Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The complete coding region of the norepinephrine transporter (NET) gene was systematically screened for genetic variants in 137 unrelated individuals (including 46 probands with bipolar affective disorder and 45 schizophrenic probands, as well as 46 blood donors) using single-strand conformation analysis. We identified 13 DNA sequence variants, among them five missense substitutions. The missense substitutions Val69Ile, Thr99Ile, Val245Ile, Val449Ile, and Gly478Ser are located at putative transmembrane domains (TMD) 1, 2, 4, 9, and 10, respectively. The Thr99Ile substitution is at the 5th position of the putative leucine-zipper in TMD2. In a case-control study distribution of missense substitutions was found to be similar in 103 patients with bipolar affective disorder, in 228 schizophrenia patients and in 187 controls, indicating that presence of these variants is not causally related to major psychiatric diseases. The detection of a highly polymorphic silent 1287G/A polymorphism was utilized to demonstrate biallelic expression of the NET in adult human brain.
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PMID:Systematic search for variation in the human norepinephrine transporter gene: identification of five naturally occurring missense mutations and study of association with major psychiatric disorders. 895 Apr 9

The monoamine neurotransmitters serotonin, norepinephrine and dopamine have been implicated in the pathogenesis of depression, schizophrenia and mood disorders. The mechanism of action of certain antidepressant drugs, particularly the tricyclics and the newly available norepinephrine and serotonin reuptake inhibitors (NSRIs) drugs, venlafaxine and nefazodone, suggest that the norepinephrine transporter, which is a target for these antidepressant drugs, and its malfunction may be involved in major depression. In this association study, we tested the hypothesis that variants of the human norepinephrine transporter (NET) gene confer susceptibility to major depression. One hundred and five patients with major depression and 74 unrelated matched controls were analyzed for a silent 1287G/A polymorphism (NET-8) in exon 9 of the NET gene. No significant differences in genotype or allele frequencies were found between controls and patients, nor between subgroups of depressed patients classified by suicidal ideation. In addition, 60 controls and 60 patients were genotyped for a missense substitution Thr99Ile in exon 2 of the NET gene (NET-1), but only one control was heterozygous for this variant. These results suggest that the NET gene is unlikely to be involved in the susceptibility to major depression.
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PMID:Norepinephrine transporter gene polymorphism is not associated with susceptibility to major depression. 1051 49

In vitro rotating disk electrode (RDE) voltammetry and in vivo microdialysis were used to characterize dopamine clearance in the rat medial prefrontal cortex (mPFC). RDE studies indicate that inhibition by cocaine, specific inhibitors of the dopamine transporter (DAT) and norepinephrine transporter (NET), and low Na(+) produced a 50-70% decrease in the velocity of dopamine clearance. Addition of the monoamine (MAO) inhibitors, l-deprenyl, clorgyline, pargyline, or in vivo nialamide produced 30-50% inhibition. Combined effects of uptake inhibitors with l-deprenyl on dopamine clearance were additive (up to 99% inhibition), suggesting that at least two mechanisms may contribute to dopamine clearance. Dopamine measured extracellularly 5 min after exogenous dopamine addition to incubation mixtures revealed that most conditions of DAT/NET inhibition did not produce elevated dopamine levels above controls. Inhibition of MAO produced elevated dopamine levels only after long-term, but not short-term, incubation in vitro. Short-term incubation of l-deprenyl combined with DAT and NET uptake inhibitors increased dopamine above control levels, consistent with more than one mechanism of dopamine clearance. Local infusion of pargyline (100 or 300 microm) into the mPFC or striatum via microdialysis produced more pronounced and immediate increases in mPFC dopamine levels compared with striatum. Furthermore, dopamine elevation in the mPFC was not accompanied by a decrease in the dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, as found in the striatum. These findings may have revealed a unique mechanism of mPFC dopamine clearance and therefore contribute to the understanding of multiple behaviors that involve mPFC dopamine transmission, such as schizophrenia, drug abuse, and working memory function.
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PMID:Characterization of extracellular dopamine clearance in the medial prefrontal cortex: role of monoamine uptake and monoamine oxidase inhibition. 1115 Mar 17

Altered dopamine regulation in the medial prefrontal cortex has been linked to drug abuse and disorders such as schizophrenia. Heterogeneous expression of the dopamine transporter, as well as the ability of the norepinephrine transporter to clear dopamine in the prefrontal cortex, delineates two potential sites for the regulation of synaptic dopamine within the cortex. The present study used in vivo microdialysis to compare the effects of local infusions of dopamine and norepinephrine uptake blockers in the caudate putamen and two subregions of the prefrontal cortex, the anterior cingulate and prelimbic/infralimbic cortices. Results revealed that all dopamine uptake blockers produced greater increases in dopamine efflux in the caudate-putamen relative to the prefrontal cortex. In addition, amphetamine administration increased dopamine efflux to a greater degree in the prelimbic, relative to the anterior cingulate, cortex. In contrast, the increase in dopamine efflux was similar in both subregions in the presence of nomifensine and desmethylimipramine. Infusions of the selective dopamine uptake blocker GBR 12909 failed to alter dopamine efflux in any prefrontocortical subregion. These data indicate a more prominent role for the dopamine transporter in the clearance of extracellular dopamine in the caudate-putamen relative to the prefrontal cortex and an important role for NET in the clearance of dopamine in both the prelimbic and anterior cingulate subregions of the rat medial prefrontal cortex.
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PMID:Effects of catecholamine uptake blockers in the caudate-putamen and subregions of the medial prefrontal cortex of the rat. 1198 30

Norepinephrine is one of the neurotransmitters which has been implicated in the pathogenesis of mood disorders and schizophrenia. The norepinephrine transporter (NET) gene may be a candidate gene for the study of the genetics of these disorders. In this study, 198 patients with schizophrenia and 100 patients with bipolar disorder were analysed for a silent mutation 1287 A/G, located in the coding region (exon 9) of the NET gene, to determine the association between this polymorphism of the NET gene and bipolar disorder or schizophrenia. No association was found between the studied polymorphism of the NET gene and either bipolar disorder or schizophrenia.
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PMID:A polymorphism of the norepinephrine transporter gene in bipolar disorder and schizophrenia: lack of association. 1209 6

Abnormalities in monoamine neurotransmission have been implicated in the pathogenesis of alcoholism, mood disorders and schizophrenia. Murine norepinephrine transporter gene (NET) has been mapped to a region on chromosome 8 where a quantitative trait locus for ethanol sensitivity. Therefore we tested whether norepinephrine transporter (NET) gene variants confer susceptibility to either alcohol dependence or severe alcohol withdrawal symptoms. There is a highly polymorphic silent G1287A mutation in the NET gene. In our study 157 alcoholics and 185 healthy unrelated matched control subjects were analyzed for a silent G1287A mutation. No significant differences in allele and genotype distribution between control subjects f(A)=0.33 and alcoholics f(A)=0.29 were found. No significant results were found in more homogenous subgroups, i.e. alcoholics with severe alcohol withdrawal (seizures, delirium), early onset age<26 nor dependent patients with positive familial history of alcoholism. These results suggest that the NET gene polymorphism in exon 9 accession number: mRNA: NM_001043, genomic contig.: NT_019610, is unlikely to be involved in the susceptibility to alcoholism and severe alcohol withdrawal.
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PMID:Norepinephrine transporter gene polymorphism is not associated with susceptibility to alcohol dependence. 1237 39

Lesions of the ventral hippocampus (VH) in neonatal rats result in post-pubertal alterations in a number of cognitive, social and motor behaviors that bear some analogy to schizophrenia. Increased sensitivity to stress and psychostimulants and prefrontal functional changes in the lesioned animals suggest an involvement of the mesocorticolimbic dopamine (DA) system. DA and norepinephrine (NE) interact in a number of ways in the medial prefrontal cortex (mPFC) to influence each other's functions. In order to assess the role of adrenergic system in the behavioral responses of neonatal VH (nVH) lesioned animals, we first examined cortical and subcortical bindings of alpha-1 and alpha-2 adrenergic receptors using [3H]-prazosin and [3H]-rauwolscine respectively, and the norepinephrine transporter (NET) using [3H]-nisoxetine. Sprague-Dawley rat pups, at post-natal day (PD) 7, received bilateral injections of ibotenic acid in the VH and were sacrificed pre (PD35)- and post (PD56)-pubertally. A significant increase in [3H]-prazosin binding was observed in the frontal and cingulate cortices of lesioned rats at PD56 without any significant change in the caudate putamen or nucleus accumbens. No significant difference was seen in [3H]-rauwolscine binding. A significant upregulation of NET binding was observed in subregions of the PFC and nucleus accumbens of PD56 lesioned rats. The functional relevance of changes in adrenergic markers on amphetamine-induced locomotor activity was examined by pre-treatment of PD56 rats with prazosin, an alpha-1 receptor antagonist. Prazosin at doses of 1.0 or 2.0 mg/kg ip significantly reduced amphetamine-induced locomotion in sham but not in PD56 lesioned animals. Taken together, these results suggest that alterations in prefrontal alpha-1 receptors likely contribute to altered behavioral responses observed in post-pubertal VH lesioned rats.
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PMID:Post-pubertal adrenergic changes in rats with neonatal lesions of the ventral hippocampus. 1465

Following exocytotic release of the biogenic amine neurotransmitters, norepinephrine and dopamine, are removed from the synaptic cleft by the respective transporter, norepinephrine transporter (NET) and dopamine transporter (DAT) located on the plasma membrane. The catecholamine transporters are the molecular targets for psychoactive drugs as well as drugs of abuse such as cocaine and amphetamine and the Parkinsonism-inducing neurotoxin, MPP+. Nicotine regulates the transport of catecholamines and MPP+ and may exert self-medicating effects for depression, schizophrenia and attention deficit hyperactivity disorder, and neuroprotective effects against MPP+ through the regulation of the transporters. The availability of cDNAs of these transporters has permitted detailed pharmacological studies in heterologous expression systems for determining the mechanisms of action of nicotine on transporters. Moreover, functional analysis of the effect of single amino acid substitution suggests that specific residues in DAT molecules may play a significant role in interaction with MPP+ and cocaine, and thus would promise a development of novel drugs with diverse chemical structures.
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PMID:Regulation of dopamine and MPP+ transport by catecholamine transporters. 1516 8

Schizophrenia and autism are neurodevelopmental disorders with genetic and environmental etiologies. Prenatal viral infection has been associated with both disorders. We investigated the effects of prenatal viral infection on gene regulation in offspring of Balb-c mice using microarray technology. The results showed significant upregulation of 21 genes and downregulation of 18 genes in the affected neonatal brain homogenates spanning gene families affecting cell structure and function, namely, cytosolic chaperone system, HSC70, Bicaudal D, aquaporin 4, carbonic anhydrase 3, glycine receptor, norepinephrine transporter, and myelin basic protein. We also verified the results using QPCR measurements of selected mRNA species. These results show for the first time that prenatal human influenza viral infection on day 9 of pregnancy leads to alterations in a subset of genes in brains of exposed offspring, potentially leading to permanent changes in brain structure and function.
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PMID:Prenatal viral infection in mouse causes differential expression of genes in brains of mouse progeny: a potential animal model for schizophrenia and autism. 1590 83

The relationship between limited tyrosine availability, DA (dopamine) synthesis and DA levels in the medial prefrontal cortex (MPFC) of the rat was examined by in vivo microdialysis. We administered a tyrosine- and phenylalanine-free mixture of large neutral amino acids (LNAA-) IP to lower brain tyrosine, and the norepinephrine transporter inhibitor desipramine (DMI) 10 mg/kg IP to raise MPFC DA levels without affecting DA synthesis. For examination of DOPA levels, NSD-1015 20 microM was included in perfusate. Neither NSD-1015 nor DMI affected tyrosine levels. LNAA- lowered tyrosine levels by 45%, and lowered DOPA levels as well; this was not additionally affected by concurrent DMI 10 mg/kg IP. In parallel studies DMI markedly increased extracellular levels of DA (420% baseline) and norepinephrine (NE) (864% baseline). LNAA- had no effect on baseline levels of DA or NE but robustly lowered DMI-induced DA (176% baseline) as well as NE (237% baseline) levels. Even when DMI (20 microM) was administered in perfusate, LNAA- still lowered DMI-induced DA and NE levels. We conclude that while baseline mesocortical DA synthesis is indeed dependent on tyrosine availability, the MPFC maintains normal extracellular DA and NA levels in the face of moderately lower DA synthesis. During other than baseline conditions, however, tyrosine depletion can lower ECF DA and NE levels in MPFC. These data offer a potential mechanism linking dysregulation of tyrosine transport and cognitive deficits in schizophrenia.
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PMID:Tyrosine depletion lowers dopamine synthesis and desipramine-induced prefrontal cortex catecholamine levels. 1808 73


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