TAAR1 Ligands as Prospective Neuroleptics: From Research of So-Called D-Neuron (Trace Amine Neuron)
Dopamine (DA) dysfunction [1,2], glutamate dysfunction [3,4], neurodevelopmental deficits [5,6], or neural stem cell (NSC) dysfunction [7,8] are well-known hypotheses for etiology of schizophrenia. DA dysfunction hypothesis suggested that mesolimbic DA hyperactivity caused positive symptoms such as paranoid-hallucinatory state of schizophrenia [1,2] (Table 1A). It is also explained by the efficacy of DA D2 blockers for paranoid-hallucinatory state and also by hallucinogenic acts of DA stimulants including methamphetamine or amphetamine [1,2]. Glutamate dysfunction theory was induced by the fact that intake of phencyclidine (PCP), an antagonist of NMDA receptor, produces equivalent to negative symptoms of schizophrenia, such as withdrawal or flattened affect, as well as positive symptoms [3,4]. The neurodevelopmental deficits hypothesis implicates that schizophrenia is the consequence of prenatal abnormalities resulting from the interaction of genetic and environmental factors [5,6]. NSC dysfunction has also been shown to be a cause of schizophrenia [7,8] (Table 1A). Although mesolimbic DA hyperactivity [1,2] has been well documented in pathogenesis of schizophrenia, the molecular basis of this mechanism has not yet been detailed. In the present article, the author hypothesized the involvement of so-called D-neurons in the striatum and trace amine (TA)-associated receptor, type 1 (TAAR1) in the pathogenesis of mesolimbic DA hyperactivity of schizophrenia .
The “D-cell” was described in 1983 in the rat central nervous system and was defined “the non-monoaminergic aromatic L-amino acid decarboxylase (AADC)-containing cell” . The D-cell contains AADC but neither DA nor serotonin . D-cells produce TAs [11,12], and may also act as an APUD (amine precursor uptake and decarboxylation) system that takes up amine precursors and transforms them to amines by decarboxylation . The localizations of D-cells were specified into 14 groups, from D1 (the spinal cord) to D14 (the bed nucleus of stria terminalis) in caudo-rostral orders of the rat central nervous system using AADC immunohistochemistry [14,15]. In this usage, the classification term “D” means decarboxylation. In rodents [13,16,17], a small number of D-cells in the striatum were rostrally described and confirmed to be neurons by electron-microscopic observation . I reported in 1997, “dopa-decarboxylating neurons specific to the human striatum [18-21]”, that is, “D-neurons” in the human striatum [20,22] (classified to be D15) , and later, the reduction of the number of D-neurons in the nucleus accumbens (Acc) of patients with schizophrenia [9,22] (Figure 1). Acc is partially overlapped with neural stem cell (NSC) area.
Trace Amine (TA)-Associated Receptor, Type 1 (TAAR1)
Cloning of TA receptors in 2001 [23,24], elicited enormous efforts for exploring signal transduction of these G-protein coupled receptors whose genes are located on chromosome focus 6q23.1  (Table 1B). The receptors have been shown to co-localize with dopamine or adrenaline transporters in monoamine neurons and to modulate the functions of monoamines [26-28]. The TA-associated receptor, type 1 (TAAR1) having a large number of ligands, including tyramine, β-phenylethylamine (PEA) and psychostimulants, for example methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA) and lysergic acid diethylamide (LSD) [23,25,29] (Table 1B), has become a target receptor for exploring novel neuroleptics [30,31]. TAAR1 knockout mice showed schizophrenia- like behaviors with a deficit in prepulse inhibition . TAAR1 knockout mice showed greater locomotor response to amphetamine and released more DA (and noradrenaline) in response to amphetamine than wild type mice .
Controls: n=5 (27-64 y.o.)
Schizophrenics: n=6 (51-78 y.o.)
Abbreviation: AADC: aromatic L-amino acid decarboxylase,
Ca: caudate nucleus, Pu putamen, Acc: nucleus accumbe
A new theory, “D-cell hypothesis” (“TA hypothesis”), for explaining mesolimbic DA hyperactivity in pathogenesis of schizophrenia is shown in Figure 2. In brains of patients with schizophrenia, dysfunction of NSCs in the subventricular zone(SVZ) of lateral ventricle causes D-neuron decrease in Acc [8,34]. This leads to TA decrease in Acc, though direct evidences have not yet been demonstrated. Enlargement of the lateral ventricle [35,36], a usual finding documented in brain imaging studies of schizophrenia, is possibly due to dysfunction of SVZ NSCs [7,8]. TAAR1 stimulation decrease on DA terminals of VTA DA neurons, caused by TA decrease, would increase the firing frequency of VTA DA neurons [30,32]. This increases DA release in Acc, resulting in mesolimbic DA hyperactivity. It has been shown that D2 stimulation of NSCs in the striatum inhibited forebrain NSC proliferation . Then, striatal DA hyper activity may accelerate D-neuron decrease, which accelerates hyperactivity of mesolimbic DA system. Actions of D2 blocking agents in pharmacotherapy of schizophrenia might partially be explained by the decrease of inhibition to forebrain NSC proliferations. It is consistent with clinical evidence that initial pharmacotherapy using D2 blockers is proved to be critical for preventing progressive pathognomonic procedures of schizophrenia. Some evidence supporting “D-cell hypothesis (TA hypothesis”) is shown in Table 2.
1. So-called D-neuron, i.e., the TA neuron, and TAAR1 is a clue for pathogenesis of DA hyperactivity of schizophrenia. Further exploration of D-neuron signal transduction is essential.
2. “D-cell hypothesis (TA hypothesis) of schizophrenia” links NSC dysfunction hypothesis with DA hypothesis.
3. TAAR1 is involved in many neuropsychiatric diseases including substance abuse, such as alcohol dependence, and parkinsonism.
4. Drug designing by TAAR1 ligand searching studies is essential for novel neuroleptic discovery.
The present study was supported by Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science (C- 22591265). The author acknowledges Grants from Ministry of Welfare and Labor, and Research Resource Network (RRN), Dainippon Sumitomo Pharmaceutical Corporation.
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