-1) revealed an open reading frame of 1335 nucleotides encoding for a 445-amino acid protein with an estimated molecular mass of 49,246 Da.

Comparison of the deduced amino acid sequence of all three clones depicted in Fig. 1suggests that LDChi-2 may be a homolog of the mammalian D1/D1A receptor, while LDChi-6 may be the species equivalent of the D5/D1B receptor. LDChi-2 was found to be 94% identical, within putative transmembrane domains, and displays 80% overall amino acid sequence identity to the mammalian (human/rat) D1/D1A receptor. Comparisons to mammalian D5/D1B receptors revealed that LDChi2 displays 81% identity within transmembrane domains and only 53% overall amino acid sequence homology. The LDChi-6 gene, however, exhibited greatest sequence resemblance to D1B receptors with 90% identity within transmembrane domains to both the mammalian (human/rat) D5/D1B receptors and to the amphibian D1B receptor homolog. Overall amino acid sequence identity of the avian D1B receptor to mammalian or amphibian D5/D1B receptors was considerably lower at 66 and 67%, respectively. The lower overall similarities between these genes and the avian D1B receptor is primarily attributable to sequence divergence within the amino-terminal, second and third intracellular-extracellular loops and portions of the carboxyl tail and is consistent with the view that this receptor subfamily is subject to an accelerated rate of accumulated evolutionary drift (41, 42) compared with the D1/D1A receptor family. One particular area of significant sequence divergence is evident within the third extracellular loop of the avian D1B receptor when compared with its mammalian counterparts. Thus, while mammalian D5/D1B receptors contain relatively large loops between transmembrane 4 and 5, the avian D1B receptor is significantly larger containing an additional 32 amino acids to encompass a total loop size of 65 amino acids. Although the functional significance third extracelluar loop is currently unknown, RT-PCR of brain D1B receptor mRNA and sequence analysis of the amplified DNA suggests that, at least in this tissue, the D1B receptor is not subject to alternative splicing (data not shown). In any event, based on the strong overall amino acid sequence homologies to either mammalian D1/D1A and D5/D1B receptors aligned in Fig. 1, we propose to term LDChi-2 and LDChi-6 the avian D1A and D1B receptor, respectively.

Figure 1: Deduced amino acid alignment of avian D1 receptors to other cloned members of the mammalian and vertebrate dopamine D1-like receptor family. Boxed and shadedareas denote conserved amino acid residues between the avian D1A, D1B, and D1D receptors and their mammalian counterparts. Putative TM domains are demarcated by boxed regions. Putative N-linked glycosylation sites are indicated by arrows. Potential phosphorylation sites for protein kinase A (cAMP-dependent) and protein kinase C are indicated by closedcircles () and closedsquares (), respectively. Single-letter amino acid code used. Sequences encoding the monkey (56) and opossum (57) D1A receptors are omitted from this alignment due to the relatively high degree of conservation in deduced amino acid sequence to human/rat D1/D1A receptors.

The third genomic clone, LDChi-1, initially believed to encode for a D1C -like receptor was found to be particularly distinct. Sequence identity between this potentially novel dopamine receptor and other cloned members of the D1 receptor family was found to be highest within transmembrane domains: 75% to mammalian D1/D1A, 77% to D5/D1B, and 81% to vertebrate D1C receptors. Sequence homologies within TM domains increased considerably when D1D was compared with all cloned vertebrate members of either the D1A (86%) or D1B (88%) receptor subfamily listed in Fig. 1. Overall similarities were considerably lower with identities of 49, 46, and 54% to the D1, D5, and D1C receptor, respectively. At the nucleotide level, LDChi-1 displays a similar profile of overall sequence identity with 57% to mammalian D1/D1A receptor genes, 60% to the D5/D1B receptor subfamily, and 60% to the amphibian D1C gene. Based on both the nucleotide and deduced amino acid sequence homologies, it was concluded that this clone did not possess a particularly striking similarity to any of the previously cloned D1-like receptors and was not likely to be a species homolog. This gene product is, therefore, referred to as an avian dopamine D1D receptor, in line with the alphabetical nomenclature scheme suggested for nonhuman dopamine D1-like receptor genes(4) .

Consensus sequences for putative post-translation modifications have been conserved in the avian D1 like receptor family. As outlined in Fig. 1, of the three avian receptors, only D1A and D1B contain consensus sites for N-linked glycosylation. The D1A receptor possesses two sites, at Asn in the amino terminus and Asn located in the third extracellular loop similar to mammalian or vertebrate counterparts. The D1B receptor, however, only contains one site, at Asn, in the third extracellular loop. As illustrated in Fig. 1, several putative phosphorylation sites for protein kinase C and cAMP-dependent protein kinase A were found in the third cytoplasmic loops of all three receptors, comparable with their mammalian counterparts. Unlike the mammalian dopamine D1/D1A or D5/D1B like receptors, but similar to the amphibian D1C and avian D1B and D1A receptor, the D1D receptor contains additional putative protein kinase C sites within the carboxyl terminus. Conserved amino acid residues characteristic of dopamine receptors are also found within the avian clones, such as the 2 serine residues within TM5, believed to mediate binding of the endogenous neurotransmitter dopamine ( (43) and references therein). Interestingly, while all D1-like receptors contain three sequential serine residues within TM5, D1D is the first dopamine receptor to possess a conserved substitution for the first of these serines at position Thr in TM5. The functional significance of this serine residue for mammalian dopamine D1-like receptor activity has not been addressed in site-directed mutagenesis studies(43) . Also present is a conserved cysteine residue, Cys D1D; Cys D1A; Cys D1B, located in the carboxyl terminus, which is believed to function as a site for palmitoylation(44) .

In order to further justify our nomenclature scheme for avian genes encoding D1-like receptors, we compared the avian D1 receptors to their mammalian counterparts in terms of their exhibited pharmacological profiles and ligand binding specificity. A 3-kb XbaI fragment of LDChi-1 (D1D) and two 3-kb PstI fragments of LDCh2 (D1A) and 6 (D1B) were subcloned into the expression vector pcD-ps. Membranes prepared from COS-7 cells transiently expressing these genes were assessed for their ability to bind the D1-selective antagonist, [H]SCH-23390. All three receptors bound [H]SCH-23390 (0.25-4.0 nM) in a concentration-dependent and saturable manner with high affinity (data not shown). Scatchard transformation of the data revealed a single class of binding site for D1A and D1B receptors with an estimated K of 180 ± 21 and 171 ± 18 pM and B values which on average were of 0.9 ± 0.2 and 0.6 ± 0.14 pmol/mg of protein, respectively. The expressed D1D receptor also bound [H]SCH-23390 with high affinity with an estimated K of 322 ± 58 pM and somewhat lower level of receptor expression ranging from 0.2-0.4 pmol/mg of protein.

[H]SCH-23390 binding to COS-7 cell membranes expressing D1A, D1B, and D1D receptors was inhibited in a concentration-dependent, stereoselective, and uniphasic manner (as indexed by Hill coefficients close to unity) by a variety of dopaminergic agonists and antagonists with a rank order of potency and pharmacological profile clearly consistent with a D1-like receptor. Estimated K values for these agents are listed in Table 1.

With regard to agonist compounds, a unique pharmacological characteristic that differentiates D1/D1A from D5/D1B receptors is the inherent ability of the D5/D1B receptor to exhibit higher affinity for the neurotransmitter dopamine and the aminotetralin, ADTN(45, 46) . Comparable with both mammalian and Xenopus D1/D1A receptor homologs, both dopamine and ADTN display a 10-fold higher affinity for the avian D1B (261/550 nM) than D1A (2000/4500 nM) receptor, consistent with our proposed classification of these receptors based on amino acid sequence homologies depicted in Fig. 1. Due to the absence of guanine-nucleotide-sensitive agonist high affinity forms following the expression of D1-like receptor genes in COS-7 cells(38, 39, 45) , direct comparisons between the avian and mammalian dopamine D1-like receptors can be made. Other compounds, listed in Table 1, that further differentiate the two receptors include, (+)-butaclamol and fluphentixol, which inhibit [H]SCH-23390 binding to avian D1A receptors at concentrations 2-5-fold lower than D1B, paralleling their mammalian/vertebrate counterparts. The estimated inhibitory constants (K) for the inhibition of [H]SCH-23390 binding by a series of dopaminergic compounds at the avian D1A correlate (r 0.989) strongly with those K values obtained for these agents at the mammalian/vertebrate D1/D1A receptors with a virtual 1:1 correspondence in estimated receptor affinity. Although a general tendency for some agonists to be more potent at the avian D1A was noted, receptor antagonists displayed very little preferential affinity for either the human or avian D1A receptor. Similarly, estimated K values for the avian D1B receptor also correlate extremely well (r 0.976.) with the mammalian or vertebrate D5/D1B receptor. Again, while some agonists (SKF-76783, N-propylnorapomorphine, and bromocriptine) displayed slightly higher affinities for the avian D1B receptor, virtually all other compounds tested exhibited affinities that were equipotent with the mammalian D1B receptor.

Although the exhibited pharmacological profile of D1D is consistent with a D1-like receptor, it displayed many unique characteristics not previously observed with other cloned members of the D1 receptor family. As depicted in Fig. 2, the D1D receptor displays a 10-fold higher affinity for dopamine than the D1A receptor. Similar results were obtained for ADTN and is suggestive of the contention that the D1D receptor shares characteristics of the D5/D1B subfamily of receptors. Interestingly, compounds that normally do not discriminate D1A from D1B receptors were particularly more potent for the D1D receptor. The most significant of these, as shown in Fig. 2, is the benzazepine, SKF-38393. Thus, while D1D does not bind the benzazepine, fenoldopam, (SKF-82526) with much higher affinity than vertebrate D1/D1A, D5/D1B, or D1C receptors, it exhibits a 13-25-fold increase in affinity for the ``partial'' agonist SKF-38393 compared with either mammalian or amphibian receptors. Similarly, while all other agonists tested displayed somewhat higher affinity (2-6-fold) for the D1D receptor compared with avian D1A or D1B receptors, nonselective D1/D2 receptor agonists, such as, N-propylnorapomorphine, apomorphine, and (-)-4,6,6a,7,8,12b-hexahydro-7-methyl-indolo[4,3-ab]phenanthridine were significantly more potent at the D1D receptors compared with any other D1-like receptor and may provide the molecular basis for some of the observed D1-like actions obtained with these D2 receptor-preferring agonists(47, 48) . Moreover, lisuride and pergolide, compounds used as adjunct therapies in the treatment of Parkinson's disease(49, 50, 51) , are also significantly more potent at the D1D receptor, with 4-10-fold higher affinities than for vertebrate D1A, D1B, or D1C receptors. As noted below, both lisuride and pergolide behave as agonists at D1D receptors stimulating cAMP accumulation. Interestingly enough, in native brain membranes a small proportion (15%) of D1-like sites labeled by [H]SCH-23390 have been reported to bind lisuride and pergolide and some of the other dopamine D2 agonists reported here with high affinity(52) .

Figure 2: Pharmacological specificity of [H]SCH-23390 binding to membranes prepared from COS-7 cells expressing avian D1A, D1B, and D1D receptors. COS-7 cells were transfected with genes encoding D1A, D1B, and D1D receptors, membranes prepared and assayed for D1 receptor activity as described under ``Experimental Procedures.'' Representative curves are illustrated for the concentration-dependent inhibition of [H]SCH-23390 binding (200-400 pM) to expressed avian D1 receptors by the dopaminergic agonists dopamine and SKF-38393. For this particular experiment, D1A, D1B, and D1D receptor concentrations varied less than 2-fold. Estimated inhibitory constants (K) for these compounds, included in Table 1, were determined by KALEIDAGRAPH and are representative of at least three independent experiments each conducted in duplicate and which varied by less than 15%.

With regard to antagonists, the D1D receptor displays affinities for compounds truly reflective of both D1A and D1B receptor profiles. Thus, D1D receptors discriminate and exhibit poor affinity for butaclamol, similar to D1B/D5 receptors, yet is bound by fluphentixol with high affinity, characteristic of D1/D1A receptors. Of particular interest is the observed low affinity (2 µM) of haloperidol for the D1D receptor. By comparison, all other D1-like receptors display relatively high affinity (70-150 nM) for the classical D2-like receptor antagonist. As illustrated in Fig. 3, direct comparison of the estimated K values of numerous agonists and antagonists at the D1D receptor with human D1, D5, and vertebrate D1C receptors, although correlative, clearly depict the lack of a simple one to one correspondence in estimated affinities for a number of compounds. As such, the D1D receptor is the first member of the D1 gene family that clearly deviates from the classical D1-like pharmacology with respect to differentiating agonist benzazepine ligands and binding D2-like agonists with high affinity. Whether the D1D receptor can further discriminate and display exquisite sensitivity for other dopaminergic compounds or ``second'' generation D1-like agonists and antagonists is currently under investigation.

Figure 3: Pharmacological homology between the avian D1D receptor and other cloned D1 receptor subtypes. Correlational plots of estimated inhibitory constants (K) of various dopaminergic agonists () and antagonists () to inhibit [H]SCH-23390 binding to for the avian D1D receptor and the human dopamine D1 (A), D5 (B), and Xenopus D1C (C) receptors transiently expressed in COS-7 cells. K values for D1, D5, and D1C receptors were taken from Refs. 38, 39, and 45. Compounds displaying major discrepancies in estimated affinities between these receptors were reassayed under identical conditions and reported here. The line of identity or equimolarity is indicated.

As classically defined, the D1 receptor stimulates adenylate cyclase affinity. We assessed the ability of various compounds to alter cAMP accumulation in COS-7 cells transiently expressing the avian D1A, D1B, and D1D receptors. As summarized in Fig. 4, all three avian dopamine receptors stimulated the production of cAMP. The addition of 10 µM dopamine or 1 µM SKF82526 to cells expressing D1D resulted in a 10-fold stimulation over basal levels, which was sensitive to antagonism by the addition of 1 µM SCH-23390. cAMP production in cells expressing avian D1A and D1B receptors increased, on average, 7- and 9-fold with the addition of dopamine (10 µM) and 5- and 6-fold with the addition of SKF82526 (1 µM), respectively. Both lisuride and pergolide (10 µM) stimulated cAMP accumulation at all three avian D1 receptors with estimated EC values at the D1D receptor of 9 and 90 nM, respectively. As such, all cloned members of the dopamine D1 receptor gene family including the amphibian D1C receptor are coupled to the stimulation of adenylate cyclase activity. While evidence suggests the existence of native dopamine D-1 like receptor that are functionally coupled to effector elements other than adenylate cyclase, particularly the activation of phosphatidylinositol hydrolysis (see above), we were unable to show in COS-7 cells any consistent stimulation of phosphatidylinositol turnover by either avian D1A, D1B, or D1D receptors in response to varying concentrations of dopamine or SKF-82526 up to 100 µM (data not shown). It is unknown, at present, whether this lack of response is due to the inappropriate complement, in COS-7 cells, of subtype-specific G protein or subunits needed for specific avian D1-like receptor stimulation of phospholipase C or the appropriate molecular form of the enzyme. Coexpression studies with these proteins in COS-7 cells may resolve this issue(53) .

Figure 4: cAMP accumulation following avian D1A, D1B and D1D receptor stimulation. COS-7 cells expressing pcD-D1A, pcD-D1B, and pcD-D1D were assayed for cAMP accumulation as described under ``Experimental Procedures.'' Following treatment with either 10 µM dopamine or 1 µM SKF-82526, avian D1A, D1B, and D1D receptors stimulate cAMP production from 7-10-fold above basal levels. Maximal stimulation with 10 µM dopamine for all three avian D1-like receptors is reversed by the addition of the D1-selective antagonist SCH-23390 (1 µM). Results shown are representative of at least two independent experiments each conducted in duplicate.

Northern blot analysis of brain and peripheral regions from chicken total RNA revealed the expression of all three receptors. As depicted in Fig. 5, an mRNA species of 3 kb was observed for the D1D receptor specifically localized only in the brain. D1A receptor mRNA (3.4 kb) was found within the brain and to a much lesser extent in the kidney. The D1B receptor mRNA (2.7 kb) was more widely distributed and found in brain, spleen, and kidney and to a much lesser extent in the heart. Whether the slightly different mRNA transcript sizes for D1B receptor mRNA in the various tissues may possibly be attributable to multiple transcription initiation or poly-adenylation sites is currently unknown. In any event, the mRNA distribution patterns of the cloned D1 receptors are in line with the known distribution patterns of both dopamine-containing cells and D1 binding sites in the avian brain. Further work, via in situ hybridization analysis, will be necessary to clearly define the tissue-specific cellular distribution profile of multiple D1 receptor mRNAs in this species.

Figure 5: Tissue-specific distribution of avian D1A, D1B, and D1D receptor mRNAs. Autoradiogram depicting the mRNA distribution of cloned avian D1D, D1A, and D1B receptor. Total chicken RNA, from various tissues, was denatured with formaldehyde, electrophoresed, transferred to nylon membrane, and probed with -P-labeled receptor fragments as described under ``Experimental Procedures.'' Blots were subjected to autoradiography for approximately 72 h. Estimated molecular size of receptor mRNAs are listed in the text.

In addition to D1A and D1B receptor genes, the existence of distinct genes encoding for Xenopus D1C and avian D1D receptors raises the intriguing question as to whether these genes are truly reflective of distinct D1-like receptor subfamilies, as may be the case with D1A and D1B receptors, or merely associated with the particular evolutionary pressures and constraints of these particular phyla or species. Clearly the identification of all four genes within one species or the isolation of mammalian counterparts to these receptors will help establish the distinctive molecular nature of these genes. To that end, preliminary molecular evidence suggests the existence of a D1C-like receptor gene in the avian species G. domesticus. Thus, Southern blots of BamHI-HindIII-digested avian DNA, hybridized under stringency conditions described under ``Experimental Procedures'' with human D1 and D5 receptor probes, revealed the presence of a 4 kb fragment hybridizing to both D5 and D1. Under high stringency conditions, however, this band was strongly hybridized to a Xenopus D1C receptor probe, but not at all to avian D1D, D1A, or D1B receptor probes. ()Although further work will be necessary to fully ascertain the molecular nature of this DNA fragment, these data suggest that at least in this avian species, an additional D1-like receptor gene more homologous to D1C may exist and is supportive of the contention that four distinct genes encoding D1-like receptors may be found in a single genome. Although the evolutionary relationship between mammals and birds is weak, (54, 55) the availability of both D1C and D1D receptor genes may provide the necessary molecular tools for the successful isolation of mammalian homologs of these or related D1 receptor variants that have, to date, eluded detection following screening with gene fragments encoding mammalian D1A or D1B receptors alone.

In any event, the availability of these vertebrate genes may provide a more practical approach by which to identify sequence specific motifs that may underlie the maintenance and expression of unique D1-like receptor characteristics. Given the fairly high degree of exhibited sequence homology between members of the D1-like receptor family, observed receptor-specific and selective pharmacological profiles would suggest that changes in key amino acid residues or domains may translate into major shifts in potency and substrate specificity. As such, the construction of human D1 or D5/avian D1D receptor chimeras may aid in the identification of those regions involved in the unique pharmacological specificity, affinity, and ability of the avian D1D receptor to differentiate agonists and antagonists of various structural classes and may ultimately provide the molecular basis for the rationale design of therapeutic compounds acting at D1-like receptors for the treatment of various psychomotor diseased states.

FOOTNOTES

*

This work was supported in part by grants from the Medical Research Council of Canada (PG-11121), the Ontario Friends of Schizophrenics and the Ontario Mental Health Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked ``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank(TM)/EMBL Data Bank with accession number(s) L36877[GenBank]-L36879[GenBank].

§

Supported by an Ontario Mental Health Foundation studentship.

¶

Recipient of a Medical Research Council studentship.

**

Holds NARSAD Established Investigator Award and is a Career Scientist of the Ontario Ministry of Health. To whom correspondence should be addressed: Laboratory of Molecular Neurobiology, Clarke Institute of Psychiatry, 250 College St., Toronto, Ontario M5T 1R8, Canada. Tel.: 416-979-4659; Fax: 416-979-4663.

()

The abbreviations used are: SKF-38393, 2,3,4,5-tetrahydro-7,8dihydroxy-1-phenyl-1H-3-benzazepine; PCR, polymerase chain reaction; kb, kilobase pair(s); SCH-23390, (R)-(+)-7-chloro-8-hydroxy3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; ADTN, 6,7-dihydroxy-2-aminotetralin; SCH-23388, S form of SCH-23390;SCH39166, (-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo-[d]-naptho-[2,1-b]-azepine; SKF-82526, 6-chloro-7,8dihydroxy-1-(p-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine; RT, reverse transcriptase; TM, transmembrane.

()

S. E. Hamadanizadeh and H. B. Niznik, unpublished observations.

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