“D-cell hypothesis” of schizophrenia: Possible theory for mesolimbic dopamine hyperactivity

The author proposes a new “D-cell hypothesis” for mesolimbic dopamine (DA) hyperactivity of schizophrenia. The “D-cell” is defined as “non-monoaminergic aromatic L-amino acid decarboxylase (AADC)-containing cell”. D-cells produce trace amines, such as tyramine and β-phenylethylamine, and may also take up amine precursors and convert them to amines by decarboxylation. Trace amine-associated receptor, type 1 (TAAR1), a subtype of trace amine receptors, has a large number of ligands, including tyramine, βphenylethylamine and methamphetamine, that influence on human mental states, and is now regarded to be a target receptor for novel neuroleptics. Recent studies revealed that the reduced stimulation of TAAR1 on DA neurons in the midbrain ventral tegmental area (VTA) increased firing frequency of VTA DA neurons. The author and her colleagues reported the decrease of D-neurons in the striatum and nucleus accumbens of postmortem brains of patients with schizophrenia. This may imply the decrease of trace amine synthesis, resulting the reduced stimulation of TAAR1 on terminals of midbrain VTA DA neurons, and may lead to mesolimbic DA hyperactivity in schizophrenia. The decrease of striatal D-neurons of postmortem brains of schizophrenia is supposed to be due to neural stem cell dysfunction in the subventricular zone of lateral ventricle. The decrease of striatal D-neurons and acts of TAAR1 signals on DA neurons might explain mesolimbic DA hyperactivity of schizophrenia.