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Dopamine D4 receptors elevated in schizophrenia

Abstract

ALTHOUGH the biological basis of schizophrenia is not known, possible causes include genetic defects, viruses1, amines2, brain structure and metabolism3–5, neuroreceptors6–8, and G proteins9. The hypothesis of dopamine overactivity in schizophrenia is based on the fact that neuroleptics block dopamine D2 receptors in direct relation to their clinical antipsychotic potencies10–11. Moreover, dopamine D2 or D2-like receptors are elevated in postmortem schizophrenia brain tissue8,12,13. This elevation, however, is only found in vivo using [11C]methylspiperone14 but not [11C]raclopride15. The dopamine D4 receptor gene16 has not yet been excluded in schizophrenia because the 21 gene variants17 of D4 have not yet been tested. Because the link between Dl and D2 receptors is reduced in schizophrenia tissue9, we tested whether one component of this link was sensitive to guanine nucleotide. We report here that the binding of [3H]raclopride to D2 receptors in schizophrenia was not sensitive to guanine nucleotide. This finding permitted analysis of data12,18 on the binding of [3H]emonapride to the D2, D3 and D4 receptors. We conclude that the combined density of D2 and D3 receptors (labelled by [3H]raclopride16,19) is increased by only 10% in schizophrenia brain, as found by Farde et al.15, but that it is the density of dopamine D4 receptors which is sixfold elevated in schizophrenia. These findings resolve the apparent discrepancy, mentioned above, wherein the density of [11C]methylspiperone-labelled sites14 (D2, D3 and D4), but not that of [11C]raclopride-labelled sites15 (D2 and D3), was found elevated in the schizophrenia striatum.

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Seeman, P., Guan, HC. & Van Tol, H. Dopamine D4 receptors elevated in schizophrenia. Nature 365, 441–445 (1993). https://doi.org/10.1038/365441a0

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