Ryosuke Miyatake

Delusional disorder: Molecular genetic evidence for dopamine psychosis

Since delusional disorder is characterized by mono-symptomatic paranoid symptoms, it can be a good clinical model for investigating the dopaminergic mechanism responsible for paranoid symptoms. We examined neuroleptic responses, plasma homovanillic acid (pHVA) and genes of the dopamine receptor (DR) and its synthesizing enzyme (tyrosine hydroxylase: TH) in patients with delusional disorder and compared them with those of schizophrenic patients and healthy controls. Results: (1) A relatively small dose of haloperidol was more effective for delusional disorder than for schizophrenia. (2) The pretreatment level of pHVA was higher in patients with persecution-type, but not in those with jealousy-type delusional disorder, compared with age- and sex-matched controls. This increased pHVA level was decreased eight weeks after successful haloperidol treatment. (3) The genotype frequency of the DRD2 gene Ser311Cys was significantly higher in patients with persecution-type delusional disorder (21%), compared with schizophrenic patients (6%) or controls (6%). (4) Patients homozygous for the DRD3 gene Ser9Ser had higher pretreatment levels of pHVA than those heterozygous for Ser9Gly. (v) A significant positive correlation was found between the polymorphic (TCAT)n repeat in the first intron of the TH gene and pretreatment levels of pHVA in delusional disorder. We suggest that delusional disorder, especially the persecution-type, includes a “dopamine psychosis,” and that polymorphism of the DRD2, DRD3 and/or TH gene is part of the genetic basis underlying the hyperdopaminergic state that produces paranoid symptoms. Further studies on a large sample size are required.

Tissue‐specific alternative splicing of mouse brain type ryanodine receptor/calcium release channel mRNA

We detected alternative splicing of the mouse brain type ryanodine receptor (RyR3) mRNA. The splicing variant was located in the transmembrane segment. The non‐splicing type (RyR3‐II) included a stretch of 341 bp, and that of the 13th codon was stop codon TAA. Reverse transcription‐polymerase chain reaction (RT‐PCR) analysis shows that RyR3‐II mRNA was expressed in various peripheral tissues and brain at all developmental stages. However, interestingly, the splicing type (RyR3‐I) mRNA was detected only in the cerebrum. These findings suggest that the splicing variants RyR3‐I and RyR3‐II may generate functional differences of RyR3 in a tissue‐specific manner.

The drug-drug interaction effects of haloperidol on plasma carbamazepine levels

The metabolic interaction between carbamazepine (CBZ) and haloperidol (HP) was studied in Japanese schizophrenic patients treated with HP but not with CBZ and with both CBZ and HP. The serum CBZ concentrations in patients treated without HP were significantly decreased (p < 0.05), on average approximately 40%, as compared to those in patients treated with both CBZ and HP, whereas the serum HP concentrations in patients treated with both HP and CBZ were significantly decreased (p < 0.05), as compared to those in patients treated with HP but not with CBZ. The effect of HP, which prevents the serum CBZ level from decreasing, was shown in this study.

No association between the neuroleptic malignant syndrome and mutations in the RYR1 gene associated malignant hyperthermia

The neuroleptic malignant syndrome (NMS) is a drug-induced disease caused by neuroleptics, but the pathogenesis of NMS is unknown. Since NMS is similar to malignant hyperthermia (MH) in clinical features and treatment, 6 mutations in the skeletal muscle ryanodine receptor (RYR1) gene, which were associated with MH, were investigated in unrelated NMS patients by single-strand conformation polymorphism analysis (SSCP). As a result, MH-susceptible RYR1 mutations were not detected in our NMS patients. A single base substitution, C7278T, was detected in one patient whose serum CPK level was repetitively elevated, but his other major symptoms did not fulfil the clinical criteria for NMS. Our results do not support the association between the neuroleptic malignant syndrome and mutations in the RYR1 gene associated with malignant hyperthermia.

Haloperidol Inhibits Neuronal Nitric Oxide Synthase Activity by Preventing Electron Transfer

The effect of a neuroleptic, haloperidol (HP), on nitric oxide formation catalyzed by neuronal nitric oxide synthase (n-NOS) in the porcine brain was investigated. HP inhibited n-NOS activity noncompetitively versus L-arginine as a substrate, decreasing the maximal velocity (Ki value for HP = 31 microM). HP also inhibited the CaM-dependent NADPH consumption by n-NOS (IC50 = 221 microM). These data demonstrate the possibility that HP may mediate some neuronal functions through inhibiting NO release by preventing either the electron transfer through n-NOS or the formation of the activated reduced species of oxygen necessary for the formation of citrulline. And an interaction of HP with CaM may possibly affect the consumption of NADPH and n-NOS enzyme activity.

Lack of association between sigma1 receptor gene variants and schizophrenia

Abstract  Several pharmacological studies suggest the possible involvement of sigma1 receptors in the pathogenesis of schizophrenia. An association has been reported between schizophrenia and two variants (GC‐241–240TT and Gln2Pro) in the sigma1 receptor gene (SIGMAR1). We also previously reported that, along with T‐485 A, these two variants alter SIGMAR1 function. To investigate the role of SIGMAR1 in conveying susceptibility to schizophrenia, we performed a case‐control study. We initially screened for polymorphisms in the SIGMAR1 coding region using PCR‐single strand conformation polymorphism analysis. The distribution of SIGMAR1 polymorphisms was analyzed in 100 schizophrenic and 104 control subjects. A novel G620A variant was detected in exon4. G620A was predicted to alter the amino acid represented by codon 211 from arginine to glutamine. Our case‐control study showed no significant association between the T‐485 A, GC‐241–240TT, Gln2Pro, and G620A (Arg211Gln) variants and schizophrenia and clinical characteristics. These findings suggest that these SIGMAR1 variants may not affect susceptibility to schizophrenia.

Dopamine Psychosis in Schizophrenia? Molecular Genetic Study on Delusional Disorder

Delusional disorder is characterized by mono-symptomatic paranoid symptoms without other schizophrenic symptoms. Thus, delusional disorder can be a good clinical model for investigating the molecular genetic mechanisms for paranoid symptoms. In this study, we hypothesized that a hyperdopaminergic state in the brain is responsible for producing paranoid symptoms. To test this hypothesis, we (1) compared neuroleptic responses between patients with delusional disorder and schizophrenia, (2) measured plasma levels of homovanillic acid (pHVA), an indicator of brain dopamine activity, in patients with delusional disorder, and (3) analysed the polymorphism of dopamine receptors (DRs) and its synthesizing enzyme gene.