Original article| Volume 40, ISSUE 12, P1191-1199, December 15, 1996

A postmortem study of frontal cortical dopamine D1 receptors in schizophrenics, psychiatric controls, and normal controls

      This paper is only available as a PDF. To read, Please Download here.
      We tested the hypothesis that aberrant dopaminergic innervation in frontal and cingulate cortices of schizophrenic patients might be revealed by examining dopamine D1 receptor density in these brain regions. A quantitative autoradiographic assay with [3H]-SCH 23390 was performed with samples from schizophrenic patients, normal controls, neuroleptic-treated controls, and suicides. There was a significant elevation in specific binding of [3H]-SCH 23390 in the intermediate layer of the prefrontal cortex from neuroleptic-treated controls (p = .05). Elevated [3H]-SCH 23390 binding in several layers from prefrontal and cingulate cortex was observed in schizophrenic subjects, although these results did not reach statistical significance. When data from subjects who had received neuroleptics (schizophrenics and neuroleptic controls) were compared to subjects who had not received neuroleptics (normal controls and suicides), there was a significant elevation in receptor density in both the prefrontal (p = .05) and cingulate cortices (p = .03). These data suggest that elevated [3H]-SCH 23390 binding in human prefrontal and cingulate cortices may occur with chronic neuroleptic treatment, although increased receptor density that may exist as a feature of psychotic illnesses cannot be excluded.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Akbarian S
        • Bunney WE
        • Potkin S
        • et al.
        Altered distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbance of cortical development.
        Arch Gen Psychiatry. 1993; 50: 169-177
        • American Psychiatric Association
        3rd ed rev. Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Press, Washington, DC1987
        • Andreasen NC
        • Nasrallah HA
        • Dunn VD
        • et al.
        Structural abnormalities in the frontal system in schizophrenia: A magnetic resonance imaging study.
        Arch Gen Psychiatry. 1986; 43: 136-144
        • Andreasen NC
        • Flashman L
        • Flaum M
        • et al.
        Regional brain abnormalities in schizophrenia measured with magnetic resonance imaging.
        JAMA. 1994; 272: 1763-1769
        • Arnsten AFT
        • Cai JX
        • Murphy BL
        • Goldman-Rakic PS
        Dopamine D1 receptor mechanisms in the cognitive performance of young adult and aged monkeys.
        Psychopharmacology. 1994; 116: 143-151
        • Benes FM
        • Bird ED
        An analysis of the arrangement of neurons in the cingulate cortex of schizophrenic patients.
        Arch Gen Psychiatry. 1987; 44: 608-616
        • Benes FM
        • Davidson J
        • Bird ED
        Quantitative cytoarchitectural studies of the cerebral cortex of schizophrenics.
        Arch Gen Psychiatry. 1986; 43: 31-35
        • Benes FM
        • Majocha R
        • Bird ED
        • Marotta CA
        Increased vertical axon numbers in cingulate cortex of schizophrenics.
        Arch Gen Psychiatry. 1987; 44: 1017-1021
        • Benes FM
        • McSparren J
        • Bird ED
        • et al.
        Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients.
        Arch Gen Psychiatry. 1991; 48: 996-1001
        • Benes FM
        • Vincent SL
        • Alsterberg G
        • et al.
        Increased GABA-A receptor binding in superficial layers of cingulate cortex in schizophrenics.
        J Neurosci. 1992; 12: 924-929
        • Berger B
        • Gaspar P
        • Verney C
        Dopaminergic innervation of the cerebral cortex: Unexpected differences between rodents and primates.
        Trends Neurosci. 1991; 14: 21-27
        • Berman KF
        • Weinberger DR
        Functional localization in the brain in schizophrenia.
        in: Tasman A Goldfinger S American Psychiatric Association Review of Psychiatry. vol 10. American Psychiatric Press, Washington, DC1991: 24-59
        • Bogerts B
        • Hantsch J
        • Herzer M
        A morphometric study of the dopamine-containing cell groups in the mesencephalon of normals, Parkinson patients and schizophrenics.
        Biol Psychiatry. 1983; 18: 951-969
        • Breier A
        • Buchanan RW
        • Elkashef A
        • et al.
        Brain morphology and schizophrenia.
        Arch Gen Psychiatry. 1992; 49: 921-926
        • Campion D
        • d'Amato T
        • Bastard C
        • et al.
        Genetic study of dopamine D1, D2 and D4 receptors in schizophrenia.
        Psychiatry Res. 1994; 51: 215-230
        • Carlsson A
        • Lindqvist M
        Effects of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain.
        Acta Pharmacol Toxicol. 1963; 20: 140-144
        • Cichon S
        • Nothen MN
        • Rietschel M
        • et al.
        Single strand conformation analysis of the dopamine D1 receptor gene reveals no significant mutation in patients with schizophrenia and manic depression.
        Biol Psychiatry. 1994; 36: 850-853
        • Dawson TM
        • McCabe T
        • Stensaas SS
        • Wamsley JK
        Autoradiographic evidence of [3H] SCH23390 binding sites in human prefrontal cortex (Brodmann's area 9).
        J Neurochem. 1987; 49: 789-796
        • DeKeyser J
        • Ebinger G
        • Vauquelin G
        Evidence for a widespread dopaminergic innervation of the human cerebral neocortex.
        Neurosci Lett. 1989; 104: 281-285
        • Ferron A
        • Thierry AM
        • Le Douarin C
        • Glowinski J
        Inhibitory influence of the mesocortical dopaminergic system on spontaneous activity or excitatory responses induced from the thalamic mediodorsal nucleus in the rat medial prefrontal cortex.
        Brain Res. 1984; 302: 257-265
        • Goldberg TE
        • Gold JM
        • Braff DL
        Neuropsychological functioning and time-linked information processing in schizophrenia.
        in: Tasman A Goldfinger S American Psychiatric Press Review of Psychiatry. vol 10. American Psychiatric Association Press, Washington, DC1991: 60-78
        • Goldman-Rakic PS
        Prefrontal cortical dysfunction in schizophrenia: The relevance of working memory.
        in: Carrol B Psychopathology and the Brain. Raven Press, Washington, DC1991: 1-23
        • Goldman-Rakic PS
        • Leranth C
        • Williams SM
        • et al.
        Dopamine synaptic complex with pyramidal neurons in primate cerebral cortex.
        in: Proceedings of the National Academy of Science. 86. 1989: 9015-9019
        • Hatta Y
        • Hatta S
        • Saito T
        Effects of ceruletide on the dopamine receptor-adenylate cyclase system in striatum and frontal cortex of rats treated chronically with haloperidol.
        Psychopharmacology. 1993; 110: 383-389
        • Hess EJ
        • Norman AB
        • Creese I
        Chronic treatment with dopamine receptor antagonist: Behavioral and pharmacologic effects on D1 and D2 dopamine receptors.
        J Neurosci. 1988; 8: 2361-2370
        • Jensen S
        • Plaetke R
        • Holik J
        • et al.
        Linkage analysis of schizophrenia: The D1 receptor gene and several flanking DNA markers.
        Hum Hered. 1993; 43: 58-62
        • Knable MB
        • Hyde TM
        • Egan MF
        • et al.
        Quantitative autoradiography of striatal dopamine D1, D2 and re-uptake sites in rats with vacuous chewing movements.
        Brain Res. 1994; 646: 217-222
        • Laruelle M
        • Jaskiw GE
        • Lipska BK
        • et al.
        D1 and D2 receptor modulation in rat striatum and nucleus accumbens after subchronic and chronic haloperidol treatment.
        Brain Res. 1992; 575: 47-56
        • Lidow MS
        • Goldman-Rakic PS
        A common action of clozapine, haloperidol, and remoxipride on D1- and D2-dopaminergic receptors in the primate cerebral cortex.
        in: Proc Nat Acad Sci USA. 91. 1994: 4353-4356
        • Lidow MS
        • Goldman-Rakic PS
        • Rakic P
        Distribution of dopaminergic receptors in the primate cerebral cortex: Quantitative autoradiographic analysis using [3H] raclopride, [3H] spiperone and [3H] SCH23390.
        Neuroscience. 1991; 40: 657-671
        • Mackenzie RG
        • Zigmond MJ
        Chronic neuroleptic treatment increase D2 but not D1 receptors in rat striatum.
        Eur J Pharmacol. 1985; 113: 159-165
        • Matsumoto T
        • Uchimura H
        • Hirano M
        • et al.
        Differential effects of acute and chronic administration of haloperidol on homovanillic acid levels in discrete dopaminergic areas of rat brain.
        Eur J Pharmacol. 1983; 89: 27-33
        • McLean PD
        The limbic brain in relation to the psychoses.
        in: Black P Physiologic Correlates of the Emotions. Academic Press, New York1970: 129-146
        • Ohara K
        • Ulpian C
        • Seeman P
        • et al.
        Schizophrenia: Dopamine D1 receptor sequence is normal but has DNA polymorphisms.
        Neuropsychopharmacology. 1993; 8: 131-135
        • Sawaguchi T
        • Goldman-Rakic PS
        D1 dopamine receptors in prefrontal cortex: Involvement in working memory.
        Science. 1991; 251: 947-950
        • Sawaguchi T
        • Matsumura M
        Laminar distribution of neurons sensitive to acetylcholine, noradrenaline and dopamine in the dorsolateral prefrontal cortex of the monkey.
        Neurosci Res. 1985; 2: 255-273
        • Scatton B
        Differential regional development of tolerance to increase in dopamine turnover upon repeated neuroleptic administration.
        Eur J Pharmacol. 1977; 46: 363-369
        • Scatton B
        • Glowinski J
        • Julou L
        Dopamine metabolism in the mesolimbic and mesocortical dopaminergic systems after single or repeated administration of neuroleptics.
        Brain Res. 1976; 109: 184-189
        • See RE
        • Aravagiri M
        • Ellison GD
        Chronic neuroleptic treatment in rats produces persisting changes in GABA-A and dopamine D2, but not dopamine D1 receptors.
        Life Sci. 1989; 44: 229-236
        • Smiley JF
        • Goldman-Rakic PS
        Heterogenous targets of dopamine synapses in monkey prefrontal cortex demonstrated by serial section electron microscopy: A laminar analysis using the silver-enhanced diaminobenzidine sulfide immunolabeling technique.
        Cereb Cortex. 1993; 3: 223-238
        • Stuss DT
        • Benson DF
        The Frontal Lobes.
        Raven Press, New York1986
        • Thierry AM
        • Mantz J
        • Milla C
        • Glowinski J
        Kalivas PW Nemeroff CB Proceedings from the Conference on the Meso-Cortical-Limbic Dopamine System. Influence of the Mesocortical/Prefrontal Dopamine Neurons on Their Target Cells. New York Academy of Science, New York1988: 101-111
        • Zipursky RB
        • Lim KO
        • Sullivan EV
        • et al.
        Widespread cerebral gray matter volume deficits in schizophrenia.
        Arch Gen Psychiatry. 1992; 49: 195-205