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 metabolism^3–5, neuroreceptors^6–8, 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 potencies^10–11. Moreover, dopamine D2 or D2-like receptors are elevated in postmortem schizophrenia brain tissue^8,12,13. 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 data^12,18 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]raclopride^16,19) 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.