Norepinephrine (NE) is a key neurotransmitter in the central and peripheral nervous systems. Dopamine β-hydroxylase (DβH) catalyzes the synthesis of NE from dopamine (DA) and occurs in the plasma as a stable heritable trait. Studies of this trait have been useful in psychiatric and neurological research. To selectively and critically review the literature on plasma DβH, and on recent progress understanding the molecular genetic basis for its inheritance. Based on this review, directions for future research in psychiatry and neurology will be suggested. We selectively review the literature on the biochemical and molecular genetics of plasma DβH activity, as well as research on plasma and cerebrospinal fluid (CSF) DβH in psychiatric and neurological disorders. Strong evidence implicates DBH, the structural locus encoding DβH enzyme, as the major quantitative trait locus influencing plasma DβH activity, with one single nucleotide polymorphism (SNP) accounting for up to 50% of the variance. Mutations at DBH appear to be responsible for the rare syndrome of DβH deficiency. Some biochemical and genetic studies suggest associations between low plasma or CSF DβH and psychotic symptoms in several psychiatric disorders. Studies combining genotyping at DBH with biochemical measurement of plasma DβH have proven useful in studies of schizophrenia, cocaine-induced paranoia (CIP), depression, attention deficit hyperactivity disorder, and alcoholism. Such studies may also elucidate the contribution of noradrenergic dysfunction to a variety of symptoms in Parkinson’s disease and other degenerative neurological disorders. A model is proposed, in which lower levels of DβH protein may lead to elevated ratios of DA to NE. This model may explain associations between lower plasma DβH activity and vulnerability to psychotic symptoms. Genotype-controlled analysis of plasma DβH holds promise for promoting further progress in research on psychiatric and neurological disorders.

Human genetics of plasma dopamine β-hydroxylase activity: applications to research in psychiatry and neurology

The CLDN5 locus may be involved in the vulnerability to schizophrenia

Cortical neurotransmitter availability is known to exert domain-specific effects on cognitive performance. Hence, normal variation in genes with a role in neurotransmission may also have specific effects on cognition. We tested this hypothesis by examining associations between polymorphisms in genes affecting cholinergic and noradrenergic neurotransmission and individual differences in visuospatial attention. Healthy individuals were administered a cued visual search task which varied the size of precues to the location of a target letter embedded in a 15-letter array. Cues encompassed 1, 3, 9, or 15 letters. Search speed increased linearly with precue size, indicative of a spatial attentional scaling mechanism. The strength of attentional scaling increased progressively with the number of C alleles (0, 1, or 2) of the alpha-4 nicotinic receptor gene C1545T polymorphism (n = 104). No association was found for the dopamine beta hydroxylase gene G444A polymorphism (n = 135). These findings point to the specificity of genetic neuromodulation. Whereas variation in a gene linked to cholinergic transmission systematically modulated the ability to scale the focus of visuospatial attention, variation in a gene governing dopamine availability did not. The results show that normal variation in a gene controlling a nicotinic receptor makes a selective contribution to individual differences in visuospatial attention.

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Specificity of the Effect of a Nicotinic Receptor Polymorphism on Individual Differences in Visuospatial Attention

Comparison of microarray-based mRNA profiling technologies for identification of psychiatric disease and drug signatures.

Objective:We present 3 new cases of psychotic symptoms in patients with adult attention-deficit/hyperactivity disorder while regularly treated with a stimulant therapy with methylphenidate.Methods:Existing literature about this theme is reviewed, and potential mechanisms are discussed.Results and Co

Methylphenidate-induced psychosis in adult attention-deficit/hyperactivity disorder: report of 3 new cases and review of the literature.

Recently, two polymorphisms (DBH5′-Ins/del and DBH 444 g/a) of the Dopamine Beta Hydroxylase (DBH) gene were isolated, and one haplotype (Del-a) was found to be associated with low DBH activity and cocaine-induced paranoia. The purpose of this study is to test for association between these two polymorphisms and schizophrenia or its phenotypic variability with respect to neuroleptic therapeutic response and symptom profile. Allelic and haplotype distributions of these two polymorphisms were compared between two groups of schizophrenic patients (excellent neuroleptic-responders; R, n = 42 and non-responders; NR, n = 64), and one group of healthy volunteers (n = 120). The “Del” and “a” alleles were in positive linkage disequilibrium. No allelic or genotype differences in the distribution of these two polymorphisms were observed between patients and controls. However, The Del-a haplotype was significantly more common in NR patients, and the mean total BPRS score was significantly higher in the group of patients with the Del-a compared to those without the Del-a haplotype. These results suggest that the DBH gene is not a causative factor in schizophrenia but that it may be a modulator of psychotic symptoms, severity of the disorder and therapeutic response to neuroleptic drugs. © 2003 Wiley-Liss, Inc.

Kenji Yamamoto

Papers

Dopamine beta-hydroxylase (DBH) gene and schizophrenia phenotypic variability: a genetic association study.

Polymorphism in the cell division cycle 45 like gene and schizophrenia