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Dl Dopamine Receptors in the Rat Brain

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Dl Dopamine Receptors in the Rat Brain The Journal of Neuroscience August 1966, 6(8): 2352-2365 D-l Dopamine Receptors in the Rat Brain: A Quantitative Autoradiographic Analysis Ted M. Dawson,* Donald R. Gehlert,*sl R. Tyler McCabe,* Allen Barnett,? and James K. Wamsley* *Departments of Psychiatry and Pharmacology, University of Utah School of Medicine, Salt Lake City, Utah 84132, and tPharmaceutical Research Division, Schering-Plough Corporation, Bloomfield, New Jersey 07003 The distribution of dopamine D-l receptors has been deter- of nonspecific binding. As such, these two compounds are not mined in the rat brain by a quantitative in vitro light-micro- suitable ligands for the study of D-l receptors by autoradiog- scopic autoradiographic method. The binding of [IV-methylsHI- raphy. SCH 23390 to slide-mounted tissue sections takes place with Recently, Iorio et al. (1983) described a putative neuroleptic, characteristics expected of a substance that recognizes D-l re- benzazepine SCH 23390 [(R)-(+)-8 chloro-2,3,4$tetrahydro- ceptors. The binding is saturable, has high affinity, and exhibits 3-methyl-5-phenyl-lH-3-benzazepine-7-01 hemimaleate], and an appropriate pharmacology and stereospecificity in several postulated that it was a selective D- 1 receptor antagonist based discrete microscopic brain regions as determined by quantitative on its potent blockade of dopamine (DA)-stimulated adenylate autoradiography. The highest density of D-l receptors occurs cyclase, its weak displacement of )H-spiperone binding, its fail- in the caudate-putamen, accumbens nucleus, olfactory tubercle, ure to induce prolactinemia, and its selective displacement of and the substantia nigra pars reticulata. High concentrations of 3H-piflutixol binding from striatal slices (Hyttel, 1983). A tri- D-l receptors were associated with the intercalated and medial tiated form of SCH 23390 has been determined to bind with nuclei of the amygdala, entopeduncular nucleus, and major is- stereospecificity, with high affinity, and in a saturable manner land of Calleja. Furthermore, moderate to low concentrations to receptor sites that have been characterized as the D- 1 recep- were observed in several other structures, such as the frontal tors (Billard et al., 1984). Therefore, )H-SCH 23390 has been cortex, subthalamic nucleus, and several thalamic, hypotha- designated as the most suitable ligand for investigations at- lamic, and hippocampal areas. The distribution of D-l receptors tempting to characterize the D-l receptor. correlates very well with projection areas of dopaminergic path- In vitro autoradiographic techniques have previously been ways. This technique furnishes a powerful assay for the accu- used to localize DA receptors microscopically. Extensive studies mulation of detailed pharmacologic and anatomical data about have localized D-2 receptors using 3H-spiperone (Klemm et al., D-l receptors, and the results suggest possible CNS sites of 1979; Murrin and Kuhar, 1979; Palacios and Wamsley, 1984; action of D-l dopamine receptor selective compounds. Palacios et al., 198 la), 3H-sulpiride (Gehlert and Wamsley, 1984, 1985; Jastrow etal., 1984), ‘H(-)-DO710 (Sokoloffet al., 1985), Pharmacological, biochemical, anatomical, and physiological and L251-iodosulpride (Martres et al., 1985a, b); these investi- studies have indicated that there are multiple receptors for do- gations have demonstrated that the D-2 receptor is associated pamine (see for review Creese and tiff, 1982; Creese et al., primarily with the tuberoinfundibular system, nigrostriatal sys- 1983; Kebabian and Calne, 1979; Stoof and Kebabian, 1984). tem, periglomerular DA system of the olfactory complex, and, Dopamine type-l (D-l) receptors are associated with stimula- to a minor extent, the mesocortical and mesolimbic systems. tion of adenylate cyclase on agonist activation (Kebabian and Recently, we utilized 3H-SCH 23390 (Dawson et al., 1985a), Calne, 1979). Dopamine type-2 (D-2) receptors mediate either and Scatton and Dubois (1985) used 3H-SKF 38393 to localize the inhibition of adenylate cyclase (Cote et al., 198 1; Onali et D-l receptors to several mesocortical and mesolimbic system al., 198 1, 1984) or are unassociated with the enzyme (Kebabian structures where the existence of DA terminals and receptors and Calne, 1979). D-2 receptors have been extensively char- was suspected but could not be demonstrated with previously acterized by radioligand binding studies using 3H-spiperone available radioligands. (Creese et al., 1977; Fields et al., 1977) and the selective D-2 In the present study, ‘H-SCH 23390 was evaluated for its antagonist ‘H-sulpiride (O’Connor and Brown, 1982; Theo- suitability and specificity as a D- 1 receptor antagonist by using dorou et al., 1979; Woodruff and Freedman, 198 1). D- 1 recep- the quantitative technique of in vitro receptor autoradiography tors have been characterized using 3H-cis-(Z)-flupenthixol (Huff (Unnerstall et al., 1982; see for review Kuhar, 1985b). In ad- and Molinoff, 1985; Hyttel, 1978a, b; Murrin, 1983) and )H- dition, the regional distribution and density of D-l dopamine cis-(Z)-piflutixol (Hyttel, 198 l), but both compounds show sim- receptors in discrete microscopic regions of the rat brain are ilar affinities for the D-l and D-2 receptors and a high degree described. Received Oct. 28, 1985; revised Jan. 30, 1986; accepted Feb. 5, 1986. Materials and Methods We wish to thank Margaret Long and Linda Miller for their excellent secretarial assistance. This work was supported by grants from the Public Health Service Materials (NS-22033) and the Scottish Rite Foundation. T.M.D. is a recipient of a P.M.A. [N-methyl-3H]-SCH 23390 (specific activity, 72 Ci/mmol), SCH 23390 Medical Student Research Fellowship. Correspondence should be addressed to James K. Wamsley, Ph.D., Department (R-enantiomer), cis-Q-piflutixol, truns-(E)-piflutixol were generous gifts of Psychiatry, University of Utah Medical Center, 50 North Medical Drive, Salt from Schering-Plough Corp. (Bloomfield, NJ). Fluphenazine (New En- Lake City, Utah 84132. gland Nuclear, Boston, MA), forskolin (Calbiochem-Behring Corp., La I Present address: Section on Biochemical Pharmacology, Hypertension-Endo- jolla, CA), k&anse& (Jan&en Pharmaceutics Inc., PiscaGway, NJ), crine Branch, National Heart, Lung, and Blood Institute, National Institutes of SKF 38393 (Smith Kline & French Labs. Philadelphia. PA). ADTN Health, Bethesda, MD 20205. and triprolidiie (Burroughs Wellcome Co., Research friar&e Park, NC), Copyright 0 1986 Society for Neuroscience 0270-6474/86/082352-14$02.00/O Naloxone (Endo Laboratories Inc., Garden City, NJ), atropine (J. T. 2352 The Journal of Neuroscience DopamineD-l Receptors 2353 Baker Chemical Co., Phillipsburg, NJ), serotonin and propranolol (Sig- dia. Micromolar concentrations of several pharmacologically unrelated ma Chemical Co., St. Louis, MO), diazepam (Hoffman-LaRoche, Nut- compounds (atropine, diazepam, forskolin, naloxone, nomifensine, pro- ley, NJ), sulpiride (S.P.A. per l’industria chemica e. Pharmaceutics, pranolol, 5-HT, and triprolidine) were added to the incubation media Milan, Italy), and methysergide (Sandoz Inc., E. Hanover, NJ) were in order to determine their effects on ‘H-SCH 23390 binding. Auto- either purchased or were gifts from the manufacturers. radiograms were then generated, and the autoradiographic grain den- sities were quantitated as described below. This provided a means for plotting saturation isotherms and displacement curves from data ob- Tissue preparation tained from several microscopic regions of the rat brain. Scatchard Male Sprague-Dawley rats (150-300 gm) were purchased from Simon- analysis was performed on the saturation data, yielding Kd’s and B,,‘s sen Laboratories and kept under a controlled light-dark cycle and tem- for several areas. Competition curves, constructed from the densito- perature until sacrificed by intracardial perfusion (while under deep metric data, were analyzed using an iterative, nonlinear, least-squares, chloroform anesthesia) with 0.9% saline. The brains were rapidly dis- curve-fitting computer program (Munson and Rodbard, 1980). sected from the skull and frozen by slow immersion into isopentane at -80°C. Sections (10 pm thick) were cut on a Harris cryostat (- 18°C) Quantitation microtome (Harris Manufacturing, N. Billerica, MA) and thaw-mount- Analysis of the autoradiographic grain densities on the film (D-l re- ed onto cold chrome-alum/gelatin-coated microscope slides. The slide- ceptors) in corresponding tissue areas was accomplished using com- mounted tissue sections were then stored for short periods of time in a puter-assisted microdensitometric analysis. A DADS model 560 (Stahl self-defrosting freezer (-20°C). Research, Rochester, NY) photometry system (an Oki computer inter- faced with an MPV-Compact photometer attached to the L&z micro- Biochemical investigations scope) was used for this purpose. Optical density values were converted The dissociation, association, and saturation kinetics of ‘H-SCH 23390 into molar quantities of bound ligand by referencing a tritium-labeled binding to slide-mounted tissue sections were studied by exposing sec- polymer (Autoradiographic [‘HI-Microscales; Amersham Corp., Ar- tions of forebrain, containing primarily striatum, to various rinse times lington Heights, IL). These standards are calibrated for the tritium con- (3 set to 20 min), incubation times (l-60 min), and incubation con- centration in gray-white matter areas according to the method of Un- centrations (0.05-10.0 nM), respectively, in
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