“D-cell hypothesis of schizophrenia”: Background theory of Novel non-D2 receptor medicinal chemistry

Abstract

The latest psychopharmacological study showed effectiveness of a novel non-D2-receptor-binding drug, SEP-363856, for the treatment of schizophrenia. Characteristic receptor profile of the compound is shown to be trace amine-associated receptor 1 (TAAR1) full agonist and 5-hydroxytryptamin 1A (5-HT 1A) receptor partial agonist. I found the TAAR1 ligand neuron, D-neuron, in the striatum and nucleus accumbens (Acc), an antipsychotic acting site, of human brain, though failed to find in the homologous area of monkey. To study human D-neuron functions, total of 154 post-mortem brains, and a modified immunohistochemical method using high qualified antibodies against monoamine-related substances, was applied. Number of D-neurons in the caudate nucleus, putamen, and Acc was reduced in post-mortem brains with schizophrenia. The reduction was significant (p<0.05) in Acc. “D-cell hypothesis of schizophrenia”, which I proposed based on this post-mortem brain study, that NSC dysfunction-induced D-neuron reduction as cellular and molecular basis of mesolimbic dopamine (DA) hyperactivity, showing progressive pathophysiology of schizophrenia, has been proved to be a predictive hypothesis for TAAR1 medicinal chemistry.