Affiliation:
1. Department of Psychiatry, Iwaki Kyoritsu General Hospital, Iwaki 973-8555, Japan
Abstract
Mesolimbic dopamine (DA) hyperactivity is a well-known pathophysiological hypothesis
of schizophrenia. The author shows a hypothesis to clarify the molecular basis of
mesolimbic DA hyperactivity of schizophrenia. An immunohistochemical method was
used to show D-neuron (trace amine (TA) neuron) decrease in the nucleus accumbens
(Acc) of postmortem brains with schizophrenia. The striatal D-neuron decrease in
schizophrenia and consequent (TAAR1) stimulation decrease onto terminals of midbrain
ventral tegmental area (VTA) DA neurons induces mesolimbic DA hyperactivity of
schizophrenia. Dysfunction of subventricular neural stem cells (NSC), located partially
overlapping Acc is the cause of D-neuron decrease in Acc. DA hyperactivity, which
inhibits NSC proliferation, causes disease progression of schizophrenia. The highlight
is the rational that the “D-cell hypothesis (TA hypothesis) of schizophrenia” is a pivotal
theory to link NSC dysfunction hypothesis to DA hypothesis. From a therapeutic
direction, (1) TAAR1 agonists, (2) DA D2 antagonists, and (3) neurotrophic substances
have potential to normalize mesolimbic DA hyperactivity. To develop novel therapeutic
strategies, metabolisms of TAAR1 ligands, and NSC- and D-neuron-pathophysiology of
neuropsychiatric illnesses should further be explored.
Publisher
Edelweiss Publications Inc
Subject
General Earth and Planetary Sciences,General Environmental Science