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Parkinson's disease (PD) is a progressive neurodegenerative disorder. The major motor symptoms of PD are mainly caused by dopamine (DA) deficiency due to the loss of dopaminergic neurons in the substantia nigra. Most patients also show non-motor symptoms, such as cognitive impairment, mood disturbance, pain, and sleep disturbance. These symptoms cannot be explained by DA deficiency alone and are likely involved with other neurotransmitter systems, including glutamate, serotonin, noradrenaline, or gamma aminobutyric acid. Other neurotransmitters may have therapeutic effects on some symptoms of PD. In this review, we discuss the pathophysiology of Parkinsonian symptoms, with a focus on neurotransmitters. (Received 2 February, 2021; Accepted 16 February, 2021; Published 1 July, 2021).

Tourette syndrome (TS) is a neurodevelopmental disorder. TS was formerly considered to be a psychogenic disease; however, TS has recently been thought to be a heterogeneous disease with neurological bases and involving environmental and genetic factors. For example, it has been suggested that neurotransmitters including dopamine and cortico-striato-thalamo-cortical circuits are suggested to be associated with TS pathogenesis. According to these recent evidence, in addition to pharmacotherapy as the standard treatment, deep brain stimulation is being applied for patients with treatment-refractory TS in clinical settings.

Abnormalities in L-glutamate signal transmission have been postulated to play a role in major mental illnesses. The glial disruption results in decreased uptake of glutamate and an elevation of extracellular glutamate levels. Elevated extracellular glutamate may cause cytotoxic damage to neurons and glia. Significant down-regulation of glial glutamate transporters, GLT1 and GLAST, in major depressive disorder has been reported. In the present study we examined the role of glial glutamate transporters in the pathogenesis of autism and schizophrenia. We generated animal models in which glutamate receptors are overstimulated by genetic down-regulation of glial glutamate transporters. Resulting mutant mice showed abnormal social interaction, increased anxiety-like behavior, and select phenotypic abnormalities related to the negative and cognitive symptoms of schizophrenia. We observed enlarged amygdala and hippocampus. These mutant mice replicate many aspects of the behavioral and neuroanatomical abnormalities seen in autism and schizophrenia. Thus, these mutants are new animal models of major mental illness.

There is the concern that adaptation range of depression is enlarged, because operation diagnosis methods of ICD-10 and DSM-IV-TR spread in a clinic of psychiatry. On the other hand, clinical condition of depressive state may diversify. This is a review of the pathogenesis, classification and diagnostic criteria of depression. In the pathogenesis, we discussed about the biological origin (a neurotransmitter-related model, a neuroendocrine model et al) and the psychosocial origin with focus on a historic flow and recent knowledge of the pathogenetic theory. In the classification and diagnostic criteria, we mainly explained the points to notice and the problems on ICD-10 and DSM-IV-TR. It is necessity to arise the problem such as clinical symptoms are inconsistent with the classification and diagnostic criteria of ICD-10 and DSM-IV-TR, because all the pathogenesis is not elucidated now. A development of the classification and criteria of depression is expected in future by scientific elucidation advancing.

Marijuana has been used as a traditional medicine and a pleasure-inducing drug for thousands of years around the world, especially in Asia. Delta(9)-tetrahydrocannabinol, major psychoactive component of marijuana, has been shown to interact with specific cannabinoid receptors, thereby eliciting a variety of pharmacological responses in experimental animals and human. In 1990, the gene encoding a cannabinoid receptor (CB1) was cloned. This prompted the search for endogenous ligands. In 1992, N-arachidonoylethanolamine (anandamide) was isolated from pig brain as an endogenous ligand, and in 1995, 2-arachidonoylglycerol was isolated from rat brain and canine gut as another endogenous ligand. Both anandamide and 2-arachidonoylglycerol exhibit various cannabimimetic activities. The results of structure-activity relationship experiments, however, revealed that 2-arachidonoylglycerol, but not anandamide, is the intrinsic natural ligand for the cannabinoid receptor. 2-arachidonoylglycerol is a degradation product of inositol phospholipids that links the function of the cannabinoid receptors with the enhanced inositol phospholipid turnover in stimulated tissues and cells. The possible physiological roles of cannabinoid receptors and 2-arachidonoylglycerol in various mammalian tissues such as those of the nervous and inflammatory cells are demonstrated. Furthermore, the future development of therapeutic drugs coming from this endocannabinoid system are discussed.

It has been suggested that different BZP (omega) receptor subtypes may mediate distinct behavioral effects of BZP receptor ligands. Several studies demonstrated that omega1 selective compounds are characterized by an increase in slow wave deep sleep with rapid onset of hypnotic action, and by reduced muscle relaxation, amnesic liability or tolerance. On the other hand, it is known that many different subtypes of GABAA receptors exist, based on the fact that many different subtypes can go into assembling GABAA receptors. GABAA receptors with alpha1 subunits may mediate sedative action and perhaps amnesia. Those with alpha2 subunits probably mediate anxiolytic actions. GABAA receptors with alpha3 subunits may regulate various neurotransmitters, and those with alpha5 subunits may also contribute to amnesia. Such discoveries could open up new avenues for drug development.

Positron emission tomography with appropriate tracers provides unique opportunity to study neurotransmitter systems in the living human brain. PET with [18F] 6-fluoro-L-dopa (FD) provides an index of the integrity of nigrostriatal pathway, and striatal FD uptake correlates linearly with the density of nigral neurons. PET allows us to assess the progression of the nigral lesions in Parkinson's disease (PD). A 68-year-old normal female volunteer was scanned by FD-PET. Subsequently, she developed parkinsonism 3.7 years after the scan. A repeated FD-PET scan revealed a significant reduction of FD uptake by 20% over the 5.2 year interval. The results suggest a relatively short presymptomatic period with fast initial losses of nigral neurons in PD. FD-PET has been used to determine the viability of fetal graft implanted in the striatum for the treatment of PD. PET imaging of dopamine D1 and D2 receptors may be useful for the differential diagnosis of PD and striatonigral degeneration. PET reveals significant reduction of dopamine D1 and D2 receptor binding in the putamen of patients with SND, while D1 and D2 receptor binding is normal or slightly upregulated in PD. We found hypersensitivity of muscarinic cholinergic receptors in the frontal cortex of patients with PD by using PET. The result suggests a loss of ascending cholinergic system in the frontal cortex in PD, which may cause the frontal lobe dysfunction in PD. Recently, acetylcholine analogs labelled with positron emitter have been developed for measurement of brain acetylcholinesterase activity in vivo. These tracers may be useful for the assessment of ascending cholinergic system in Alzheimer's disease and PD.

Excitatory sulfur amino acids (SAAs) seem to be important, because derangement of SAA metabolism has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Since the concentration of excitatory SAAs in the neural tissue is extremely low, their presence or absence has not been conclusive in the literature. I determined cysteine sulfinic acid (CSA), cysteic acid (CA), homocysteine sulfinic acid (HCSA) and homocysteic acid (HCA) in rat brain by high-performance liquid chromatography using a Shimazu HPLC system LC10. Among the 4 excitatory SAAs mentioned above, the peaks of CA, HCSA and HCA did not appear at the chromatographic retention time corresponding to that of the authentic compounds. Only the peak of CSA was identified by matching retention time with the external standard as well as consistent co-elution with the added authentic compound. Thus the existence of CSA was confirmed and its concentration was 9.18 +/- 3.54 pmol/mg wet weight. Although the other 3 excitatory SAAs were not detected in rat brain, their presence in human brain cannot presently be excluded, because the size of the amino acid pool in rat brain is not the same as that in human brain. I examined in rat brain whether the concentration of CSA would possibly change when taurine, the final product of the metabolic pathway of SAAs, is experimentally increased. The inhalation of nitrous oxide (N2O) and the thyroidectomy have both been known to give rise to the elevation of taurine in the central nervous system, the mechanism of which is reportedly due to the impairment of the folate cycle. The metabolic flow of the SAA pathway is increased as a result of slowing down of the folate cycle, the damage of which has been shown in the brain of N2O-inhaled rats and thyroidectomized rats as well as of patients with ALS. The concentration of CSA was significantly increased in the cerebrum and the brainstem of the N2O-inhaled rats and the thyroidectomized rats, and in the cerebellum of the latter. CSA, recently demonstrated as a neurotransmitter, has been reported to have neurotoxicity stronger than that of gultamate in cultured rat cerebral neurons. The measurement of excitatory SAAs, especially CSA in nervous tissue of ALS will be required, although relevance of excitatory SAAs to the pathogenesis of ALS is not certain at present.

Ehrlich ascites tumor cells (EAT) could not proliferate in a basal medium (BM). L-Cysteine (L-CYS) added to BM in a concentration of 0.5 to 2 mM could promote the growth of EAT. At an unusual concentration of L-CYS (1 mM), the growth-rate was 233% (n = 50) at 72 hr after EAT transplantation. A similar growth-rate was obtained when EAT was transplanted 24 hr after addition of L-CYS to BM, although the free SH content in L-CYS-added BM at this time decreased to the level of that in BM. S-Methyl- and S-benzyl-L-cysteine showed no growth-promoting effect. The metabolic products of L-CYS (L-cysteine sulfinic acid, hypotaurine and taurine) showed a lower effect or none, but L-cystine showed the same activity as L-CYS. The EAT cultured in L-CYS-added BM was found to have an increased intracellular free SH and unchanged protein SH. These findings suggest that L-CYS added to BM is changed in a non-SH compound (possibly L-cystine) that is taken up into the cells and increases the intracellular free SH, resulting in the cell growth promotion.

Glutamate (Glu) receptors are classified into two major categories in the mammalian central nervous system: inotropic receptors linked to ion channels and metabotropic receptors linked to phosphatidylinositol (PI) metabolism. Classification of the inotropic Glu receptors is based on the differential sensitivity to excitement by N-methyl-D-aspartic acid (NMDA), DL-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainic acid (KA). The NMDA-sensitive subclass is supposed to be a receptor ionophore complex consisting of at least four different subcomponents, including an NMDA recognition site, a glycine (Gly) recognition site, a polyamine recognition site and a cation channel. The NMDA site is radiolabeled by both Glu and competitive antagonists, such as (+-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) and DL-(E)-2-amino-4-propyl-5-phosphono-3-pentenoic acid (CGP 39653). The Gly domain, which is labeled by both [3H]Gly and [3H]5,7-dichlorokynurenic acid, is sensitive to D-serine but insensitive to strychnine, and this domain seems to be absolutely required for an activation of the NMDA channel by agonists. The ionophore domain is identified by radiolabeled non-competitive NMDA antagonists that gain access to the binding sites within the channel only when it is gated by agonists. The opening of an NMDA channel is allosterically potentiated by Gly and several polyamines. In contrast, an activation of the NMDA channel is blocked by both H+ and divalent cations such as Mg2+ and Zn2+. [3H]AMPA binding displays pharmacological profiles of the AMPA-sensitive subclass with a rank order of agonistic potencies of quisqualic acid (QA) greater than or equal to AMPA greater than Glu greater than KA, which is apparently different from that found for the KA-sensitive subclass (domoic acid greater than or equal to KA greater than QA greater than Glu). In contrast, several quinoxaline derivatives competitively antagonize neuronal responses mediated not only by the AMPA receptor but also by the KA receptor. The metabotropic Glu receptors, which stimulate PI metabolism through an activation of the guanosine triphosphate-binding proteins, are activated by Glu, QA and trans-1-amino-cyclopentyl-1,3-di-carboxylic acid (ACPD). Responses mediated by the metabotropic receptors are competitively blocked by 2-amino-3-phosphonopropionic acid. Three or four cloned complementary deoxyribonucleic acids (cDNAs) encoding inotropic Glu receptors are isolated from a rat brain cDNA library. Pharmacological and electrophysiological properties of receptor-ion channels encoded by a transfection of these cDNAs are similar to those observed with the AMPA receptor as well as the KA receptor, but not with the NMDA receptor.

Recent advances in the field of peptide chemistry and gene technology have resulted in an explosive accumulation of information on the chemical structures of gastrointestinal hormones. Based on the information, chemical syntheses of these peptides or their shorter fragments and analogs have been performed. Synthetic peptides related to the hormones have now become important tools in searching for functions of peptides and in producing region-specific antisera to the respective peptides. Using these antisera, hormone-producing cells were clearly identified and the post-translational biosynthetic processings in the cells were demonstrated. Recent immunohistochemical studies have also revealed that cells contain and can release a variety of peptides or amines that are capable of influencing target cells and acting as hormone, neurotransmitter or neuromodulator. In addition, recent studies on galanin and glucagon-like peptide-1 (GLP-1) are described.

The concentrations of taurine and other sulfur-containing amino acids in the fetal, neonatal and maternal liver, placenta, and whole fetal body between the 15th day of gestation and the 14th day after birth were determined using an automatic amino acid analyzer. In the fetal liver and placenta, the taurine concentration was the highest among all ninhydrin positive compounds. In these tissues the concentration of taurine increased significantly with the number of gestational days. Moreover, the total amount of taurine per fetus increased markedly up to term after the 15th day of gestation, and reached almost the same value as the total amount for adult rat liver. A striking difference in the changes in taurine concentrations during gestation between the fetal and maternal rat liver was observed: In contrast to the increase in the fetal liver, a significant decrease in the maternal liver was observed near term. But in these organs, no significant change in methionine, cystathionine and cysteine concentrations was observed during the perinatal period. These results suggest that taurine is supplied to the developing rat fetus from the maternal liver throughout gestation.

Neuropeptide Y (NPY) is widely distributed in the central and sympathetic nervous systems and has a variety of central actions including regulation of blood pressure and peripheral actions; e.g., continuous vasoconstriction and inhibition of catecholamine release. The NPY receptor can be divided into 2 subclasses (Y1, Y2), and these subclasses are coupled to GTP binding proteins (Gi, Go, Gp ......). Recently, human and rat prepro-NPY mRNA and NPY gene structures have been determined by cDNA and genomic cloning and sequencing. The strong evolutionary conservation of these structures suggested that NPY is an essential peptidergic neurotransmitter. Little is known about the biosynthesis, processing, degradation of NPY and NPY gene expression. We showed that NPY gene expression and NPY biosynthesis are regulated by neural activity, hormone, and intracellular second messengers via neurotransmitter receptors. The change of NPY gene expression by these neural factors is considered to be a good model for a synaptic plasticity, because these changes cause the changes of synaptic transmission. Furthermore, because NPY is expressed in sympathetic neurons and its gene expression increased markedly on the differentiation of adrenergic cells, this study about NPY gene expression could provide good clues for elucidating the differentiation of sympathetic neurons.