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Cited by 880

The DOI matches its Crossref record; 3 of the 3 references it cites were found in a registry or an index.

Dopamine receptors and the dopamine hypothesis of schizophrenia

Seeman, Philip·1987·Synapse
DOI 10.1002/syn.890010203
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Abstract

The discovery of neuroleptic drugs in 1952 provided a new strategy for seeking a biological basis of schizophrenia. This entailed a search for a primary site of neuroleptic action. The Parkinsonian effects caused by neuroleptics suggested that dopamine transmission may be disrupted by these drugs. In 1963 it was proposed that neuroleptics blocked “monoamine receptors” or impeded the release of monoamine metabolites. The neuroleptic concentration in plasma water or cerebrospinal fluid was of the order of 2 nM for haloperidol in clinical therapy. A systematic research was made between 1963 and 1974 for a primary site of neuroleptic action which would be sensitive to 2 nM haloperidol and stereoselective for (+)‐butaclamol. Direct evidence that neuroleptics selectively blocked dopamine receptors occurred in 1974 with the finding that nanomolar concentrations of these drugs stereoselectively inhibited the binding of [3 H]‐dopamine or [3 H]‐haloperidol. These binding sites, now termed D 2 dopamine receptors (which inhibit adenylate cyclase), are blocked by neuroleptics in direct relation to the antipsychotic potencies of the neuroleptics. No such correlation exists for D 1 receptors (which stimulate adenylate cyclase). Based on the fact that dopamine‐mimetic drugs elicited hallucinations, and that neuroleptics caused rigidity, Van Rossum in 1966 had suggested a hypothesis that dopamine pathways may be overactive in schizophrenia. The D 2‐selective blockade by all neuroleptics (except the monoamine‐depleting reserpine) provided strong support for the dopamine hypothesis. Further support now comes from postmortem data and in vivo positron tomographic data, both of which indicate that the density of D 2 receptors are elevated in the schizophrenic brain. The postmortem data indicate a bimodal pattern with half the schizophrenics having striatal D 2 densities of 14 pmol/g (control is 13 pmol/g) and the other half having 26 pmol/g. Current positron tomographic data indicate D 2 densities of 14 pmol/g in control subjects, but values of 34 pmol/g in drug‐naive schizophrenics. Future tests of the dopamine hypothesis of schizophrenia may entail an examination of the amino acid composition and genes for D 2 receptors in schizophrenic tissue, an examination of the ability of the D 2 receptor to become phosphorylated and to desensitize into the low‐affinity state, and an examination of the interaction of D 2 receptors with D 1 receptors or other neurotransmitters.

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Metadata

Authors
Seeman, P.
Venue
Synapse
Publisher
Wiley
Published
1987-01
Volume
1
Issue
2
Pages
133-152
ISSN
  • 0887-4476 (ISSN-L)
  • 1098-2396
DOI
10.1002/syn.890010203
OpenAlex
W2025240330
Cited by
880
References
3
FWCI
21.18
Type
journal article
Language
en
Open access
closed

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