Sigma-1 receptors (Sig-1Rs) have been implicated in many neurological and psychiatric conditions. Sig-1Rs are intracellular chaperones that reside specifically at the endoplasmic reticulum (ER)–mitochondrion interface, referred to as the mitochondrion-associated ER membrane (MAM). Here, Sig-1Rs regulate ER–mitochondrion Ca2+ signaling. In this review, we discuss the current understanding of Sig-1R functions. Based on this, we suggest that the key cellular mechanisms linking Sig-1Rs to neurological disorders involve the translocation of Sig-1Rs from the MAM to other parts of the cell, whereby Sig-1Rs bind and modulate the activities of various ion channels, receptors, or kinases. Thus, Sig-1Rs and their associated ligands may represent new avenues for treating aspects of neurological and psychiatric diseases.

Although to date there have been no conclusive pathophysiological findings in support of the degenerative theory of the etiology of schizophrenia, the results of neuroimaging studies have suggested that progressive changes in the brain do occur during the clinical course of schizophrenia. However, there has been no report on alterations in regional cerebral blood flow (rCBF) under resting condition, which was compared between the first-episode and the chronic patients of schizophrenia and healthy controls. Therefore, in this study, we applied three-dimensional stereotactic surface projection analysis of resting SPECT (3D-SSP SPECT) in patients with first-episode (n = 18) and chronic schizophrenia (n = 23) and age-/sex-matched healthy controls (n = 40). The rCBFs in the middle/inferior/medial frontal gyrus and the anterior cingulate gyrus were significantly decreased in both patient groups, relative to the respective controls (Z > 3.0, P < 0.001, uncorrected). The chronic group showed significant hypoperfused region in the left inferior parietal lobule and middle/inferior temporal gyrus. Furthermore, within-cases comparison between the first-episode and chronic schizophrenia, revealed that the significant hypoperfused regions in the chronic group, compared to the first-episode group, were not only the lateral and medial prefrontal cortex, but also the inferior parietal cortex, posterior part of the temporal lobe, and the cuneus. The present study suggested that the reduction in rCBF occurs in the posterior brain area in addition to the frontal lobe across all clinical stages of schizophrenia.

Accumulating evidence suggests that phosphatidylinositol (PI) pathways have been involved in the secretion of dopamine (DA) and the regulation of DA transporter, which is a target of methamphetamine (METH). A recent large-scale gene-association study in a Dutch population demonstrated that the PIK4CA gene was closely linked to schizophrenia [Jungerius et al. (2007); Mol Psychiatry]. Here, we conducted a case (N = 232)-control (N = 233) study of the PIK4CA gene on Japanese METH abusers, which can manifest severe psychosis similar to schizophrenia. The genotype and allelic distributions of all four single nucleotide polymorphisms (SNPs) did not differ significantly between the METH abusers and the controls. The comparisons based on the classification of the psychosis as transient or prolonged and on the presence or absence of spontaneous relapse revealed no significant distribution of the four SNPs compared to the controls. Furthermore, haplotype analyses showed almost the same frequencies between the METH abusers and the controls. The present study suggests that the PIK4CA gene does not play a significant role in the vulnerability to METH use disorder in the Japanese population.

Accumulating evidence suggests that oxidative stress plays a role in the mechanisms of action of methamphetamine (METH) in the brain. In the present study, we investigated the association between the genetic polymorphisms among glutathione (GSH)‐related enzymes; glutathione S‐transferases (GSTs) such as GSTT1 (Non‐deletion/Null), GSTT2 (Met139Ile), GSTA1 (−69C/T), and GSTO1 (Ala140Asp); glutathione peroxidase 1 (GPX1) (Pro198Leu); and glutamate‐cysteine ligase modifier (GCLM) subunit and METH use disorder in a Japanese population. Two hundred eighteen METH abusers and 233 healthy controls were enrolled in the study. There was a significant difference in GSTT1 genotype frequency between patients with METH psychosis and controls (P = 0.039, odds ratio: 1.52, 95% CI 1.03–2.24). Furthermore, the frequency (66.0%) of the GSTT1 null genotype among prolonged‐type METH psychotic patients with spontaneous relapse was significantly higher (P = 0.025, odds ratio: 2.43, 95% CI 1.13–5.23) than that (44.4%) of transient‐type METH psychotic patients without spontaneous relapse. However, there were no associations between the polymorphisms of other genes and METH abuse. The present study suggests that the polymorphism of the GSTT1 gene might be a genetic risk factor of the development of METH psychosis in a Japanese population. © 2008 Wiley‐Liss, Inc.

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OBJECTIVE:Protein interacting with C-kinase-1 (PICK1) plays a role in the targeting and clustering of dopamine transporter, which is the primary target site for the abused drug methamphetamine. Based on the interaction of PICK1 with dopamine transporter, it is of particular interest to investigate the association between the PICK1 gene and methamphetamine abusers.METHOD:The authors studied the association between PICK1 gene polymorphisms and methamphetamine abusers in a Japanese group. Two hundred and eight methamphetamine abusers and 218 healthy comparison subjects were enrolled in the study. Furthermore, the authors also examined the effects of single nucleotide polymorphisms (SNPs) in the promoter and 5'-untranslated region on transcription levels of PICK1.RESULTS:The authors identified four highly frequent SNPs, rs737622 (-332 C/G) and rs3026682 (-205 G/A) in the promoter region and rs713729 (T/A) in intron3 and rs2076369 (T/G) in intron4. Of these SNPs, rs713729 was significantly associated with methamphetamine abusers in general, and rs713729 and rs2076369 were significantly associated with those with spontaneous relapse of psychosis. Furthermore, haplotype analysis revealed that specific haplotypes of these SNPs were associated with methamphetamine abusers. A gene reporter assay revealed that the two SNPs in the promoter region significantly altered transcriptional activity.CONCLUSIONS:Our findings suggest that the PICK1 gene may be implicated in the susceptibility to spontaneous relapse of methamphetamine psychosis and that, as an intracellular adapter protein, PICK1 may play a role in the pathophysiology of methamphetamine psychosis.

Although preclinical studies suggest that methylone (2-methylamino-1-[3,4-methylenedioxyphenyl]propan-1-one) and 5-MeO-MIPT (5-methoxy-N-methyl,N-isopropyl tryptamine) may have psychostimulant properties, the scientific reports about the clinical effects of these agents are scant. We describe a 27-year-old male patient with substance intoxication after a single ingestion of the mixture of methylone and 5-MeO-MIPT. Though he bought the drug as pure methylone powder via an internet order, our chemical analyses indicated that the drug was composed of about 60% methylone (120 mg) and 38% 5-MeO-MIPT (76 mg). This case report suggests that clinicians should be alert to the possibility of the emergence of methylone or 5-MeO-MIPT intoxication, and substance-related mental disorder may be complicated by combined use of other psychoactive drugs.

In 1980s, abuse and dependence of BRON-W syrup (cough suppressant), which contains methylephedrine, dihydrocodeine, chlorpheniramine and caffeine, were prevalent in Japan. Pharmacological and clinical studies suggest that methylephedrine and dihydrocodeine cause dependence. Although BRON-L syrup, newly modified cough suppressant contains only chlorpheniramine and caffeine, there still are abuse and dependence of this drug. In this report, three cases of BRON-L syrup abuse are demonstrated. All cases started using BRON-L syrup in the late teens in their peer groups, and dropped out from school. Case 1 misused only BRON-L syrup, but case 2 and 3 were multi-drug abusers (case 2: amphetamine, cocaine, and marijuana, case 3: solvent, alcohol, bromovalerylurea), and had kept in tough with the peer groups. Case 2 and 3 hospitalized more than 2 times. Withdrawal symptoms, such as headache, insomnia, and irritability were mild and improved in a few weeks after drug use was stopped. These findings suggest that 1) psychosocial backgrounds of these cases are in common with those of BRON-W syrup abusers, but 2) the clinical course and prognosis of multi-drug abusers are different from the BRON single abuser, 3) chlorpheniramine and caffeine possibly cause dependence, 4) abusers are likely to choose BRON brand although two main dependence-producing constituents are removed from it now. Therefore, prevention and care of BRON-L abusers requires both psychosocial and pharmacological aspects.

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.