Шаблоны LeoTheme для Joomla.
GavickPro Joomla шаблоны

Research Article

TAAR1 Ligands as Prospective Neuroleptics: From Research of So-Called D-Neuron (Trace Amine Neuron)

Keiko Ikemoto*1
Department of Psychiatry, Iwaki Kyoritsu General Hospital, Japan

*Corresponding author: Dr. Keiko Ikemoto, Department of Psychiatry, Iwaki Kyoritsu General Hospital, Iwaki, Fukushima, 973- 8555, Japan, Tel: +81-246-3-26-3151; Fax: +81-246-27-2148;
Email: ikemoto@iwaki-kyoritsu.iwaki.fukushima.jp

Submitted02-27-2015 Accepted: 04-23-2015 Published: 05-26-2015

Download PDF





Recent pharmacological studies has been shown the importance of trace amine-associated receptor, type 1 (TAAR1), a subtype of trace amine receptors, as a prospective target receptor for novel neuroleptics. The author introduces so-called D-neuron (trace amine (TA)-producing neuron) research in psychiatric field. Although dopamine (DA) dysfunction is a well-known hypothesis of etiology of schizophrenia, its molecular basis has not yet been clarified. To explain this, modulating function of TAs on DA neurotransmission was noticed. The TAAR1 has a large number of ligands, including tyramine, β-phenylethylamine and methamphetamine that influence on human mental state. Reduced stimulation of TAAR1 on DA neurons in the midbrain ventral tegmental area (VTA) has been revealed to increase firing frequency of VTA DA neurons. Significant D-neuron decrease has been reported in the nucleus accumbens (Acc) of postmortem brains of patients with schizophrenia. This implies the decrease of TA synthesis and consequent TAAR1 stimulation reduction on terminals of midbrain VTA DA neurons, that leads to mesolimbic DA hyperactivity in schizophrenia. D-neuron decrease in Acc of postmortem brains, due to neural stem cell (NSC) dysfunction in the subventricular zone of lateral ventricle, might be pivotal in etiology of schizophrenia. The new “D-cell hypothesis (TA hypothesis)”, in which D-neurons and TAAR1 are involved, is in agreement of recent reports showing effectiveness of TAAR1 ligands for schizophrenia model animals.

Keywords: Dopamine; D-neuron; Trace amine; Schizophrenia; TAAR1; Dopa Decarboxylase (DDC)

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 [9].
med chem table 1.1D-neuron

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” [10]. The D-cell contains AADC but neither DA nor serotonin [10]. 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 [13]. 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 [13]. 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) [20], 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 [25] (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 [32]. TAAR1 knockout mice showed greater locomotor response to amphetamine and released more DA (and noradrenaline) in response to amphetamine than wild type mice [32].
med chem fig 1.1
Figure 1. Number of D-neurons reduced in the Acc of post-mortem brains of patients with schizophrenia. As the average number of AADC-positive neurons per one section of 50 μm thick in the striatum reduced in the brains with longer postmortem period to death (PMI), analysis was performed using brain samples with PMI less than 8 hours [9].

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
It has been shown that TAAR1 has a thermoregulatory function [33]. membranes of DA neurons in the midbrain ventral tegmental area (VTA) reduced firing frequency of VTA DA neurons [30-32].
med chem table 1.3
A New “D-Cell Hypothesis” (“TA Hypothesis”) of Schizophrenia (Figure 2)

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 [37]. 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.
med chem table 1.2

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.



1.Hökfelt T, Ljungdahl A, Fuxe K, Johansson O. Dopamine nerve terminals in the rat limbic cortex: aspects of the dopamine hypothesis of schizophrenia. Science. 1974, 184(4133): 177-179.

2.Toru M, Nishikawa T, Mataga N, Takashima M. Dopamine metabolism increases in post-mortem schizophrenic basal ganglia. J Neural Transm. 1982, 54(3-4): 181-191.

3.Watis L, Chen SH, Chua HC, Chong SA, Sim K. Glutamatergic abnormalities of the thalamus in schizophrenia: a systematic review. J Neural Transm. 2008, 115(3): 493-511.

4.Olbrich HM, Valerius G, Rüsch N, Buchert M, Thiel T, et al. Frontolimbic glutamate alterations in first episode schizophrenia: evidence from a magnetic resonance spectroscopy study. World J Biol Psychiatry. 2008, 9(1): 59-63.

5.Christison GW, Casanova MF, Weinberger DR, Rawlings R, Kleinman JE. A quantitative investigation of hippocampal pyramidal cell size, shape, and variability of orientation in schizophrenia. Arch Gen Psychiatry. 1989, 46(11): 1027-1032.

6.McGlashan TH, Hoffman RE. Schizophrenia as a disorder of developmentally reduced synaptic connectivity. Arch Gen Psychiatry. 2000, 57(7): 637-648.

7.Duan X, Chang JH, Ge S, Faulkner RL, Kim JY et al. Disrupted- In- Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell. 2007, 130(6): 1146-1158.

8.Reif A, Fritzen S, Finger M, Strobel A, Lauer M et al. Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol Psychiatry. 2006, 11(5): 514-522.

9.Ikemoto K, Nishimura A, Oda T, Nagatsu I, Nishi K. Number of striatal D-neurons is reduced in autopsy brains of schizophrenics. Leg Med (Tokyo). 2003, 5: S221-224.

10.Jaeger CB, Teitelman G, Joh TH, Albert VR, Park DH et al. Some neurons of the rat central nervous system contain aromatic- L-amino-acid decarboxylase but not monoamines. Science. 1983, 219(4589): 1233-1235.

11.Sabelli HC, Mosnaim AD. Phenylethylamine hypothesis of affective behavior. Am J Psychiatry. 1974, 131(6): 695-699.

12.Boulton AA, Juorio AV. The tyramines: are they involved in the psychoses? Biol Psychiatry. 1979, 14(2): 413-419.

13.Komori K, Fujii T, Karasawa N, Yamada K, Ikuko N. Some neurons of the mouse cortex and caudo-putamen contain aromatic L-amino acid decarboxylase but not monoamines. Acta Histochem Cytochem. 1991, 24(6): 571-577.

14.Jaeger CB, Ruggiero DA, Albert V R, Joh TH, Reis DJ. Immunocytochemical localization of aromatic-L-amino acid decarboxylase, in Handbook of Chemical Neuroanatomy. Classical Transmitters in the CNS, Part I. (Vol 2), Elsevier, Amsterdam 1984, 387-408.

15.Jaeger CB, Ruggiero DA, Albert VR, Park DH, Joh TH, et al. Aromatic L-amino acid decarboxylase in the rat brain: immunocytochemical localization in neurons of the brain stem. Neuroscience. 1984, 11(3): 691-713.

16.Tashiro Y, Kaneko T, Sugimoto T, Nagatsu I, Kikuchi H et al. Striatal neurons with aromatic L-amino acid decarboxylase- like immunoreactivity in the rat. Neurosci Lett. 1989, 100(1-3): 29-34.

17.Mura A, Linder JC, Young SJ, Groves PM. Striatal cells containing aromatic L-amino acid decarboxylase: an immunohistochemical comparison with other classes of striatal neurons. Neuroscience. 2000, 98(3): 501-511.

18.Ikemoto K, Kitahama K, Jouvet A, Arai R, Nishimura A et al. Demonstration of L-dopa decarboxylating neurons specific to human striatum. Neurosci Lett. 1997, 232(2): 111-114.

19.Ikemoto K, Nagatsu I, Kitahama K, Jouvet A, Nishimura A et al. A dopamine-synthesizing cell group demonstrated in the human basal forebrain by dual labeling immunohistochemical technique of tyrosine hydroxylase and aromatic L-amino acid decarboxylase. Neurosci Lett. 1998, 243(1-3): 129-132.

20.Kitahama K, Ikemoto K, Jouvet A, Nagatsu I, Sakamoto N et al. Aromatic L-amino acid decarboxylase- and tyrosine hydroxylase- immunohistochemistry in the adult human hypothalamus. J Chem Neuroanat. 1998, 16(1): 43-55.

21.Kitahama K, Ikemoto K, Jouvet A, Araneda S, Nagatsu I et al. Aromatic L-amino acid decarboxylase-immunoreactive structures in human midbrain, pons, and medulla. J Chem Neuroanat. 2009, 38(2): 130-140.

22.Ikemoto K. Significance of human striatal D-neurons: implications in neuropsychiatric functions. Prog Neuropsychopharmacol Biol Psychiatry. 2004, 28(3): 429-434.

23.Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G et al. Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor. Mol Pharmacol. 2001, 60(6): 1181-1188.

24.Borowsky B, Adham N, Jones KA, Raddatz R, Artymyshyn R et al. Trace amines: identification of a family of mammalian G protein-coupled receptors. Proc Natl Acad Sci U S A. 2001, 98(16): 8966-8971.

25.Miller GM. The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity. J Neurochem. 2011, 116(2): 164-176.

26.Xie Z, Miller GM. Trace amine-associated receptor 1 is a modulator of the dopamine transporter. J Pharmacol Exp Ther 2007, 321(1): 128-136.

27.Xie Z, Miller GM. Trace amine-associated receptor 1 as a monoaminergic modulator in brain. Biochem Pharmacol. 2009, 78(9): 1095-1104.

28.Lindemann L, Meyer CA, Jeanneau K, Bradaia A, Ozmen L, et al. Trace amine-associated receptor 1 modulates dopaminergic activity. J Pharmacol Exp Ther. 2008, 324(3): 948-956.

29.Zucchi R, Chiellini G, Scanlan TS, Grandy DK. Trace amine-associated receptors and their ligands. Br J Pharmacol. 2006, 149(8): 967-978.

30.Bradaia A, Trube G, Stalder H, Norcross RD, Ozmen L et al. The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system. Proc Natl Acad Sci U S A. 2009, 106(47): 20081-20086.

31.Revel FG, Moreau JL, Pouzet B, Mory R, Bradaia A et al. A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight. Mol Psychiatry. 2013, 18(5): 543-556.

32.Panas HN, Lynch LJ, Vallender EJ, Xie Z, Chen GL et al. Normal thermoregulatory responses to 3-iodothyronamine, trace amines and amphetamine-like psychostimulants in trace amine associated receptor 1 knockout mice. J Neurosci Res. 2010, 88(9): 1962-1969.

33.Wolinsky TD, Swanson CJ, Smith KE, Zhong H, Borowsky B et al. The Trace Amine 1 receptor knockout mouse: an animal model with relevance to schizophrenia. Genes Brain Behav. 2007, 6(7): 628-639.

34.Ikemoto K. Striatal D-neurons: in new viewpoints for neuropsychiatric research using post-mortem brains. Fukushima J Med Sci. 2008, 54(1): 1-3.

35.Degreef G, Ashtari M, Bogerts B, Bilder RM, Jody DN et al. Volumes of ventricular system subdivisions measured from magnetic resonance images in first-episode schizophrenic patients. Arch Gen Psychiatry. 1992, 49(7): 531-537.

36.Horga G, Bernacer J, Dusi N, Entis J, Chu K et al. Correlations between ventricular enlargement and gray and white matter volumes of cortex, thalamus, striatum, and internal capsule in schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2011, 261(7): 467-476.

37.Kippin TE, Kapur S, van der Kooy D. Dopamine specifically inhibits forebrain neural stem cell proliferation, suggesting a novel effect of antipsychotic drugs. J Neurosci. 2005, 25(24): 5815-5823.

38.Grimsby J, Toth M, Chen K, Kumazawa T, Klaidman L et al. Increased stress response and beta-phenylethylamine in MAOB-deficient mice. Nat Genet. 1997, 17(2): 206-210.

39.Golomb BA. Chocolate habits of Nobel prizewinners. Nature. 2013, 499: 409.

Cite this article: Ikemoto K. TAAR1 Ligands as Prospective Neuroleptics: From Research of So-Called D-Neuron (Trace Amine Neuron). J J Medicinal Chem. 2015, 1(1): 001.


Contact Us:
TRAIL # 150 W
E-mail : info@jacobspublishers.com
Phone : 512-400-0398