Differential localization of D2, D3, and D4 mRNA in midgestational human forebrain by in situ hybridization

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BlOL PSYCUlATRY 1996:39:~OO-666

452. DIFFERENTIAL LOCALIZATION OF D;2' D3 , AND D4 MRNA IN MIDGESTATIONAL HUMAN FOREBRAIN BY IN SITU HYBRIDIZATION A.S. Unis, M.D. Roberson, K. Hill, M.W. Hamblin, & D.M. Dorsa Depanment of Psychiervations of hybridizution signill using 33P-ATP endlabeled oligonucleotide antiscnse to D4 receplor mRNA su~gcsls lin intermediate pattern of expression between Dz and 0,1 receptor mRNA's. Spccifically, hybridization signal could be detected both in betterdifferentiiltcd subconical nuclei nnd ill geoninal matrix nnd cortiClll plale. Ifdopamlnc plays II role In neuronal diffcrentill!ion in the human brain. the prominent expression of 0.1 receptors in cxtrn·slriatill, rllpidly developing brJin regions makes this receptor a likely candidote to mediate dopamine's proposed morphogenic effects.

453. BIOSYNTHESIS OF THE DOPAMINE Dl, D4, AND D5 RECEPTOR POLYPEPTIDES C. Bergson', M, Lidow 2 , P. Goldman-Rakic 2 • & R. Levenson I I Pennsylvania Slate College of Medicine, Hershey. PA 17033: 2Ynle School of Medicine, New Haven. cr 06510

We have developed llntibooie~ !>pccific for lite 01, 04 lind OS dopamine (DA) receptor subtypes and have used these antibodies to characterizl;llhe

corresponding receptor proteins. StructurcJfunction analyses of the 0 I. D4 and D5 receptor proteins expressed in transfectcd mammalian cells were undertaken to eXlImine biosynthctic steps regulating DA receptor funclion. The D1 receptor gene 3ppears to encode u single hclerolleneously glycosylnled polypeptide. In contrast, the 05 receptor gene yields at least two major glycosylatcd polypeptide product~. One product corresponds to the ful]-!<.:ngth OS receptor protein. The Glher corrcspom.ls to a lruncated 05 receptor, basctl on its molecular nlass, Studies on OS receptor biosynthesis and funClion indiCiitc that specilic binding of the 01 tmtagonist SCH23390 is abrogmcd in the presence of 0.5 lLg/ml lunicamycin. on inhibitor of protein glycosylation. Confocal immunonuorcsccncc fCvcals that unglycosyhllcd 05 receptors do not rellch the plasma mcmbmne. but accumulate in a perinuclear compartment. In conlrasllo 01 lind DS receptors, glycosylatcd spct'ies of Ihe Dol receptor arC not detected. aLlll Western blots suggest that the D4 receptor may form dimers. Taken together these initial studies suggcst lhal the DA receptor subtypes differ considernbly Wilh respect to their biosynthesis OInd post-trnnslational processing. They :Ilso hinlthat glycosylation plays a role in regulating DA reccptor nctivity,

454. HIPPOCAMPAL GATING OF CORTICAL THROUGHPUT IN THE NUCLEUS ACCUMBENS: MODULATION BY DOPAMINE

P. O'Donnell & A.A. Grace Departments of Neuroscience :md Psychiatry. Univel1iity of Piusburgh, Pitl!iburgh. FA 15260 The nuclcus m:cumben~, prefrontal cortex, and hippocampus have been implicated in the palhogenesis of schizophrenic symptoms. We have recently shown that hippocampal input to the nucleus nccumbens is necessary to cnable inputs arriving from the prefrontal cortex 10 induce spike activity in :Iccumbens ncurons (O'Oonnell IlnLl Grace, J Nellrosci. 1995,1 5:3622-3639). This study focuses on the nction!> of dopuminc (DA) on this galing mechtlnism. In this stully, we analyzed lhe effects of DA-reluted drogs on the pattern of spontaneous firing observed in nucleus accumbcns cells recorded inlracellularly ;11 ~'i~'u, ;Inti on the :lbility ofconical afferent stimulation to evoke action potential discharge. Inlraccllular recordings wcre made it, ~.jl'O from 8 accumbens neurons, 5 of whieh cxhibited a bistable membr.me potential consistent with hippocampal SOling. Syslemic lldministmlion of Q combination of Ihe DI agonist SKF3~393 (10 mg/kg. i.v,) nnd the 02 agonist quinpirole (0.1 mg/kg Lv.) reduced the frequency ut which the membrane switched to the dcpoillrizcd.llctive state from O.9±O.4 Hz lo 0.4±O.2 Hz. Analysis of the distribution of membrune pOlential values over time revealed that the clear bimodal distribution lhese cells exhibited initially was less distinct nftt:r drug Iluministration. Funhermorc. under thesc condilions, stimulation of the prefrontal conex was less likely to evoke spikes. Since we had previously shown Ihllt spike responses to prefrontal cortical inputs were elicited only during Ihe depolarizc:L1 state (O'Donnell and Grnce. 1995), II dccrea.o;e In the frequency of depolarizing pcriods would result In n functional blockade of conical throughput in the nucleu!> llccumbens. ThCliC rC!iults suggesl a novel Dction of DA receplor activation, which may interfere wilh the abilil)' of Ihe hippocampus lo seleclively gate prefrontal cortical Ihroughput in Ihe nucleus nccumbens, Supponed by 11 NARSAO Young Investigator Awanl