Dopamine D4-like Binding Sites Labeled by [3H]Nemonapride Include Substantial Serotonin 5-HT2A Receptors in Primate Cerebral Cortex

Current and Novel Approaches to the Drug Treatment of Schizophrenia

“…Interest was further fueled by studies comparing D 2 and D 4 receptor affinity with plasma concentrations of antipsychotic drugs showing that, at clinically relevant doses, clozapine could preferentially occupy dopamine D 4 receptors in the brain (but note that the same argument could also implicate 5-HT 2A , 5-HT 6 , 5-HT 7 , α 1 adrenoceptors, histamine H 1 receptors, and muscarinic receptors). Additional evidence also suggested that D 4 -like receptors were increased in the striatum of schizophrenic brain, − although these results have proved somewhat controversial and have not been replicated by other groups. , Furthermore, the indirect methods used to identify D 4 -like receptors, based on the subtraction of [ 3 H]-raclopride ( 28 ) binding (to D 2 and D 3 receptors) from [ 3 H]-nemonapride ( 29 ) binding (to D 2 , D 3 and D 4 receptors) are problematic, in that nemonapride binds to additional sites (5-HT 1A , σ, and 5-HT 2A receptors) − which may not have been adequately masked and because selective D 4 antagonists were not available to confirm that this residual binding was indeed to the D 4 receptor. More recently, D 4 receptors have been visualized in human brain using the selective D 4 radiolabel [ 3 H]-NGD-94-1 ( 30 ) .…”

“…Additional evidence also suggested that D 4 -like receptors were increased in the striatum of schizophrenic brain, [133][134][135][136] although these results have proved somewhat controversial and have not been replicated by other groups. 137,138 Furthermore, the indirect methods used to identify D 4 -like receptors, based on the subtraction of [ 3 H]-raclopride ( 28) binding (to D 2 and D 3 receptors) from [ 3 H]-nemonapride ( 29) binding (to D 2 , D 3 and D 4 receptors) are problematic, in that nemonapride binds to additional sites (5-HT 1A , σ, and 5-HT 2A receptors) [139][140][141] which may not have been adequately masked and because selective D 4 antagonists were not available to confirm that this residual binding was indeed to the D 4 receptor. More recently, D 4 receptors have been visualized in human brain using the selective D 4 radiolabel [ 3 H]-NGD-94-1 (30).…”