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Sept 1982, Vol 39, No. 9 >
Article | Sept 1982

Increased Brain Dopamine and Dopamine Receptors in Schizophrenia

Solomon H. Snyder, MD; Ian Creese, PhD; Alberto Arregui, MD; Edward Bird, MD; Ernest Spokes, MD; Martin Rossor, MB; Leslie L. Iversen, MA, PhD; Angus V. P. Mackay, MB, PhD
[+] Author Affiliations

Accepted for publication Dec 31, 1981.

Reprint requests to Argyll and Bute Hospital, Lochgilphead, PA31 8LD Argyll, United Kingdom (Dr Mackay).


Arch Gen Psychiatry. 1982;39(9):991-997. doi:10.1001/archpsyc.1982.04290090001001
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Comments

• In postmortem samples of caudate nucleus and nucleus accumbens from 48 schizophrenic patients, there were significant increases in both the maximum number of binding sites (Bmax) and the apparent dissociation constant (KD) for tritiated spiperone. The increase in apparent KD probably reflects the presence of residual neuroleptic drugs, but changes in Bmax for tritiated spiperone reflect genuine changes in receptor numbers. The increases in receptors were seen only in patients in whom neuroleptic medication had been maintained until the time of death, indicating that they may be entirely iatrogenic. Dopamine measurements for a larger series of schizophrenic and control cases (n > 60) show significantly increased concentrations in both the nucleus accumbens and caudate nucleus. The changes in dopamine were not obviously related to neuroleptic medication and, unlike the receptor changes, were most severe in younger patients.

REFERENCES

1 +
Van Praag HM:  The significance of dopamine for the mode of action of neuroleptics and the pathogenesis of schizophrenia . Br J Psychiatry 1977;;130:463-474.
2 +
Iversen LL:  Biochemical and pharmacological studies: The dopamine hypothesis , in Wing J (ed): Schizophrenia Towards a New Synthesis . New York, Academic Press Inc, 1978;, pp 89-116.
3 +
Snyder SH, Banerjee SP, Yamamura HI, et al:  Drugs, neurotransmitters and schizophrenia . Science 1974;;184:1243-1253.
4 +
Post RM, Fink E, Carpenter WT Jr, et al:  Cerebrospinal fluid amine metabolites in acute schizophrenia . Arch Gen Psychiatry 1975;;32:1063-1069.
5 +
Bird ED, Spokes EGS, Iversen LL:  Increased dopamine concentration in limbic areas of brain from patients dying with schizophrenia . Brain 1979;;102:347-360.
6 +
Lee T, Seeman P, Tourtelotte WW, et al:  Binding of 3H-neuroleptics and 3H-apomorphine in schizophrenic brains . Nature 1978;;274:897-900.
7 +
Lee T, Seeman P:  Elevation of brain neuroleptics/dopamine receptors in schizophrenia . Am J Psychiatry 1980;;137:191-197.
8 +
Reisine TD, Rossor M, Spokes E, et al:  Opiate and neuroleptic receptor alterations in human schizophrenic brain tissue , in Pepeu G, Kuhar MJ, Enna SJ (eds): Receptors for Neurotransmitters and Peptide Hormones . New York, Raven Press, 1980;, pp 443-450.
9 +
Owen F, Crow TJ, Poulter M, et al:  Increased dopamine-receptor sensitivity in schizophrenia . Lancet 1978;;2:223-225.
10 +
Burt DR, Creese I, Snyder SH:  Antischizophrenic drugs: Chronic treatment elevates dopamine receptor binding in brain . Science 1977;;196:326-328.
11 +
Clow A, Theodorou A, Jenner P, et al:  Changes in rat striatal dopamine turnover and receptor activity during one year's neuroleptic administration . Eur J Pharmacol 1980;;63:135-144.
12 +
Owen F, Cross AJ, Waddington JL, et al:  Dopamine-mediated behaviour and 3H-spiperone binding to striatal membranes in rats after nine months' haloperidol administration . Life Sci 1980;;26:55-59.
13 +
Mackay AVP, Bird ED, Spokes EG, et al:  Dopamine receptors and schizophrenia: Drug effect or illness? Lancet 1980;;2:915-916.
14 +
Wing JK, Cooper JE, Sartorius N: The Measurement and Classification of Psychiatric Symptoms . London, Cambridge University Press, 1974;.
15 +
Schneider K: Clinical Psychopathology , Hamilton MW (trans). New York, GrĂĽne & Stratton Ine, 1959;.
16 +
Davis JM:  Dose equivalence of the antipsychotic drugs . J Psychiatr Res 1974;;11:65-69.
17 +
Spokes EGS:  An analysis of factors influencing measurements of dopamine, noradrenaline, glutamic acid decarboxylase and choline acetylase in human post-mortem brain . Brain 1979;;102:333-346.
18 +
Creese I, Schneider R, Snyder SH:  'H-Spiroperidol labels dopamine receptors in pituitary and brain . Eur J Pharmacol 1977;;46:377-381.
19 +
Quik M, Iversen LL, Larder A, et al:  Use of ADTN to define specific 3H-spiperone binding to receptors in brain . Nature 1978;;274:513.
20 +
Mackay AVP, Doble A, Bird ED, et al:  'H-Spiperone binding in normal and schizophrenic post-mortem brain . Life Sci 1978;;23:527-532.
21 +
Clow A, Theodorou A, Jenner P, et al:  Cerebral dopamine function in rats following withdrawal from one-year continuous neuroleptic administration . Eur J Pharmacol 1980;;63:145-157.
22 +
Seeman P:  Dopamine receptors in post-mortem schizophrenic brains . Lancet 1981;;2:1130.
23 +
Iversen LL, Mackay AVP:  Brain dopamine receptor densities in schizophrenics . Lancet 1981;;2:149.
24 +
Pradhan SN:  Central neurotransmitters and aging . Life Sci 1980;;26:1643-1656.
25 +
Arregui A, Mackay AVP, Spokes EG, et al:  Reduced activity of angiotensin converting enzyme in basal ganglia in early onset schizophrenia . Psychol Med 1980;;10:307-313.
26 +
Spokes EG, Garrett NJ, Rossor MN, et al:  Distribution of GABA in post-mortem brain tissue from control, psychotic and Huntingtons chorea subjects . J Neurol Sci 1980;;48:303-313.
27 +
Bird ED, Crow TJ, Iversen LL, et al:  Dopamine and homovanillic acid concentrations in the post-mortem brain in schizophrenia . J Physiol 1979;;293:36-37.
28 +
Bacopoulos NC, Spokes EG, Bird ED, et al:  Antipsychotic drug action in schizophrenic patients: Effect on cortical dopamine metabolism after long-term treatment . Science 1979;;205:1405-1407.

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1 +
Van Praag HM:  The significance of dopamine for the mode of action of neuroleptics and the pathogenesis of schizophrenia . Br J Psychiatry 1977;;130:463-474.
2 +
Iversen LL:  Biochemical and pharmacological studies: The dopamine hypothesis , in Wing J (ed): Schizophrenia Towards a New Synthesis . New York, Academic Press Inc, 1978;, pp 89-116.
3 +
Snyder SH, Banerjee SP, Yamamura HI, et al:  Drugs, neurotransmitters and schizophrenia . Science 1974;;184:1243-1253.
4 +
Post RM, Fink E, Carpenter WT Jr, et al:  Cerebrospinal fluid amine metabolites in acute schizophrenia . Arch Gen Psychiatry 1975;;32:1063-1069.
5 +
Bird ED, Spokes EGS, Iversen LL:  Increased dopamine concentration in limbic areas of brain from patients dying with schizophrenia . Brain 1979;;102:347-360.
6 +
Lee T, Seeman P, Tourtelotte WW, et al:  Binding of 3H-neuroleptics and 3H-apomorphine in schizophrenic brains . Nature 1978;;274:897-900.
7 +
Lee T, Seeman P:  Elevation of brain neuroleptics/dopamine receptors in schizophrenia . Am J Psychiatry 1980;;137:191-197.
8 +
Reisine TD, Rossor M, Spokes E, et al:  Opiate and neuroleptic receptor alterations in human schizophrenic brain tissue , in Pepeu G, Kuhar MJ, Enna SJ (eds): Receptors for Neurotransmitters and Peptide Hormones . New York, Raven Press, 1980;, pp 443-450.
9 +
Owen F, Crow TJ, Poulter M, et al:  Increased dopamine-receptor sensitivity in schizophrenia . Lancet 1978;;2:223-225.
10 +
Burt DR, Creese I, Snyder SH:  Antischizophrenic drugs: Chronic treatment elevates dopamine receptor binding in brain . Science 1977;;196:326-328.
11 +
Clow A, Theodorou A, Jenner P, et al:  Changes in rat striatal dopamine turnover and receptor activity during one year's neuroleptic administration . Eur J Pharmacol 1980;;63:135-144.
12 +
Owen F, Cross AJ, Waddington JL, et al:  Dopamine-mediated behaviour and 3H-spiperone binding to striatal membranes in rats after nine months' haloperidol administration . Life Sci 1980;;26:55-59.
13 +
Mackay AVP, Bird ED, Spokes EG, et al:  Dopamine receptors and schizophrenia: Drug effect or illness? Lancet 1980;;2:915-916.
14 +
Wing JK, Cooper JE, Sartorius N: The Measurement and Classification of Psychiatric Symptoms . London, Cambridge University Press, 1974;.
15 +
Schneider K: Clinical Psychopathology , Hamilton MW (trans). New York, GrĂĽne & Stratton Ine, 1959;.
16 +
Davis JM:  Dose equivalence of the antipsychotic drugs . J Psychiatr Res 1974;;11:65-69.
17 +
Spokes EGS:  An analysis of factors influencing measurements of dopamine, noradrenaline, glutamic acid decarboxylase and choline acetylase in human post-mortem brain . Brain 1979;;102:333-346.
18 +
Creese I, Schneider R, Snyder SH:  'H-Spiroperidol labels dopamine receptors in pituitary and brain . Eur J Pharmacol 1977;;46:377-381.
19 +
Quik M, Iversen LL, Larder A, et al:  Use of ADTN to define specific 3H-spiperone binding to receptors in brain . Nature 1978;;274:513.
20 +
Mackay AVP, Doble A, Bird ED, et al:  'H-Spiperone binding in normal and schizophrenic post-mortem brain . Life Sci 1978;;23:527-532.
21 +
Clow A, Theodorou A, Jenner P, et al:  Cerebral dopamine function in rats following withdrawal from one-year continuous neuroleptic administration . Eur J Pharmacol 1980;;63:145-157.
22 +
Seeman P:  Dopamine receptors in post-mortem schizophrenic brains . Lancet 1981;;2:1130.
23 +
Iversen LL, Mackay AVP:  Brain dopamine receptor densities in schizophrenics . Lancet 1981;;2:149.
24 +
Pradhan SN:  Central neurotransmitters and aging . Life Sci 1980;;26:1643-1656.
25 +
Arregui A, Mackay AVP, Spokes EG, et al:  Reduced activity of angiotensin converting enzyme in basal ganglia in early onset schizophrenia . Psychol Med 1980;;10:307-313.
26 +
Spokes EG, Garrett NJ, Rossor MN, et al:  Distribution of GABA in post-mortem brain tissue from control, psychotic and Huntingtons chorea subjects . J Neurol Sci 1980;;48:303-313.
27 +
Bird ED, Crow TJ, Iversen LL, et al:  Dopamine and homovanillic acid concentrations in the post-mortem brain in schizophrenia . J Physiol 1979;;293:36-37.
28 +
Bacopoulos NC, Spokes EG, Bird ED, et al:  Antipsychotic drug action in schizophrenic patients: Effect on cortical dopamine metabolism after long-term treatment . Science 1979;;205:1405-1407.

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