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)

Increased levels of dopamine have been associated with schizophrenia and mania; conversely, decreased levels of dopamine are associated with depression. Since the main mechanism for the termination of dopamine's pharmacological action is by re-uptake into the presynaptic cell, the speed of dopamine transport dramatically influences the concentration of dopamine present in the synaptic cleft, which in turn could determine brain disorders. Our preliminary studies have found that ATP can stimulate dopamine transport in rat synaptosomal preparation. We have also observed this ATP-regulated moiety of the dopamine uptake system when tested in PC12 cells. The large magnitude of ATP stimulation suggests that this dopamine uptake pathway may be important in the etiology and treatment of brain disorders. In order to test the relevance of ATP-stimulated dopamine uptake, we tested the effect of lithium salts on this system. Lithium chloride, one of the first drugs used in the treatment of mania, has become one of the most important agents utilized for the treatment of manic-depression and many schizoeffective disorders. Unfortunately, despite all efforts that have been made to explain lithium's mode of action, a clear cut biochemical mechanism has not been defined. We have found that lithium chloride, at therapeutic levels, is able to stimulate the ATP-regulated component of the dopamine uptake system by 49%. The further enhancement of dopamine re-uptake by lithium ions is consistent with its therapeutic effect. It is suggested that any substance that facilitates dopamine re-uptake could be of great importance in defining a useful treatment for mania and schizophrenia, as well as depression.
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PMID:Li+ stimulates ATP-regulated dopamine uptake in PC12 cells. 775 92

Acutely manic bipolar patients, like patients with schizophrenia, Tourette's syndrome, panic disorder, and obsessive compulsive disorder, exhibit deficits in sensorimotor gating, as measured by prepulse inhibition (PPI) of the startle response. Here, we assessed the ability of four drugs used in the treatment of bipolar mania-phenytoin, carbamazepine, valproate, and lithium-to reduce the PPI-disruptive effects of ketamine or amphetamine in the 129SvPasIco inbred strain of mice. For comparison, we also assessed the interaction of lithium and amphetamine in C57BL/6J mice. This set of studies yielded four major results. 1) Lithium chloride (85 mg/kg) prevented amphetamine-induced but not ketamine-induced disruption of PPI in both strains of mice. 2) Carbamazepine (50 mg/kg) prevented ketamine-induced but not amphetamine-induced disruption of PPI. 3) Sodium valproate (100 mg/kg) did not prevent amphetamine- or ketamine-induced disruption of PPI. 4) Phenytoin (30 mg/kg) did not prevent amphetamine- or ketamine-induced disruption of PPI but increased PPI on its own. These studies did not reveal a consistent relationship between the ability of a drug to protect PPI from disruption by ketamine or amphetamine and efficacy in the treatment of bipolar mania. Instead, the diverse effect profiles of these four treatments in reversing the PPI deficits produced by amphetamine or ketamine in mice presumably reflect the differences in their respective pharmacological mechanisms. Hence, further studies using these dopaminergic and glutamatergic models of deficient PPI may provide valuable insights into the mechanisms underlying the differential therapeutic effects of antimanic and mood-stabilizing treatments.
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PMID:An investigation of the efficacy of mood stabilizers in rodent models of prepulse inhibition. 1612 8

Bipolar disorder (BPD) is a debilitating heritable psychiatric disorder. Contemporary rodent models for the manic pole of BPD have primarily utilized either single locus transgenics or treatment with psychostimulants. Our lab recently characterized a mouse strain termed Madison (MSN) that naturally displays a manic phenotype, exhibiting elevated locomotor activity, increased sexual behavior, and higher forced swimming relative to control strains. Lithium chloride and olanzapine treatments attenuate this phenotype. In this study, we replicated our locomotor activity experiment, showing that MSN mice display generationally-stable mania relative to their outbred ancestral strain, hsd:ICR (ICR). We then performed a gene expression microarray experiment to compare hippocampus of MSN and ICR mice. We found dysregulation of multiple transcripts whose human orthologs are associated with BPD and other psychiatric disorders including schizophrenia and ADHD, including: Epor, Smarca4, Cmklr1, Cat, Tac1, Npsr1, Fhit, and P2rx7. RT-qPCR confirmed dysregulation for all of seven transcripts tested. Using a novel genome enrichment algorithm, we found enrichment in genome regions homologous to human loci implicated in BPD in replicated linkage studies including homologs of human cytobands 1p36, 3p14, 3q29, 6p21-22, 12q24, 16q24, and 17q25. Using a functional network analysis, we found dysregulation of a gene system related to chromatin packaging, a result convergent with recent human findings on BPD. Our findings suggest that MSN mice represent a polygenic model for the manic pole of BPD showing much of the genetic systems complexity of the corresponding human disorder. Further, the high degree of convergence between our findings and the human literature on BPD brings up novel questions about evolution by analogy in mammalian genomes.
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PMID:A new mouse model for mania shares genetic correlates with human bipolar disorder. 2267 14

Schizophrenia patients show a high rate of premature mortality due to suicide. The pathophysiological mechanisms of these suicidal behaviors in schizophrenia do not appear to involve serotonergic neurotransmission as found in the general population. Our aim was to develop an in vivo model of schizophrenia presenting suicide-trait-related behaviors such as aggressiveness, impulsivity, anxiety and helplessness. We opted for a two-hit model: C57BL/6 dams were injected with polyI:C on gestational day 12. The pups were submitted to social isolation for 4weeks after weaning. During the last week of social isolation and 30min before behavioral testing, the mice received vehicle, lithium chloride or clozapine. Lithium chloride is well known for its suicide preventive effects in the non-schizophrenic population, while clozapine is the antipsychotic with the best-established suicide preventive effect. The two-hit model induced several schizophrenia-related and suicide-trait-related behaviors in male, but not female, mice. Additionally, lithium chloride improved prepulse inhibition, aggressiveness, impulsivity and anxiety-like behavior in socially isolated mice only, whereas clozapine prevented behavioral abnormalities mainly in mice prenatally exposed to polyI:C and submitted to isolated rearing. The distinct effects of lithium chloride and clozapine suggested that mice prenatally exposed to polyI:C and submitted to social isolation presented a distinct phenotype from that of mice submitted to social isolation only. Because diagnosing suicidal risk in patients is a challenge for psychiatrists given the lack of specific clinical predictors, our in vivo model could help in gaining a better understanding of the mechanisms underlying suicidal behavior in the context of schizophrenia.
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PMID:A two-hit model of suicide-trait-related behaviors in the context of a schizophrenia-like phenotype: Distinct effects of lithium chloride and clozapine. 2677 20