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Localization of adrenergic receptors and CRH in human hypothalamus
BIOL PSYCHIATRY 1990,27:41A-179A
76A
Basic and Clinical Studies
80 LOCALIZATION OF ADRENERGIC RECEPTORS AND CRH IN HUMAN HYPOTHALAMUS Gary Duncan, Ph.D., Kelley Y. Li~:tle, M.D., I. Merchenthaler, Ph.D., George Breese, Ph.D. Universi~ of North Carolina School of Medicine, Chapel I-till, NC 27599-7160. Large numbers of noradrenergic fibers innervate die 1:ypathalamt,.,~ and may affect hypothalamie-pi~itaryadrenal (HPA) axis function through synaptic comact with CRH.::ontaining herons. Noradrenergic and HPA-axis dysfunction are common in persons with maj~T depressive, disorders. Many antidepressant treatments appear to down. regulate noradrenergic recept,ar~ ='~drecent evidence ~).,~ests they may also alter HPA function. Preliminary to a study of suicide victims with major depression, we explored the type, density, and dis~bution of adrenergic-receptor binding in human hypothalamus by use of quantitative autoradiography and the areas where mis binding was co-localized with CRH-containing neurons by use of immunohistochemistry. Brain tissue was obtained at autopsy from accident or homicide victims, as authorized by the Chief Medical Examiner, within 24 hours of death. The middle to anterior hypothalamus was freshly dissected and either quick frozen with dry ice or fixed. Autoradiographic sections were incubated with t2sI pindolol and t2sI clonidine. Specific binding was quantified with densitome~, in a number of hypothalamic nuclei. Initial findings include high specific beta-adrenergic binding in SON, moderate beta-binding in PVN, and diffusely low alpha2 binding. CRH fibers and cell ~dies were observed in PVN, as well as the SON, which has not been previously described. Further results from this ongoing study will be presented.
81
-3PPP EFFECTS ON LOCAL CEREBRAL GLUCOSE UTILIZATION IN THE RAT L.B. Dixon, H. Kaneda, N.G. Cascella, J.R. Walters, C.A. Tamminga Maryland Psychiatric Research Center, University of Maryland, Baltimore, MD 21228. Partial dopamine (DA) agonists, including the prototypical 3-(3-hydroxyphenyl)-N-(l-propyl)piperidine (3PPP), are currently of considerable interest in the treatment of schizophrenia. At low doses, -3PPP selectively stimulates the autoreceptor to reduce DA release and neuronal firing. At higher doses, -3PPP blocks apomorphine's postsynaptic actions. Thus, -3PPP may diminish DA-mediated transmission through two distinct actions. The goal of this study is to I) assess -3PPP action on local cerebral gluccse utilization (LCGU) in rats to demonstrate its functional localization at low and high doses; and 2) to compare -3PPP's effects with that of a typical neuroleptic, haloperidol. Doses of -3PPP were determined from electrophysiological evidence of DA auto- and postsynaptic-receptor action. Low dose -3PPP produced significantly increased glucose uptake in cortical areas (e.g., medial, prefrontal, cingulate, sensorimotor, auditory, p < 0.05), as well as in limbic regions, including hippocampus, septal nucleus, nucleus accumbens, and medial and basolateral amygdala (p < 0.05), compared with saline, control ~i~c higher dose of -3PPP produced vi~ually no significant changes in LCGU. The distribution of m~tabolic changes induced by either the low (autoreceptor) or h;gh (i)os)~ynaptic) dose is distinctive for each dose, as predicted from other preclinical findings. Comparison of -3PPP effects on LCGU with acute and ehroiiic haloperidol treatment will be presented to propose the locus of partial DA-agonist, antipsychotic action.
82 COM?UTER MOLECULAR MODELING OF L-PHOSPHOSERINE TO THE NMDA RECEPTOR R.J. McClure, Ph.D., W.E. Klunk, M.D., Ph.D., J.W. Pettegrew, M.D. Western Psychiatric Institute and Clinic, UMversiO~of Pittsburgh, Pittsburgh, PA 15213. Recent studies by both in-vitro mid in-vivo 3tp NMR have demonstrated increased levels of phosphomonoesters (PME), such as phosphocholine, phosphoethanolamine and L-phosphoserine (L-PS), in A]zheimer's diseased (AD) brain. The: widespread cell loss in AD suggests that there could be an endogenous neurotoxic
76A
Basic and Clinical Studies
80 LOCALIZATION OF ADRENERGIC RECEPTORS AND CRH IN HUMAN HYPOTHALAMUS Gary Duncan, Ph.D., Kelley Y. Li~:tle, M.D., I. Merchenthaler, Ph.D., George Breese, Ph.D. Universi~ of North Carolina School of Medicine, Chapel I-till, NC 27599-7160. Large numbers of noradrenergic fibers innervate die 1:ypathalamt,.,~ and may affect hypothalamie-pi~itaryadrenal (HPA) axis function through synaptic comact with CRH.::ontaining herons. Noradrenergic and HPA-axis dysfunction are common in persons with maj~T depressive, disorders. Many antidepressant treatments appear to down. regulate noradrenergic recept,ar~ ='~drecent evidence ~).,~ests they may also alter HPA function. Preliminary to a study of suicide victims with major depression, we explored the type, density, and dis~bution of adrenergic-receptor binding in human hypothalamus by use of quantitative autoradiography and the areas where mis binding was co-localized with CRH-containing neurons by use of immunohistochemistry. Brain tissue was obtained at autopsy from accident or homicide victims, as authorized by the Chief Medical Examiner, within 24 hours of death. The middle to anterior hypothalamus was freshly dissected and either quick frozen with dry ice or fixed. Autoradiographic sections were incubated with t2sI pindolol and t2sI clonidine. Specific binding was quantified with densitome~, in a number of hypothalamic nuclei. Initial findings include high specific beta-adrenergic binding in SON, moderate beta-binding in PVN, and diffusely low alpha2 binding. CRH fibers and cell ~dies were observed in PVN, as well as the SON, which has not been previously described. Further results from this ongoing study will be presented.
81
-3PPP EFFECTS ON LOCAL CEREBRAL GLUCOSE UTILIZATION IN THE RAT L.B. Dixon, H. Kaneda, N.G. Cascella, J.R. Walters, C.A. Tamminga Maryland Psychiatric Research Center, University of Maryland, Baltimore, MD 21228. Partial dopamine (DA) agonists, including the prototypical 3-(3-hydroxyphenyl)-N-(l-propyl)piperidine (3PPP), are currently of considerable interest in the treatment of schizophrenia. At low doses, -3PPP selectively stimulates the autoreceptor to reduce DA release and neuronal firing. At higher doses, -3PPP blocks apomorphine's postsynaptic actions. Thus, -3PPP may diminish DA-mediated transmission through two distinct actions. The goal of this study is to I) assess -3PPP action on local cerebral gluccse utilization (LCGU) in rats to demonstrate its functional localization at low and high doses; and 2) to compare -3PPP's effects with that of a typical neuroleptic, haloperidol. Doses of -3PPP were determined from electrophysiological evidence of DA auto- and postsynaptic-receptor action. Low dose -3PPP produced significantly increased glucose uptake in cortical areas (e.g., medial, prefrontal, cingulate, sensorimotor, auditory, p < 0.05), as well as in limbic regions, including hippocampus, septal nucleus, nucleus accumbens, and medial and basolateral amygdala (p < 0.05), compared with saline, control ~i~c higher dose of -3PPP produced vi~ually no significant changes in LCGU. The distribution of m~tabolic changes induced by either the low (autoreceptor) or h;gh (i)os)~ynaptic) dose is distinctive for each dose, as predicted from other preclinical findings. Comparison of -3PPP effects on LCGU with acute and ehroiiic haloperidol treatment will be presented to propose the locus of partial DA-agonist, antipsychotic action.
82 COM?UTER MOLECULAR MODELING OF L-PHOSPHOSERINE TO THE NMDA RECEPTOR R.J. McClure, Ph.D., W.E. Klunk, M.D., Ph.D., J.W. Pettegrew, M.D. Western Psychiatric Institute and Clinic, UMversiO~of Pittsburgh, Pittsburgh, PA 15213. Recent studies by both in-vitro mid in-vivo 3tp NMR have demonstrated increased levels of phosphomonoesters (PME), such as phosphocholine, phosphoethanolamine and L-phosphoserine (L-PS), in A]zheimer's diseased (AD) brain. The: widespread cell loss in AD suggests that there could be an endogenous neurotoxic