D-neuron, ligand neuron of trace amine-associated receptor 1: Key of novel non-D2 receptor-binding antipsychotics

The latest psychopharmacological study showed effectiveness of a novel non-D2-receptor-binding drug, SEP-363856, for the treatment of schizophrenia. The compound is trace amine-associated receptor 1 (TAAR1) full agonist and also 5-hydroxytryptamin 1A (5-HT 1A) receptor partial agonist. I found the TAAR1 ligand neuron, D-neuron, in the striatum and nucleus accumbens (Acc), a neuroleptic acting site, of human brains, though failed to find in the homologous area of monkey brains. 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. The number of D-neuron in the caudate nucleus, putamen, and Acc was reduced in post-mortem brains with schizophrenia. The reduction was significant (p<0.05) in Acc. I proposed “D-cell hypothesis of schizophrenia”, that NSC dysfunction-based D-neuron reduction is cellular and molecular basis of mesolimbic dopamine (DA) hyperactivity, progressive pathophysiology and prospectiveness of TAAR1 medicinal chemistry, emphasizing importance of D-neuron.