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Chlorpromazine and the prototypical D1 dopamine receptor antagonist SCH23390 identify multiple subtypes of D1-like receptors not linked to adenylate cyclase
Basic Science I1
BIOL PSYCHIATRY |99| ~-~9:43A-| 85A
| 61A
258 CHLORPROMAZINE AND THE PROTOTYPICAL D! DOPAMINE RECEPTOR ANTAGONIST SCH233q0 IDENTIFY MULTIPLE SUBTYPES OF DI-LIKE RECEPTORS NOT LINKED TO ADENYLATE CYCLASE John M. Petitto, M.D., Larry L. Cook, Ph.D., Mark H. Lewis, Ph.D., Daniel H. Mooney, B.A., David E. Nichols, Ph.D., Richard B. Mailman, Ph.D. Department of Ps3'chiat~', UniversiO' of North Carolina at Chapel Hill, N C 27599, and the Department of Medicinal Chemistry' and Pharmacognoo,, Purdue Universi~'. The D~ class of dopamine receptors pla: a central role in dopamine-mediated behavioral and neur,".,che~caI functions previously ascribed solely to ~he D2 receptor class. Until recently, it was commonly believed that all D~ receptors were linked to the stimulation of cAMP synthesis. We have previously shown that Dr-like receptors in the amygdala are not linked to cAMP synthesis. This and other evidence led to the hypothesis that there are multiple subtypes of the D~ receptor class. In the present series of experiments, the recognition characteristics of cyclase-linked (striatam) and nonlinked (amygdala) Di binding sites were examined using the prototypical D, receptor ligand [3H]SCH23390. As expected, in the striatum competition of ~ 2 3 3 ~ and chlorpromazine had kinetics consi~ten t with interaction of the ligartd with a single population of binding sites. Conversely, in the amygdala analysis of the data clearly fit a model with two or more recognition sites. Moreover, additional experiments ruled out the possibility, that these binding sites in the a m y g ~ a are D2, D3, or serotonin receptors. Tlds study provides additional evidence that there are multiple subtypes of brain Dl-like receptors. Developing drug selective for these may have vital implications for the biological therapy of neuropsychiatric disorders. This work was supported by grants MH40537, MH42705, ~ 3 1 2 7 , and GM07040.
259 EFFECT OF APOMORPHINE ON DOPAMINE RECEPTOR GENE EXPRESSION IN THE RAT BRAIN James H. Meador-Woodruff, M.D., Alfred Mansour, Ph.D., Scott P. Damask, Qun-Yong Zhou, James R. Bunzow, Olivier Civelli, Ph.D., Stanley J. Watson, Ph.D., M.D. Department of Psychiatry an,J Mental Health Research Institute, Universi~. of Michigan, Ann Arbor, Mi 48109-0720. With the cloning of members of the dopamine (DA) receptor family, it has become increasingly clear that the brain DA systems are more complex than previously appreciated. We and others have previously reported on the distribution of the messenger RNA (mRNA) encoding DA D, and D2 receptor':, in brain, as well as the lack of an effect of chronic haloperidol treatment on the expression of DA receptor genes. The present study d.~scribes the effects of chronic DA agonist treatment on D~ and D2 dopamine gene expression by quantitating the corresponding mRNAs by in situ hybridization in the nigrostriatal system of the rat. Six Sprague-Dawley rats were treated with apomorphine (5 mg/kg twice a day), and six with a vehicle control. Brains v,-~re removed and frozen, cryostat sectioned (10 p.m), and treated with probes specific for the presence of mRNAs encoding the D~, D2 (total), D~, and D2a receptors. This treatment had no significant effect on the levels of any of these mRNAs in any region studied. These results suggest :bat these mRNAs are particularly difficmt to pharmacologically regulate with either DA agonists or antagonists; this may be important in postmortem studies of schizophrenia, as the effect of chronic psychotropic medication may not be reflected in the levels of mRNA detected.
BIOL PSYCHIATRY |99| ~-~9:43A-| 85A
| 61A
258 CHLORPROMAZINE AND THE PROTOTYPICAL D! DOPAMINE RECEPTOR ANTAGONIST SCH233q0 IDENTIFY MULTIPLE SUBTYPES OF DI-LIKE RECEPTORS NOT LINKED TO ADENYLATE CYCLASE John M. Petitto, M.D., Larry L. Cook, Ph.D., Mark H. Lewis, Ph.D., Daniel H. Mooney, B.A., David E. Nichols, Ph.D., Richard B. Mailman, Ph.D. Department of Ps3'chiat~', UniversiO' of North Carolina at Chapel Hill, N C 27599, and the Department of Medicinal Chemistry' and Pharmacognoo,, Purdue Universi~'. The D~ class of dopamine receptors pla: a central role in dopamine-mediated behavioral and neur,".,che~caI functions previously ascribed solely to ~he D2 receptor class. Until recently, it was commonly believed that all D~ receptors were linked to the stimulation of cAMP synthesis. We have previously shown that Dr-like receptors in the amygdala are not linked to cAMP synthesis. This and other evidence led to the hypothesis that there are multiple subtypes of the D~ receptor class. In the present series of experiments, the recognition characteristics of cyclase-linked (striatam) and nonlinked (amygdala) Di binding sites were examined using the prototypical D, receptor ligand [3H]SCH23390. As expected, in the striatum competition of ~ 2 3 3 ~ and chlorpromazine had kinetics consi~ten t with interaction of the ligartd with a single population of binding sites. Conversely, in the amygdala analysis of the data clearly fit a model with two or more recognition sites. Moreover, additional experiments ruled out the possibility, that these binding sites in the a m y g ~ a are D2, D3, or serotonin receptors. Tlds study provides additional evidence that there are multiple subtypes of brain Dl-like receptors. Developing drug selective for these may have vital implications for the biological therapy of neuropsychiatric disorders. This work was supported by grants MH40537, MH42705, ~ 3 1 2 7 , and GM07040.
259 EFFECT OF APOMORPHINE ON DOPAMINE RECEPTOR GENE EXPRESSION IN THE RAT BRAIN James H. Meador-Woodruff, M.D., Alfred Mansour, Ph.D., Scott P. Damask, Qun-Yong Zhou, James R. Bunzow, Olivier Civelli, Ph.D., Stanley J. Watson, Ph.D., M.D. Department of Psychiatry an,J Mental Health Research Institute, Universi~. of Michigan, Ann Arbor, Mi 48109-0720. With the cloning of members of the dopamine (DA) receptor family, it has become increasingly clear that the brain DA systems are more complex than previously appreciated. We and others have previously reported on the distribution of the messenger RNA (mRNA) encoding DA D, and D2 receptor':, in brain, as well as the lack of an effect of chronic haloperidol treatment on the expression of DA receptor genes. The present study d.~scribes the effects of chronic DA agonist treatment on D~ and D2 dopamine gene expression by quantitating the corresponding mRNAs by in situ hybridization in the nigrostriatal system of the rat. Six Sprague-Dawley rats were treated with apomorphine (5 mg/kg twice a day), and six with a vehicle control. Brains v,-~re removed and frozen, cryostat sectioned (10 p.m), and treated with probes specific for the presence of mRNAs encoding the D~, D2 (total), D~, and D2a receptors. This treatment had no significant effect on the levels of any of these mRNAs in any region studied. These results suggest :bat these mRNAs are particularly difficmt to pharmacologically regulate with either DA agonists or antagonists; this may be important in postmortem studies of schizophrenia, as the effect of chronic psychotropic medication may not be reflected in the levels of mRNA detected.