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Localization of Dopamine D, Receptor Mrna and D, and D, Receptor Binding in the Rat Brain and Pituitary: an in Situ Hybridization-Receptor Autoradiographic Analysis

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Localization of Dopamine D, Receptor Mrna and D, and D, Receptor Binding in the Rat Brain and Pituitary: an in Situ Hybridization-Receptor Autoradiographic Analysis The Journal of Neuroscience, August 1990, 70(8): 2587-2800 Localization of Dopamine D, Receptor mRNA and D, and D, Receptor Binding in the Rat Brain and Pituitary: An in situ Hybridization-Receptor Autoradiographic Analysis Alfred Mansour,’ James H. Meador-Woodruff,i James R. Bunzow,2 Olivier Civelli,* Huda Akil,’ and Stanley J. Watson’ ‘Mental Health Research Institute, University of Michigan, Ann Arbor, Michigan 48109-0720, and *Vellum Institute for Advanced Biomedical Research, The Oregon Health Sciences University, Portland, Oregon 97201 Several lines of evidence suggest the existence of multiple Cumulative evidence suggeststhe existence of at least 2 distinct dopamine receptor subtypes, referred to as D, and D,. The dopaminergic receptor subtypes, referred to as D, and D,. D, present study examines the distribution of these dopamine dopamine (DA) receptors are positively coupled to adenylate binding sites in the rat brain and pituitary in relation to the cyclase (Stoof and Kebabian, 1984), widely distributed in the distribution of D, receptor mRNA using a combination of in CNS (Boyson et al., 1986; Dawson et al., 1986; Dubois et al., vitro receptor autoradiographic and in situ hybridization 1986; Bouthenet et al., 1987; Wamsley et al., 1989), and abun- techniques. 3H-Raclopride and 3H-SCH23390 (in the pres- dant in the parathyroid gland (Attie et al., 1980). D, DA recep- ence of 1 ELM ketanserin) were used to label D, and D, re- tors, on the other hand, are either not coupled to adenylate ceptor binding sites, respectively, while a 495 bp cRNA probe cyclase (Memo et al., 1986) or negatively coupled (Onali et al., synthesized from the Sac I-Bglllfragment of a rat D, receptor 1985) and are densely distributed in the basal ganglia (Martres cDNA was used to visualize the D, receptor mRNA. Analysis et al., 1985; Charuchinda et al., 1987; Joyce and Marshall, 1987; of adjacent tissue sections in which receptor autoradiog- Richfield et al., 1987) and pituitary gland (Kohler and Fahlberg, raphy and in situ hybridization had been performed revealed 1985; Pazos et al., 1985; DeSouza, 1986). several brain regions where the D, binding site and corre- Selective lesion studies(Creese et al., 1977; Nagy et al., 1978; sponding mRNA appear to be similarly distributed, including Schwartz et al., 1978; Cross and Waddington, 1981; Joyce and the caudate-putamen, nucleus accumbens, olfactory tuber- Marshall, 1987; Trugman and Wooten, 1987; Filloux et al., cle, globus pallidus, substantia nigra, and ventral tegmental 1988; Porceddu et al., 1986) suggestthat while D, and D, re- area. In the pituitary gland, D, binding sites and mRNA ap- ceptors are both localized on pre- and postsynaptic membranes, pear to be codistributed with very dense levels in the inter- the D, subtype may function as an “autoreceptor,” modulating mediate lobe and individually labeled cells in the anterior the synthesisand/or releaseof DA. Support for this hypothesis lobe. Brain regions demonstrating a lack of correspondence has come from findings demonstrating that D, receptors can be between the distribution of the D, binding site and D, receptor localized on DA-containing cells (Reisine et al., 1979) and that mRNA include the olfactory bulb, neocortex, paleocortex, application of selective D, agonists produces a decreasein cell hippocampus, and zona incerta. Several hypotheses are dis- firing (White and Wang, 1983) DA release,and synthesis(Stoof cussed to explain the lack of correspondence in certain brain et al., 1982; Brown et al., 1985). Similar changesin DA release regions; these include the localization of receptor binding and turnover have not been observed with selective D, receptor sites on both fibers and cell bodies and receptor transport. agonists(Stoof et al., 1982; Brown et al., 1985; Clark and Gal- These studies provide a better understanding of the ana- loway, 1985). tomical distribution of the D, receptor and serve as a frame- The rat D, receptor has been recently cloned (Bunzow et al., work for future regulatory and anatomical mapping studies. 1988) and is structurally similar to membersof the family of G By focusing on specific brain regions, such as the nigro- protein-coupled receptors that include the o(- and @-adrenergic striatal system, hippocampus, and olfactory bulb, they pro- receptors, the muscarinic receptors and rhodopsin. Northern vide insights into D, receptor synthesis, transport, and in- blot analysis suggeststhat the mRNA coding for the D, receptor sertion into cell membranes. showsa similar distribution to the D, sitesreported with ligand binding, with high levels observed in the striatum and pituitary. Further, transfection of the D, receptor DNA into cells normally not demonstrating DA receptors results in the expression of Received Nov. 6, 1989; revised Mar. 14, 1990; accepted Mar. 15, 1990. specific D, receptor binding. We are grateful to Elizabeth Cox for her expert secretarial assistance and for Given these findings, we have recently examined the distri- grants from the National Institute for Mental Health (MH4225 I, MH15794, bution of the D, receptor mRNA using in situ hybridization MH456 14), National Alliance for the Mentally Ill, Lucille P. Markey Charitable Trust, Theophile Raphael, National Alliance for Research on Schizophrenia and (Meador-Woodruff et al., 1989). D, receptor mRNA was vi- Depression, and Eli Lilly (APA/Lilly Psychiatric Fellowship). sualized in DA projections fields, such as the caudate-putamen, Correspondence should be addressed to Alfred Mansour, Ph.D., Mental Health Research Institute, University of Michigan, 205 Washtenaw Place, Ann Arbor, nucleus accumbens,and olfactory tubercle, as well as in dopa- MI 48 109-0720. mine-containing cell groups such as the substantia nigra (SN), Copyright 0 1990 Society for Neuroscience 0270-6474/90/082587-14$03.00/O ventral tegmental area (VTA), and zona incerta. Such a distri- 2588 Mansour et al. - Localization of Dopamine D, Receptor Binding bution would suggest that the D, receptor has both a pre- and labeled with jH-SCH23390 were given four 4-min washes. All slides postsynaptic localization and the receptors visualized in the SN were then quickly dipped in 250 ml distilled water (4°C) and dried with a portable hair dryer set to “cool.” Nonspecific binding was evaluated and VTA may serve as autoreceptors. Consistent with this hy- by treating a parallel set of slides with the same concentrations of tri- pothesis, unilateral 6-hydroxydopamine lesions of the DA neu- tiated ligand with a 1 PM final concentration of an unlabeled competitor: rons in the medial forebrain bundle produce a complete ipsi- spiperone to displace 3H-raclopride and SCH23390 to displace 3H- lateral loss of D, receptor mRNA in the SN and VTA and a SCH23390. compensatory increase in the D, receptor mRNA of the dener- Saturation studies. Prior to preparing tissue for receptor autoradiog- raphy, saturation experiments were performed on slide-mounted brain vated striatum (Mansour et al., 1990). sections to determine the binding kinetics of 3H-raclopride and )H- The purpose of the present set of studies is to compare the SCH23390. Forebrain sections were incubated with a minimum of 8 distribution of D, receptor mRNA in the brain and pituitary to concentrations of either 3H-raclopride (15.0-O. 12 nM) or ‘H-SCH23390 D, and D, binding sites using a combination of in situ hybrid- (7.6-0.06 nM) and washed and dried as described earlier. The binding was quantified by placing brain sections in scintillation vials containing ization and in vitro receptor autoradiographic techniques. These 10 ml of scintillant and vigorously shaking for 30 min in a metabolic anatomical studies provide a more precise analysis of the dis- shaker. Each data point is an average of 2 brain sections. Saturation tribution of D, receptor mRNA and dopaminergic ligand bind- experiments were performed at least twice and graphed as Scatchard ing sites than is possible with Northern analysis and homogenate plots. Kd and B,,, values were determined with the LIGAND program binding. Moreover, while the transfection studies (Bunzow et developed by Munson and Rodbard (1980). Competition studies. To characterize the binding sites labeled by 3H- al., 1988) discussed previously are essential for identifying a D, raclopride and ‘H-SCH23390, competition studies were performed with receptor, studies combining in situ hybridization and receptor slide-mounted brain sections at concentrations 3 times the Kd value for autoradiography are necessary in supporting, validating, and each ligand. These concentrations correspond to the ones used in sub- extending these findings to the CNS. sequent autoradiographic mapping studies and represent a 75% receptor occupancy for each ligand. Competition studies were performed with a Several quantitative studies are available describing the dis- series of dopaminergic compounds [haloperidol, chlorpromazine, spi- tribution of D, and D, binding sites in the brain (e.g., Bouthenet perone, (+) and (-) butaclamol, droperidol, raclopride, and SCH233901, et al., 1987; Charuchinda et al., 1987; Wamsley et al., 1989). It as well as nondopaminergic drugs (propranolol, clonidine, mianserin, is not the focus of the present study to replicate these findings, and bremazocine). The brain sections were incubated, washed, and but to examine in serial sections the distribution of the mRNA dried, and the binding was quantified as described earlier. Autoradiographic mapping. After being brought to room temperature, encoding for the D,
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