Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology最新文献

Attention deficit/hyperactivity disorder (AD/HD) is characterized by significant difficulties of inattention and/or hyperactivity and impulsiveness. Dopamine transporter (DAT) knockout (KO) mice have been suggested to constitute an animal model of AD/HD. DAT KO mice exhibit persistently and profoundly elevated extracellular dopamine levels in the striatum and nucleus accumbens. These mice display numerous behavioral alterations that model aspects of AD/HD that include hyperactivity in novel environments and impulsivity. Both hyperactivity and impulsivity can be ameliorated by treatment with methylphenidate and nisoxetine. These drugs increase extracellular dopamine and norepinephrine levels in the prefrontal cortex. It is likely that methylphenidate and nisoxetine activate the prefrontal catecholamine systems by blocking the norepinephrine transporter (NET) function, thereby helping to improve AD/HD-like behavior in DAT KO mice.

Reduced glutamate neurotransmission via the NMDA receptor has been hypothesized to be involved in the pathophysiology of schizophrenia chiefly based upon the following observations: (1) non-competitive and competitive antagonists for the NMDA receptor including phencyclidine mimic not only positive symptoms but also negative and cognitive symptoms of schizophrenia, (2) the rank order potency of schizophrenomimetic effects of NMDA receptor antagonists is strictly correlated with that of their NMDA receptor-current blocking efficacies, (3) non-psychotomimetic doses of NMDA receptor antagonists for healthy controls produce psychotic symptoms in the remitted patients with schizophrenia, and (4) a schizophrenia-like psychotic state has often been reported in patients with encephalitis with anti-NMDA receptor antibody in the central nervous system. The possible NMDA receptor hypofunction could be caused by understimulation of its glycine site and/or by loss of NMDA receptor-possessing cells due to excess synaptic glutamate contents, or could lead to overactivation of the non-NMDA glutamate receptors. Therefore, agents for direct or indirect facilitation of the glycine site function or for attenuation of glutamate release have been studied to develop a novel pharmacotherapy for schizophrenia that could ameliorate both its antipsychotic-responsive and -resistant symptoms.

Recent human brain imaging studies have examined differences in activity in the nucleus accumbens (N.Acc.) in response to heat stimuli between controls and patients with chronic pain, and have revealed that the N.Acc. plays a role in predicting the value of a noxious stimulus and its offset, and in the consequent changes in the motivational state. Nevertheless, the molecular mechanisms of change in the circuitry involved in emotion and motivation in response to chronic pain stimuli were not fully explored. On the other hand, it has been considered that micro RNAs (miRNAs) play important roles as key modulators of post-transcriptional gene expression. We have reported that changes in miRNAs are associated with predicted changes in gene expression of candidate targets in the N.Acc. under neuropathic pain. Therefore, we have introduced a new insight into an epigenetic dysfunction of "mesolimbic motivation/valuation circuitry" under a neuropathic pain-like state. These findings raise intriguing possibilities that miRNA-modulating cellular events along with epigenetic modifications may be associated with neural plasticity and neuronal adaptive responses in mesolimbic motivation/valuation circuitry under which the neuropathic pain may induce negative emotions, exacerbating pain.

Opioids, such as morphine and fentanyl, are widely used as effective analgesics for the treatment of acute and chronic pain. In addition, the opioid system has a key role in the rewarding effects of morphine, ethanol, cocaine and various other drugs. The authors have focused on G-protein-activated inwardly rectifying potassium (GIRK) channel subunits, GIRK2 and GIRK3, which are important molecules in opioid transmission, and found that the SNPs within the GIRK2 and GIRK3 gene region were significantly associated with postoperative analgesic requirements, one of which was also associated with vulnerability to methamphetamine (METH) dependence. Further, by conducting a multistage genome-wide association study (GWAS) in healthy subjects, the authors found that the rs2952768 single-nucleotide polymorphism (SNP) was strongly associated with the requirements for postoperative opioid analgesics after painful cosmetic surgery and consistent results were obtained in patients who underwent abdominal surgery. In addition, the SNP also showed significant association with vulnerability to severe drug dependence in patients with METH dependence, alcohol dependence, and eating disorders and a lower 'Reward Dependence' score on a personality questionnaire in healthy subjects. These outcomes provide valuable information for the personalized treatment of pain and drug dependence.

We analyzed the cases of side effects due to antipsychotics reported to Japan's Pharmaceuticals and Medical Devices Agency (PMDA) from Jan. 2004 to Dec. 2012. We used the Japanese Adverse Drug Event Report Database (JADER) and analyzed 136 of 216,945 cases using the defined terms. We also checked the cardiac adverse effects listed in the package inserts of the antipsychotics involved. We found cases of Ikr blockade resulting in sudden death (49 cases), electrocardiogram QT prolonged (29 cases), torsade de pointes (TdP, 19 cases), ventricular fibrillation (VF, 10 cases). M2 receptor blockade was observed in tachycardia (8 cases) and sinus tachycardia (3 cases). Calmodulin blockade was involved in reported cardiomyopathy (3 cases) and myocarditis (1 case). Multiple adverse events were reported simultaneously in 14 cases. Our search of package inserts revealed warnings regarding electrocardiogram QT prolongation (24 drugs), tachycardia (23), sudden death (18), TdP (14), VF (3), myocarditis (1) and cardiomyopathy (1). We suggest that when an antipsychotic is prescribed, the patient should be monitored regularly with ECG, blood tests, and/or biochemical tests to avoid adverse cardiac effects.

The author proposes the "D-cell hypothesis" for molecular basis of the mesolimbic dopamine (DA) hyperactivity of schizophrenia. D-neurons, which were defined as "non-monoaminergic aromatic L-amino acid decarboxylase (AADC)-containing cells", produce trace amines (TAs), such as tyramine, phenylethylamine (PEA) and tryptamine. D-neurons may also take up amine precursors, and may convert them to amines by decarboxylation. The author's preliminary report showed that the number of AADC-containing neurons, that is D-neurons, was reduced in the striatum and nucleus accumbens of patients with schizophrenia. TA-associated receptor type 1 (TAAR1) has been shown to have a number of ligands, such as tyramine, PEA, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), and lysergic acid diethylamide (LSD), that may change human mental states. In patients with schizophrenia, the reduction of striatal D-neurons and possible decrease of striatal TA, is caused by neural stem cell dysfunction in the subventricular zone of the lateral ventricle. The reduced stimulation of TAAR1 on terminals of ventral tegmental area (VTA) DA neurons increases the firing frequency of VTA DA neurons, as recently published reports have shown, resulting in mesolimbic DA hyperactivity. In addition, increased DA D2 receptor stimulation, caused by striatal DA hyperactivity, may suppress forebrain neural stem cell proliferation, and would cause an additional decrease of D-neurons.

Ethanol has a variety of action on neuronal functions, though its mechanism of action remains uncertain. Previous investigations have demonstrated functional alteration of neurotransmitter receptors and ion channels by ethanol at its concentration observed in the blood of alcoholics. Our recent studies have shown that chronic ethanol treatment up-regulates high voltage-gated L-type calcium channels and ryanodine receptors, both of which regulate intracellular Ca2+ concentration, and that the up-regulation of these calcium channels participates in behavioral changes including the rewarding effect. Among inositol 1,4,5-trisphosphate receptors (IP3Rs) classified into three different subtypes (type 1 (IP3R-1), type 2, and type 3 IP3Rs) with distinct physiological properties, IP3R-1 is the major neuronal member in the central nervous system, predominantly enriched in cerebellar Purkinje cells and abundant in neurons in the cerebral cortex. Although the most important result of IP3R channel functions is the change in intracellular Ca2+ concentration and phosphorylation of IP3Rs, there are few available data on ethanol effect on IP3Rs. In this report, we demonstrate the functional relationship between ethanol-induced rewarding effect and IP3R-1 expression and regulatory mechanisms of IP3R-1 expression after chronic ethanol exposure, especially focusing on Ca(2+)-related signal transduction pathways via dopamine D1 receptors using mouse cerebral cortical neurons.

Various molecules are involved in drug addiction induced by drugs of abuse. Therefore, the mechanism of drug addiction is still not clear, and it has been a difficulty in the development of preventive and curative drugs for drug dependence. We tried to identify the molecules associated with drug dependence, and found three molecules including shati/nat81. Recently, it has been demonstrated that the substrate for shati/nat81 is aspaltate and shati/nat8l biosynthesizes N-acetylaspartate, which exists abundantly in the mammalian brain. In this study, we investigated the physiological function of shati/nat81 and the role of shati/nat81 in drug dependence. The overexpression of shati/nat81 in the dorsal striatum of mice led to social abnormality and depression-like behavior, and worsened a part of the motor dysfunction induced by Ca2+ channel agonist BAY-K 8644. The overexpression of shati/nat81 in the nucleus accumbens of mice inhibited methamphetamine-induced behavioral and biochemical abnormalities. These findings suggest that the shati/nat81-associated system could play a role in the regulation of mental activity and motor action, and be a new target in the development of therapeutic drugs for drug dependence.

Development of animal models is a crucial issue in biological psychiatry for the search of novel drug targets as well as the screening of candidate compounds. Epidemiologic studies suggest that environmental insults, such as prenatal infection and perinatal complication, are involved in the development of schizophrenia. Recently, we have developed a novel mouse model of viral infection during the perinatal stage by injecting polyriboinosinic-polyribocytidilic acid (polyI:C) into neonatal mice. Neonatal treatment of mice with polyI:C, an inducer of innate immune responses via toll-like receptor 3, caused a significant increase in interferon-induced transmembrane protein 3 (IFITM3) levels in the astrocytes of the hippocampus, which resulted in long-lasting brain dysfunction, including cognitive and emotional impairments as well as a deficit in depolarization-evoked glutamate release in the hippocampus in adulthood. Neonatal polyI:C-induced neuronal impairments have not been observed in IFITM3-KO mice. These findings suggest that the induction of IFITM3 expression in astrocytes by the activation of the innate immune system during the early stages of neurodevelopment has non-cell autonomous effects that affect subsequent neurodevelopment, leading to neuropathological impairments and brain dysfunction, by impairing endocytosis in astrocytes.

In this study, the relationship between the haplotypes consisting of single nucleotide polymorphisms (SNPs) of GSK-3beta -50T/C and -1727A/T and the derivation of smoking was studied among 102 smokers and 103 non-smokers. It was shown that the GSK-3beta -50T/C polymorphism may be linked with the smoking. There is significantly lower T-allele frequency in the smokers than non-smokers (chi2 (2) = 21.01, P = 0.000027; chi2 (1) 13.28, P = 0.00026). According to haplotype analysis, there was an association between smokers and non-smokers (global P = 0.00029). Higher haplotype 1 (T-A) frequency was observed in non-smokers than in smokers (P = 0.00036), whereas higher haplotype 2 (C-A) frequency was observed in smokers than in non-smokers (P = 0.000053). Pairwise D' and r2 values between the two SNPs in this study were 0.51 and 0.042, respectively. The two SNPs showed weak linkage disequilibrium with each other. This study suggests that GSK-3beta -50T/C polymorphism and two haplotypes may be related to smoking behavior.