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)

We have previously observed that addition of an alpha(2)-adrenoceptor antagonist to a selective dopamine (DA) D(2) receptor antagonist enhances the antipsychotic-like effect of the D(2) blocker and also selectively increases DA output in the medial prefrontal cortex (mPFC) in rats. These data also correlate well with previous clinical trials showing augmentation by an equivalent drug combination in schizophrenia. Since the selective noradrenaline reuptake inhibitor reboxetine was found to cause similar effects on the mesolimbocortical DA system as alpha(2)-adrenoceptor antagonists, the present study was undertaken to explore whether also reboxetine might augment the effect of the DA D(2) receptor antagonist raclopride in the same preclinical model of antipsychotic activity, the conditioned avoidance response (CAR) test. We also investigated the effect of this combination in the catalepsy test for extrapyramidal side effect liability, as well as on DA output in the mPFC and the nucleus accumbens, respectively. Reboxetine (6 mg/kg, i.p.) significantly enhanced the suppressant effect of raclopride (0.1 mg/kg, s.c.) on CAR without affecting catalepsy. Administration of raclopride (0.1 mg/kg, s.c.) to rats pretreated with reboxetine (6 mg/kg, i.p.) resulted in a greatly enhanced effect on DA output in the mPFC but not in the nucleus accumbens when compared with raclopride alone. Consequently, these results suggest that noradrenaline reuptake inhibition may provide means of augmenting the efficacy of classical D(2)-antagonists in the treatment of schizophrenia, and, in principle, to generate an atypical antipsychotic drug profile.
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PMID:Noradrenaline reuptake inhibition enhances the antipsychotic-like effect of raclopride and potentiates D2-blockage-induced dopamine release in the medial prefrontal cortex of the rat. 1243 44

It has recently been reported that the human corpus striatum, especially its ventral part, named as the nucleus accumbens, contains numerous non-monoaminergic aromatic L-amino acid decarboxylase (AADC; the second-step monoamine synthesizing enzyme) neurons (D-neurons). D-neurons are the neurons immunoreactive for AADC but not immunoreactive for dopamine or serotonin. They lack the first-step monoamine synthesizing enzymes, tyrosine hydroxylase and tryptophan hydroxylase. AADC is also the rate-limiting enzyme of phenylethylamine (PEA) synthesis. D-neurons might participate in the manifestation of efficacy of pharmacotherapy for Parkinson's disease by uptaking monoamine precursors including L-dopa or droxidopa (L-threo-DOPS) and by converting them to dopamine or noradrenaline, respectively. As the nucleus accumbens is one of the brain regions that are involved in the pathogenesis of schizophrenia and drug dependence, D-neurons might be related to the etiology of these mental disorders. It has also been suggested that striatal D-neurons are the pluripotential cells that have compensating functions against aging or degeneration.
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PMID:[Localization of non-monoaminergic aromatic L-amino acid decarboxylase neurons (D-neurons) in the human striatum and their functional significance]. 1255 14

A family with a high prevalence of Parkinson's disease, schizophrenia, neoplasms, syndrome-X, rheumatoid arthritis and epilepsy has been described. The psychological behavioural patterns of the family were as follows--creativity and high IQ, hypersexual behaviour, reduced appetite and eating behaviour, insomnia and reduced sleep patterns, increased tendency for spirituality, increased tendency for addiction, less of bonding and affectionate behaviour and left handedness. Digoxin, an endogenous Na(+)-K(+) ATPase inhibitor secreted by the hypothalamus, was found to be elevated and RBC membrane Na(+)-K(+) ATPase activity was found to be reduced in all the disorders and in the indexed family studied. Hypothalamic digoxin can modulate conscious perception and its dysfunction may lead to schizophrenia. Digoxin can also preferentially upregulate tryptophan transport over tyrosine resulting in increased levels of depolarising tryptophan catabolites - serotonin, quinolinic acid, strychnine and nicotine and decreased levels of hyperpolarising tyrosine catabolites dopamine, noradrenaline and morphine contributing to membrane Na(+)-K(+) ATPase inhibition in all the above disorders and the indexed family. Digoxin induced membrane Na(+)-K(+) ATPase inhibition can result in increased intracellular Ca(2+) and reduced Mg(++) levels leading to glutamate excitotoxicity, oncogene activation and immune activation. Digoxin induced altered Ca(++)/Mg(++) ratios, reduced ubiquinone and increased dolichol can affect glycoconjugate metabolism, membrane formation and structure and mitochondrial function leading to the diverse disorders described above including those in the indexed family. The isoprenoid pathway and neurotransmitter patterns were compared in right-handed/left hemispheric dominant and left-handed/right hemispheric dominant individuals. The biochemical patterns in the indexed family and the diverse disorders studied correlated with those obtained in right hemispheric dominance. The hyperdigoxinemic state indicates right hemispheric dominance. Hypothalamic digoxin can thus function as the master conductor of the neuroimmunoendocrine orchestra and co-ordinate the functions of various cellular organelles.
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PMID:Hypothalamic digoxin--central role in conscious perception, neuroimmunoendocrine integration and coordination of cellular function--relation to hemispheric dominance. 1260 43

The N-methyl-d-aspartate glutamate receptors (NMDAR) act in the CNS as regulators of the release of neurotransmitters such as dopamine, noradrenaline, acetylcholine, and GABA. It has been suggested that a weakened glutamatergic tone increases the risk of sensory overload and of exaggerated responses in the monoaminergic system, which is consistent with the symptomatology of schizophrenia. We studied two silent polymorphisms in GRIN1. GRIN1/1 is a G/C substitution localized on the 5' untranslated region; GRIN1/10 is an A/G substitution localized in exon 6 of GRIN1. Minor allele frequencies in our sample were calculated to be 0.05 and 0.2 respectively. We genotyped 86 nuclear families and 91 ethnically matched case-control pairs. Both samples were collected from the Toronto area. We tested the hypothesis that GRIN1 polymorphisms were associated with schizophrenia using the transmission disequilibrium test (TDT) and comparing allele frequencies between cases and controls. The results are as follows: GRIN1/1: chi(2) = 2.19, P = 0.14; GRIN1/10: chi(2) = 1.5, P = 0.22. For the case-control sample: GRIN1/1: chi(2) = 0.013, P = 0.908; GRIN1/10: chi(2) = 0.544, P = 0.461. No significant results were obtained. Haplotype analyses showed a borderline significant result for the 2,1 haplotype (chi(2) = 3.86, P-value = 0.049). An analysis of variance (ANOVA) to evaluate the association between genetic makeup and age at onset was performed, with no significant results: GRIN1/1, F[df = 2] = 0.42, P-value = 0.659; GRIN1/10, F[df = 2] = 0.16, P-value = 0.853. We are currently collecting additional samples to increase the power of the analyses.
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PMID:N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) in schizophrenia: TDT and case-control analyses. 1270 33

Epidemiological studies have reported that the risk of developing schizophrenia increases with the number of genes one shares with patients suffering from schizophrenia [Gottesman Schizophrenia Genesis, New York: Freeman; 1991]. In addition, stressful life events are known to increase the risk of developing schizophrenia [Schizophr Res 30 (1998) 251] resulting in the stress hypothesis of schizophrenia. Remarkably, stress increases the release of dopamine and noradrenaline in the nucleus accumbens [Brain Res 554 (1991) 217], which links the stress hypothesis with the known dopamine hypothesis of schizophrenia. Additionally an increased dopamine transmission in the nucleus accumbens (Nacc) is known to disturb prepulse inhibition (ppi) [Pharmacol Biochem Behav 49 (1994) 155], a phenomenon observed in, among others, schizophrenics [Arch Gen Psychiatry 47 (1990) 181]. Some years ago we have genetically selected two rat-lines which are marked by a high (APO-SUS) and by a low (APO-UNSUS) apomorphine susceptibility. Similar to schizophrenics the APO-SUS rat-line shows a reduced ppi [J Neurosci 15 (1995) 7604]. However, these data were obtained after a period of mild stress, namely a 24-h period of social isolation. Mild stress changes the line specific differences of APO-SUS and APO-UNSUS rats. The stress pushes the APO-SUS rat in the direction of an APO-UNSUS and vice versa, especially as far as it concerns the dopamine and noradrenaline activity in the nucleus accumbens [Cools AR, van-den Bos R, Ellenbroek BA, Gaiting function of noradrenaline in the ventral striatum: its role in behavioural responses to environmental and pharmacological challenges. In: Willner P, Scheel-Kruger J, editors. The mesolimbic dopamine system: from motivation to action. New York: Wiley; 1991 [Chapter 6]; Cools AR, Rots NY, De-Kloet ER, Apomorphine-susceptible and apomorphine-unsusceptible Wistar rats: a new tool in the search for the function of striatum in switching behavioural strategies. In: Pea G (Ed.), The basal ganglia IV, New York: Plenum Press; 1994; Brain Res Bull 24 (1990) 49; Behav Neurosci 108 (1994) 1107]. Therefore, in the present paper we investigated the ppi response in non-stressed, i.e. non-isolated APO-SUS and APO-UNSUS rats. In agreement with this hypothesis, we found that removal of the stress led to an increase of ppi in the APO-SUS, but a decrease in the APO-UNSUS. These data clearly shows that the ppi is stress-dependent in APO-SUS and APO-UNSUS rats. It is suggested that the differential stress-induced change in the dopaminergic and the noradrenergic system influences the reaction of APO-SUS and APO-UNSUS rats on ppi.
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PMID:Removal of short-term isolation stress differentially influences prepulse inhibition in APO-SUS and APO-UNSUS rats. 1274 53

Psychiatric abnormalities have been described in primary neurological disorders like multiple sclerosis, primary generalized epilepsy, Parkinson's disease, subacute sclerosing panencephalitis (SSPE), central nervous system glioma, and syndrome X with vascular dementia. It was therefore considered pertinent to compare monoamine neurotransmitter pattern in schizophrenia with those in the disorders described above. The end result of neurotransmission is changes in membrane Na(+)-K+ ATPase activity. Membrane Na(+)-K+ ATPase inhibition can lead to magnesium depletion, which can lead to an upregulated isoprenoid pathway. The isoprenoid pathway produces three important metabolites--digoxin, an endogenous membrane Na(+) -K+ ATPase inhibitor; ubiquinone, a membrane antioxidant and component of mitochondrial electron transport chain; and dolichol, important in N-glycosylation of protein. The serum/plasma levels of digoxin, dolichol, ubiquinone, magnesium, HMG CoA reductase activity, and RBC Na(+)-K+ ATPase activity were estimated in all these disorders. The result showed that the concentration of serum tryptophan and serotonin was high and serum tyrosine, dopamine, adrenaline, and noradrenaline low in all the disorders studied. The plasma HMG CoA reductase activity, serum digoxin, and serum dolichol levels were high and serum ubiquinone levels, serum magnesium, and RBC Na(+)-K+ ATPase activity were low in all the disorders studied. The significance of these changes in the pathogenesis of syndrome X, multiple sclerosis, primary generalized epilepsy, schizophrenia, SSPE, and Parkinson's disease is discussed in the setting of the interrelationship between these disorders documented in literature.
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PMID:Schizoid neurochemical pathology-induced membrane Na(+)-K+ ATPase inhibition in relation to neurological disorders. 1460 43

Schizophrenia is a common mental disorder with a complex pattern of inheritance. Despite a large number of studies in the past decades, its molecular etiology remains unknown. In this study, we proposed a 'system-thinking' strategy in seeking the combined effect of susceptibility genes for a complex disorder by using paranoid schizophrenia as an example. We genotyped 85 reported single-nucleotide polymorphisms (SNPs) present in 23 genes for the dopamine (DA) metabolism pathway among 83 paranoid schizophrenics and 108 normal controls with detailed clinical and genetic information. We developed two novel multilocus approaches-the potential effective SNP combination pattern and potential effective dynamic effects analysis, by which three susceptibility genotype combinations were found to be associated with schizophrenia. These results were also validated in a family-based cohort consisting of 95 family trios of paranoid schizophrenia. The present findings suggest that the COMT and ALDH3 combination may be the most common type involved in predisposing to schizophrenia. Since the combination blocks the whole pathways for the breakdown of DA and noradrenaline, it is very likely to play a central role in developing paranoid schizophrenia.
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PMID:Association study of an SNP combination pattern in the dopaminergic pathway in paranoid schizophrenia: a novel strategy for complex disorders. 1511 36

The human striatum, especially its ventral part, the nucleus accumbens (Acc), contains numerous nonmonoaminergic aromatic L-amino acid decarboxylase (AADC) [=dopa decarboxylase (DDC)] neurons (D-neurons). AADC is the second-step synthesizing enzyme for monoamines and is also the rate-limiting enzyme of phenylethylamine (PEA) synthesis. D-neurons may participate in the manifestation of efficacy of pharmacotherapy for Parkinson's disease by taking up monoamine precursors including L-dopa or droxidopa (L-threo-DOPS) and by converting them to dopamine or noradrenaline, respectively. Although previous studies have shown that AADC activity was elevated in the striatum of drug-naive schizophrenia, the number of striatal D-neurons was reduced in autopsy brains of schizophrenia. It is unclear whether or not such reduction of striatal D-neurons implies downregulation. Possible pluripotentiality of D-neurons, including compensatory functions against aging and degeneration, was discussed based on recent published works.
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PMID:Significance of human striatal D-neurons: implications in neuropsychiatric functions. 1509 49

Investigation of neuropsychological functioning in bipolar disorder provides a potential link from the prominent cognitive symptoms of the disorder to the underlying neural mechanisms. Continuous performance measures of sustained attention have yielded consistent findings in bipolar disorder patients. There are impairments that appear to be both state- and trait-related. Impaired target detection may represent one of the most sensitive markers of illness course in bipolardisorder. It is unrelated to residual mood symptomatology and medication status, and is present in patients with good functional recovery. The impairment in target detection is exacerbated in the manic state, and is accompanied by an increased rate of false responding. Sustained attention deficit is present early in the course of the disorder, but becomes more pronounced with repeated episodes. This cognitive profile, of an early-onset, state-modulated, trait marker, is distinct from the profile of attentional disruption seen in schizophrenia or unipolar depression. The state- and trait-related impairments may be differentially associated with the ascending dopamine and noradrenaline projections.
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PMID:State- and trait-related deficits in sustained attention in bipolar disorder. 1514 34

In this article we show some recent findings that constitute a great progress in the molecular knowledge of synaptic dynamics. To communicate, neurons use a code that includes electrical (action potentials) and chemical signals (neurotransmitters, neuromodulators). At the moment a great variety of molecules are known, whose neurotransmitter function in brain and the peripheral nervous system are out of question. Monoamines like acetylcholine, dopamine, noradrenaline, adrenaline, histamine, serotonin, glutamate, aspartate, glycine, ATP and GABA are good examples. Opioid neuropeptides, vasoactive intestinal peptide (VIP), neurokinines (substance P), somatostatin, neurotensin, neuropeptide Y, cholecystokinine, vasopressin or oxitocin have been related to the control of the stress response, sexual behaviour, food intake, pain, learning and memory, qualities that are also related to nitric oxide (NO). A great part of the molecular structure of the secretory machinery is known to be responsible for fast neurotransmitter release at the synapse, in response to action potentials. Proteins like sinaptobrevin (located in the membrane of the synaptic vesicle), sintaxin and SNAP-25 (both located at the presynaptic plasma membrane) constitute a trimeric complex which is responsible of the vesicular docking at the active sites for exocytosis. From this strategic location, vesicles release their neurotransmitter within few milliseconds, when the action potential invades the nerve terminal and activates the opening of the different subtypes of voltage-dependent Ca2+ channels. The asymmetric geographical distribution of each type of channel, in different neurons, rose the hypothesis that Ca2+ that enters through each subtype of channel is compartmentalised, thus favouring the generation of Ca2+ microdomains, in the cytosol and the nucleus, involved in different cellular functions. This great biochemical synaptic heterogeneity is facilitating the selection of many biological targets to develop drugs with potential therapeutic applications in neuropsychiatric diseases i.e. Alzheimer's, Parkinson, epilepsies, stroke, vascular dementia, depression, schizophrenia, anxiety and so on.
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PMID:[Neurotransmitters, calcium signalling and neuronal communication]. 1515 88


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