Effect of COMT Val108/158Met genotype on risk for polydipsia in chronic patients with schizophrenia.

Polydipsia is a serious condition often seen among patients with schizophrenia (SCZ). The cause of polydipsia is unknown; hence, it is hard to treat or manage. Animal studies showed that the drinking behavior is regulated by central dopaminergic neurotransmission at the hypothalamus. Meanwhile, the existence of a genetic predisposition to polydipsia in patients with SCZ has been suggested. The purpose of this study was to assess whether a functional polymorphism, Val(108/158)Met in the gene for catechol-O-methyltransferase (COMT), is associated with susceptibility to polydipsia using a Japanese sample of SCZ. Our sample includes 330 chronic patients with SCZ (83 polydipsic patients and 247 non-polydipsic controls). The common COMT Val(108/158)Met polymorphism was genotyped, and the differences in genotype distribution and allele frequency between cases and controls were evaluated using the χ(2) test. A significant association between the COMT Val(108/158)Met polymorphism and polydipsia was found (genotype distribution: χ(2) = 13.0, df = 2, p = 0.001; allele frequency: χ(2) = 7.50, df = 1, p = 0.006). The high-COMT activity group (Val/Val) was more frequent among patients with polydipsia compared with the low-COMT activity group (Val/Met + Met/Met) [odds ratio (OR) = 2.46]. The association survived after controlling for other possible confounding factors, including gender, age, age of onset, current antipsychotic dose, and smoking status. Our results suggest that the COMT Val(108/158)Met genotype may confer susceptibility to polydipsia in SCZ. To our knowledge, this is the first association study between the COMT gene and polydipsia in SCZ. Further studies with larger sample sizes are warranted to confirm present findings.

Genetic association between the dopamine D3 receptor gene polymorphism (Ser9Gly) and tardive dyskinesia in patients with schizophrenia: a reevaluation in East Asian populations.

The dopamine D3 receptor gene (DRD3) is considered being one of the candidate genes contributing to the development of tardive dyskinesia (TD). In a recent meta-analysis with mixed ethnicities, only a barely positive association was found between the functional DRD3 Ser9Gly polymorphism and TD in patients with schizophrenia (OR=1.17; 95% CI: 1.01-1.37; p=0.041). To further evaluate the controversial association between the polymorphism and TD using only Japanese subjects, we tested the association in a case-control design. We also conducted a meta-analysis including 8 studies with 3 East Asian populations (Japanese, Chinese, and Korean). In our Japanese case-control sample (43 with TD/157 without TD), we found no association between the DRD3 Ser9Gly polymorphism in schizophrenia and TD (genotype: p=0.92; allele: p=1.00). Furthermore, no significant difference in the mean AIMS score among the three genotypic groups was observed in our sample. The meta-analysis comprising 1291 East Asian subjects also showed no association between the polymorphism and TD; the Mantel-Haenszel pooled OR for TD among carriers of the DRD3 Ser9Gly of the eight Asian studies was 0.94 (95% CI: 0.78-1.12). Overall, our results suggest that the DRD3 Ser9Gly polymorphism may not confer susceptibility to TD in East Asian populations. Given that the Ser9Gly variant may play a putative role in the DRD3 function, further studies on the DRD3 are warranted.

Lack of association between the leptin receptor gene (LEPR) Gln223Arg polymorphism and late-onset Alzheimer disease.

The principal hypothesis for pathogenesis of Alzheimer disease (AD) is the amyloid cascade hypothesis, which emphasizes an imbalance between production and clearance of beta-amyloid (Abeta) in the brain. Insulin has important effects on the regulation of the Abeta level in the brain, modulating both Abeta production and clearance. An optimal brain insulin level promotes Abeta clearance, which may play protective roles against AD. A functional human leptin receptor gene (LEPR) polymorphism, a glutamine to an arginine substitution at codon 223 (Gln223Arg), has been associated with insulin resistance capacity and an altered leptin-binding activity. The LEPR Gln223Arg polymorphism may thus play an important role in the pathogenesis of AD. In this study, we examined the association between the LEPR Gln223Arg polymorphism and late-onset Alzheimer disease (LOAD) in a Japanese population. Our sample includes 49 patients with LOAD and 134 normal controls. Our preliminary data showed no significant association between the LEPR Gln223Arg polymorphism and LOAD (genotype distribution: chi=0.11, df=2, P=0.945; allele frequency: chi=0.058, df=1, P=0.81, odds ratio=1.08, 95% confidence interval=0.59 to 2.03). Our results suggest that the LEPR polymorphism may not play a major role in the development of LOAD.

Association analysis between the C-1291G polymorphism in the promoter region of the adrenergic alpha2A receptor gene and polydipsia in schizophrenia.

Several lines of studies have shown the existence of an important inhibitory mechanism for the control of water intake involving adrenergic alpha2A receptors (ADRA2A). A human study using patients with schizophrenia demonstrated an exacerbation of polydipsia by the administration of clonidine, an ADRA2A-agonist, and a relief of polydipsia by mianserin, an ADRA2A-antagonist, suggesting the involvement of the central adrenergic system in the drinking behavior of patients with schizophrenia. Based on these findings we examined a possible association between the C-1291G polymorphism in the promoter region of the ADRA2A gene and polydipsia in schizophrenia using a Japanese case-control sample. Our sample includes 348 patients with schizophrenia (DSM-IV) (84 with polydipsia and 264 without polydipsia). No significant association between the ADRA2A C-1291G polymorphism and polydipsia was found. Our result suggests that the ADRA2A C-1291G polymorphism may not confer susceptibility to polydipsia in schizophrenia in our sample. Further studies with larger samples are warranted.

No association between a functional polymorphism in the promoter region of the neuropeptide Y gene (-485C>T) and schizophrenia.

It has been suggested that hypoactivity of neuropeptide Y (NPY) may be involved in the pathophysiology of schizophrenia. A post-mortem study revealed a decreased level of NPY in the brain of patients with schizophrenia. An increased level of NPY after antipsychotic treatment was also reported in animal brain and cerebrospinal fluid of patients. Previously Itokawa et al. reported a positive association between the functional -485C>T polymorphism in the NPY gene and schizophrenia in a Japanese population. The aim of this study is to replicate their positive findings in an independent Japanese case-control sample. Our sample includes 260 patients with schizophrenia (DSM-IV) and 196 control subjects. No significant differences in distribution of genotype or allele frequencies between patients and controls were observed. Our results suggest that the NPY -485C>T polymorphism may not confer susceptibility to schizophrenia, at least in our sample. Further studies in larger samples are warranted.

Genetic association between the dopamine D3 gene polymorphism (Ser9Gly) and schizophrenia in Japanese populations: evidence from a case-control study and meta-analysis.

Dysregulation in the dopaminergic system has been implicated in the pathophysiology of schizophrenia (SCZ). Dopamine D3 receptors (DRD3) concentrated in limbic regions of the brain (important for cognitive, emotional and endocrine function) may be particularly relevant to SCZ. A recent meta-analysis with mixed ethnicities reported a marginal significant association between the Ser9Gly homozygosity in the first exon of the DRD3 gene and SCZ. To further evaluate the controversial association between this polymorphism and SCZ, a case-control study and meta-analysis was conducted using the homogeneous Japanese population. In our Japanese case-control sample (246 cases/198 controls), we found an association between the DRD3 Ser9Gly polymorphism and SCZ (genotype: chi(2) = 9.76, d.f. = 2, p = 0.008; Ser allele versus Gly allele: chi(2) = 7.96, d.f. = 1, p = 0.0048; OR = 0.65; 95% CI = 0.48-0.88). However in a meta-analysis of nine Japanese case-control studies comprising 2056 subjects the association between DRD3 Ser9Gly polymorphism and SCZ did not persisted. The Mantel-Haenszel pooled OR for SCZ among carriers of the DRD3 Ser9Gly homozygosity (Ser/Ser homozygotes and Gly/Gly homozygotes) of the nine Japanese studies was 1.16 (95% CI 0.97-1.39), pointing to a non-significant effect of the DRD3 Ser9Gly homozygosity as a risk factor for SCZ. Overall, our results suggest that the DRD3 Ser9Gly polymorphism may not confer susceptibility to SCZ in the Japanese population. Given that the Ser9Gly variant may play a putative role in DRD3 function, further studies on the DRD3 with linked variants are warranted.

Functional polymorphism of the human multidrug resistance gene (MDR1) and polydipsia-hyponatremia in schizophrenia.

P-glycoprotein (P-gp), which is coded by the MDR1 gene, in the brain capillary endothelial cell limits the entry of many drugs including antipsychotics into the brain. The aim of this study is to examine whether a functional polymorphism, a C to T substitution at position 3435 in exon 26 of the MDR1 gene, is associated with susceptibility to polydipsia-hyponatremia in schizophrenia (SCZ) in a Japanese case-control sample. It has been reported that individuals homozygous for this polymorphism had significantly lower MDR1 expression levels and dysfunction of MDR1 (PNAS 97:3473-3478, 2000). Furthermore, the brain entry of risperidone and 9-hydroxyrisperidone has been shown to be greatly limited by P-gp (Int J Neuropsychopharmacol 7:415-419, 2004). In order to our knowledge, this is the first association study between the MDR1 polymorphism and polydipsia-hyponatremia in SCZ. Our sample includes 331 patients with SCZ (DSM-IV) (84 with polydipsics and 247 non-polydipsic controls). The common C3435T polymorphism of the MDR1 was genotyped for both groups and differences in genotype and allele frequency between cases and controls were evaluated using the chi(2)-test. A significant association between the MDR1 C3435T polymorphism and polydipsia was found (chi(2) = 4.43, d.f. = 1, P = 0.035; OR = 1.46; 95%CI = 1.03-2.07). Our results suggest that the MDR1 C3435T polymorphism may confer susceptibility to polydipsia in SCZ.

The orexin 1 receptor (HCRTR1) gene as a susceptibility gene contributing to polydipsia-hyponatremia in schizophrenia.

The underlying pathophysiology of primary polydipsia in schizophrenia (SCZ) is poorly understood. Our previous study, however, suggested that this condition may have a genetic component [Shinkai et al 2003 Am J Med Genet 119B 7-12]. Orexins, also called hypocretins, play an important role in feeding and drinking behavior. Administration of orexin in rats has been shown to induce increased water intake with a longer-lasting effect than angiotensin II, which is also known as a potent dipsogen. Meerabux et al. [2005 Biol Psychiatry 58 401-407] reported an association between the 408Val allele of the orexin 1 receptor (HCRTR1) gene and polydipsia-hyponatremia in a sample of Japanese patients with SCZ. In the present study, we attempted to replicate the findings of Meerabux et al. in an independent Japanese case-control sample. Our sample included 312 patients with SCZ (DSM-IV) (65 with polydipsia and 247 without polydipsia). We also observed an association between the HCRTR1 Ile408Val polymorphism and polydipsia (genotype distribution: chi2 = 9.85, df = 2, P = 0.007). Meerabux et al. (2005) previously demonstrated an association between the 408Val allele of the HCRTR1 gene and polydipsia. In contrast with Meerabux et al. study, we found that the 408Ile allele was associated with polydipsia in our sample (chi2 = 8.00, df = 1, P = 0.0047; OR = 0.53; 95%CI = 0.34-0.83). How either allele contributes to the development of polydipsia in SCZ is unclear at this stage. It is possible that Ile408Val polymorphism is a non-functional marker that lies in linkage disequilibrium with an as-yet undetected functional variant. In any case, our results support the hypothesis that the HCRTR1 Ile408Val polymorphism may confer susceptibility to polydipsia in SCZ. Further studies examining the association between the orexin system and polydipsia in SCZ are warranted.

No association between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and schizophrenia in Asian populations: Evidence from a case-control study and meta-analysis.

Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that plays an important role in the development and maintenance of adult neurons and is important regulator of synaptic plasticity in human brain. It has been reported that there are alterations in BDNF levels in the brains of patients with schizophrenia. It has also been reported that transneuronal transfer of BDNF is dependent on neuronal activity, suggesting that BDNF plays an important role in neurotransmission. A single nucleotide polymorphism (SNP) in the BDNF gene that causes a valine to methionine substitution at codon 66 (Val66Met) has been demonstrated to affect human memory and hippocampal function. A possible positive association between the BDNF Val66Met polymorphism and schizophrenia has also been shown in Scottish and Spanish populations. Furthermore, the BDNF Val66Met polymorphism has been implicated in the age of onset of schizophrenia. In the present study, we attempted to replicate these findings in a Japanese case-control sample (211 patients with schizophrenia and 205 controls). We did not find an association between the BDNF Val66Met polymorphism and schizophrenia. An association between the Val66Met polymorphism and age of onset was not observed either. Furthermore, a meta-analysis including the present and previous Asian studies comparing 2059 patients with schizophrenia and 2765 controls also revealed no significant association between the BDNF Val66Met polymorphism and schizophrenia. Our results do not support a significant role for the BDNF Val66Met polymorphism in the development of schizophrenia in Asian populations.

Plasma levels of brain derived-neurotrophic factor and catecholamine metabolites are increased during active phase of psychotic symptoms in CNS lupus: a case report.

In the present study, the authors reported a case of systemic lupus erythematosus (SLE) with central nervous system involvement (CNS lupus). The authors also longitudinally investigated plasma levels of brain-derived neurotrophic factor (BDNF) and catecholamine metabolites in the patient, and found that plasma levels of BDNF, 3-methoxy-4-hydroxyphenylglycol (MHPG), and homovanillic acid (HVA) were raised in accordance with the severity of psychotic symptoms in this case of CNS lupus. These results suggest that it is useful to measure plasma levels of BDNF and the catecholamine metabolites in order to predict the severity of psychotic symptoms in CNS lupus and to provide a differential diagnosis from that of steroid-induced psychosis.

Stimulation of catecholamine synthesis by environmental estrogenic pollutants.

Environmental estrogenic pollutants are compounds that have been shown to have estrogenic effects on fetal development and reproductive systems. Less attention, however, has been paid to their influence on neuronal functions. We report here the effects of estrogenic pollutants on catecholamine synthesis in bovine adrenal medullary cells used as a model system of noradrenergic neurons. Treatment of cultured bovine adrenal medullary cells with p-nonylphenol and bisphenol A at 10 nM for 3 d stimulated [14C]catecholamine synthesis from [14C]tyrosine and tyrosine hydroxylase activity, an effect that was not inhibited by ICI 182,780, an antagonist of estrogen receptors. Significant effects of p-nonylphenol on [14C]catecholamine synthesis were observed at 0.1 nM, which is 45 times lower than that of the international regulatory standard (4.5 nM), and the maximum effects were around 10-100 nM. The concentrations (0.1-10 nM) used in the present study are similar to the range observed in rivers in the United States or Europe. On the other hand, short-term treatment of cells with 10 nM p-nonylphenol for 10 min also activated tyrosine hydroxylase, which was suppressed by U0126, an inhibitor of MAPK kinase. Furthermore, treatment of cells with p-nonylphenol for 5 min increased the phospho-p44/42MAPK in a concentration-dependent (1-1000 nM) manner, whereas p-nonylphenol (100 nm, 2 d) enhanced both levels of non-phospho- and phospho-p44/42MAPK. These findings suggest that short-term and long-term treatment of cells with estrogenic pollutants at environmental concentrations stimulates catecholamine synthesis and MAPK through an estrogen receptor-independent pathway.

Inhibition of the norepinephrine transporter function in cultured bovine adrenal medullary cells by bisphenol A.

We report here the effects of an environmental estrogen, bisphenol A, on norepinephrine (NE) transporter function in cultured bovine adrenal medullary cells. The effects of bisphenol A were compared to those of 17beta-estradiol. Bisphenol A significantly inhibited [3H]NE uptake by the cells in a concentration-dependent manner (1-100 microM). Kinetic analysis revealed that bisphenol A, as well as 17beta-estradiol, noncompetitively inhibited [3H]NE uptake. Bisphenol A and 17beta-estradiol inhibited the specific binding of [3H]desipramine to plasma membranes isolated from bovine adrenal medulla. As shown by Scatchard analysis of [3H]desipramine binding, bisphenol A increased the dissociation constant (K(d)) and decreased the maximal binding (B(max)), indicating a mixed type of inhibition. 17beta-Estradiol increased the K(d) without altering the B(max), thereby indicating competitive inhibition. The present findings suggest that bisphenol A inhibits the function of the NE transporter by acting on a site different from that of 17beta-estradiol in the adrenal medulla and probably in the brain noradrenergic neurons.

Stimulation of catecholamine synthesis by orexin-A in bovine adrenal medullary cells through orexin receptor 1.

Orexin-A has recently been identified as a new hypothalamic peptide working as a mediator in the regulation of feeding behavior and sleep control. To determine the role of orexin-A in peripheral metabolic processes, we examined direct effects of orexin-A on catecholamine synthesis and secretion in cultured bovine adrenal medullary cells. Incubation of cells with orexin-A (100 pM) for 20 min caused a small but significant increase in 14C-catecholamine synthesis from [14C]tyrosine, but not from L-3,4-dihydroxyphenyl[3-14C]alanine. Orexin-A (100 pM) potentiated the stimulatory effects of acetylcholine (0.3 mM) on 14C-catecholamine synthesis. Orexin-A significantly increased tyrosine hydroxylase activity, which was evident at 1 pM and maximal at 100 pM. 4 beta-Phorbol-12 beta-myristate-13 alpha-acetate, an activator of protein kinase C, did not enhance the stimulatory effects of orexin-A on tyrosine hydroxylase activity, while H-7 and staurosporine, inhibitors of protein kinase C, nullified the effects of orexin-A. Orexin-A had little effect on catecholamine secretion from the cells. Orexin receptor 1 (OX(1)R) but not orexin receptor 2 (OX(2)R) mRNA was detected in bovine adrenal medullary cells by reverse transcriptase-polymerase chain reaction. These findings suggest that orexin-A activates tyrosine hydroxylase and then stimulates catecholamine synthesis, probably via activation of the OX(1)R-protein kinase C pathway in adrenal medullary cells.

Regulation of catecholamine synthesis by leptin.

Obesity is often associated with cardiovascular and metabolic disorders such as hypertension and hyperglycemia. Leptin, a protein product of the obese gene, regulates satiety and energy expenditure through its receptors in the hypothalamus. Recent studies have shown that leptin has extrahypothalamic and peripheral actions. The presence of leptin receptors has been reported in the adrenal medulla. In the present study, we examined the effects of leptin on catecholamine synthesis in cultured bovine adrenal medullary cells. Leptin (3-30 nM) caused a significant increase in (14)C-catecholamine synthesis from [(14)C] tyrosine, but not from [(14)C] DOPA. Incubation of cells with leptin resulted in an activation and phosphorylation of tyrosine hydroxylase. Leptin caused a transient activation of mitogen-activated protein kinases (MAPKs). U0126, an inhibitor of MAPK kinase, abolished the effect of leptin on (14)C-catecholamine synthesis. High concentrations of leptin (10-100 nM) produced an increase in intracellular Ca(2+) concentration, which was blocked by Cd(2+), an inhibitor of voltage-dependent Ca(2+) channels. Concurrent treatment of cells with leptin (10 nM) and acetylcholine (0.3 mM) potently enhanced the stimulatory effect of acetylcholine on (14)C-catecholamine synthesis. Leptin, however, failed to enhance the stimulatory effect of acetylcholine on the phosphorylation and activity of tyrosine hydroxylase. Acetylcholine (0.3 mM) decreased the intracellular pH (pHi). Leptin (10 nM) affected neither the basal pHi nor the acetylcholine-induced fall in pHi. These findings suggest that leptin phosphorylates and activates tyrosine hydroxylase and subsequently stimulates catecholamine synthesis through MAPK and probably Ca(2+) pathways in the adrenal medulla.