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

Sensorimotor gating, which is severely disrupted in schizophrenic patients, can be measured by assessing prepulse inhibition of the acoustic startle response (PPI). Acute administration of D2-like receptor agonists such as quinpirole reduces PPI, but tolerance occurs upon repeated administration. In the present study, PPI in rats was reduced by acute quinpirole (0.1 mg/kg, s.c.), but not following repeated quinpirole treatment once daily for 28 days. Repeated quinpirole treatment did not alter the levels of basal-, forskolin- (5 microM), or SKF 82958- (10 microM) stimulated adenylate cyclase activity in the nucleus accumbens (NAc), but significantly increased cAMP-dependent protein kinase (PKA) activity. Phosphorylation of cAMP response element-binding protein (CREB) was significantly greater in the NAc after repeated quinpirole treatment than after repeated saline treatment with or without acute quinpirole challenge. Activation of PKA by intra-accumbens infusion of the cAMP analog, Sp-cAMPS, prevented acute quinpirole-induced PPI disruption, similar to the behavioral effect observed following repeated quinpirole treatment. Thus, repeated quinpirole treatment increases NAc PKA activity and CREB phosphorylation, and this neuroadaptive response might facilitate the recovery of sensorimotor gating in schizophrenia.
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PMID:Repeated quinpirole treatment increases cAMP-dependent protein kinase activity and CREB phosphorylation in nucleus accumbens and reverses quinpirole-induced sensorimotor gating deficits in rats. 1513 41

A "partial" rodent model for schizophrenia has been used to characterize the regulation of hippocampal genes in response to amygdalar activation. At 96 h after the administration of picrotoxin into the basolateral nucleus, we have observed an increase in the expression of genes associated with 18 different monoamine (ie adrenergic alpha 1, alpha 2 and beta 2, serotonergic 5HT5b and 5HT6, dopamine D4 and muscarinic m1, m2 and m3) and peptide (CCK A and B, angiotensin 1A, mu and kappa opiate, FSH, TSH, LH, GNRH, and neuropeptide Y) G-protein coupled receptors (GPCRs). These latter receptors are associated with three different G protein signaling pathways (Gq, Gs, and Gi) in which significant changes in gene expression were also noted for adenylate cyclase (AC4), phosphodiesterase (PDE4D), protein kinase A (PKA), and protein kinase C (PKC). Quantitative RT-PCR was used to validate the results and demonstrated that there were predictable increases of three GPCRs selected for this analysis, including the dopamine D4, alpha 1b, and CCK-B receptors. Eight out of the nine monoamine receptors showing these changes have moderate to high affinity for the atypical antipsychotic, clozapine. Taken together, these results suggest that amygdalar activation may play a role in the pathophysiology and treatment of psychosis by regulating the activity of multiple GPCR and metabolic pathways in hippocampal cells.
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PMID:Acute amygdalar activation induces an upregulation of multiple monoamine G protein coupled pathways in rat hippocampus. 1517 Apr 62

Pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1: adenylate cyclase-activating polypeptide 1), a neuropeptide with neurotransmission modulating activity, is a promising schizophrenia candidate gene. Here, we provide evidence that genetic variants of the genes encoding PACAP and its receptor, PAC1, are associated with schizophrenia. We studied the effects of the associated polymorphism in the PACAP gene on neurobiological traits related to risk for schizophrenia. This allele of the PACAP gene, which is overrepresented in schizophrenia patients, was associated with reduced hippocampal volume and poorer memory performance. Abnormal behaviors in PACAP knockout mice, including elevated locomotor activity and deficits in prepulse inhibition of the startle response, were reversed by treatment with an atypical antipsychotic, risperidone. These convergent data suggest that alterations in PACAP signaling might contribute to the pathogenesis of schizophrenia.
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PMID:Pituitary adenylate cyclase-activating polypeptide is associated with schizophrenia. 1738 18

Disrupted-in-schizophrenia 1 (DISC1) is a gene disrupted by a (1;11) (q42.1;q14.3) translocation that segregates with major psychiatric disorders in a Scottish family. To investigate how DISC1 confers susceptibility to psychiatric disorders, we previously identified fasciculation and elongation protein zeta-1 and Kendrin as DISC1-interacting molecules in a yeast two-hybrid screen of a human brain complementary DNA library. Here, we have further identified a novel DISC1-interacting protein, termed DISC1-Binding Zinc-finger protein (DBZ), which has a predicted C(2)H(2)-type zinc-finger motif and coiled-coil domains. DBZ was co-immunoprecipitated with DISC1 in lysates of PC12 cells and rat brain tissue. The domain of DISC1 interacting with DBZ was close to the translocation breakpoint in the DISC1 gene. DBZ messenger RNA (mRNA) was expressed in human brains, but not in peripheral tissues. In situ hybridization revealed high expression of DBZ mRNA in the hippocampus, olfactory tubercle, cerebral cortex and striatum in rats. Because this pattern of localization was similar to that of the pituitary adenylate cyclase (PAC(1)) receptor for pituitary adenylate cyclase-activating polypeptide (PACAP), which has recently been implicated in neuropsychological functions, we examined whether DISC1/DBZ interaction was involved in the PACAP signaling pathway. PACAP upregulated DISC1 expression and markedly reduced the association between DISC1 and DBZ in PC12 cells. A DISC1-binding domain of DBZ reduced the neurite length in PC12 cells after PACAP stimulation and in primary cultured hippocampal neurons. The present results provide some new molecular insights into the mechanisms of neuronal development and neuropsychiatric disorders.
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PMID:A novel DISC1-interacting partner DISC1-Binding Zinc-finger protein: implication in the modulation of DISC1-dependent neurite outgrowth. 1738 5

Pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1: adenylate cyclase-activating polypeptide 1) is a neuropeptide with neurotransmission modulating activity. The associations of the PACAP gene with schizophrenia and hippocampal volume have been reported. We recently reported depression-like behavior in the forced swimming test in PACAP deficient mice. Here we examined a possible association between the PACAP gene and major depressive disorder (MDD) in 637 patients and 967 controls and found that a genetic variant in the gene was associated with MDD. The present results suggest that PACAP signaling might contribute to the pathogenesis of MDD.
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PMID:Possible association between the pituitary adenylate cyclase-activating polypeptide (PACAP) gene and major depressive disorder. 1991 36

The adenylate cyclase-activating polypeptide 1 (ADCYAP1) gene encodes a neuropeptide with neurotransmission activity, which is known as the pituitary adenylate cyclase-activating polypeptide. Associations of two polymorphisms, rs1893154 and rs2856966 (Asp54Gly), in the ADCYAP1 gene with schizophrenia were reported earlier by a Japanese case-control study. In this study, we tried to confirm the association in 2027 Japanese patients with schizophrenia and 2058 controls. The power to detect an association was more than 0.9. However, we did not detect allelic associations of rs1893154 with schizophrenia (P=0.36). Although rs2856966 was nominally significant (P=0.045), the association was in the opposite direction from that reported earlier. Combined data and meta-analysis of the two studies comprising nearly 6000 Japanese case-control patients did not show significant associations (P=0.53-0.86). It is concluded that single-nucleotide polymorphisms, including Asp54Gly, of the ADCYAP1 gene are unlikely to play a sizeable role in the genetic susceptibility to schizophrenia.
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PMID:Replication study of association between ADCYAP1 gene polymorphisms and schizophrenia. 2041 43

Astrocytes express dopamine receptors and respond to dopamine stimulation. However, the role of astrocytes in psychiatric disorders and the effects of antipsychotics on astroglial cells have only been investigated recently. S100B is a glial-derived protein, commonly used as a marker of astroglial activation in psychiatric disorders, particularly schizophrenia. We investigated S100B secretion in three different rat brain preparations (fresh hippocampal slices, C6 glioma cells and primary astrocyte cultures) exposed to apomorphine and antipsychotics (haloperidol and risperidone), aiming to evaluate, ex vivo and in vitro, whether dopamine activation and dopaminergic antagonists modulate astroglial activation, as measured by changes in the extracellular levels of S100B. The serum S100B elevation observed in schizophrenic patients is not reflected by the in vitro decrease of S100B secretion that we observed in hippocampal slices, cortical astrocytes and C6 glioma cells treated with apomorphine, which mimics dopaminergic hyperactivation. This decrease in S100B secretion can be explained by a stimulation of D2 receptors negatively coupled to adenyl cyclase. Antipsychotic medications and antioxidant supplementation were able to prevent the decline in S100B secretion. Findings reinforce the benefits of antioxidant therapy in psychiatric disorders. Based on our results, in hippocampal slices exposed to apomorphine, it may be suggested that antipsychotics could help to normalize S100B secretion by astrocytes.
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PMID:In vitro S100B secretion is reduced by apomorphine: effects of antipsychotics and antioxidants. 2151 66

In the early 1970s, receptors for neurotransmitters acting via second messengers had not been identified biochemically nor were there definitive links to such messengers. The discovery by John W. Kebabian and Paul Greengard of a dopamine-sensitive adenyl cyclase, accordingly, was a giant step forward. The investigators first characterized the enzyme in sympathetic ganglia wherein dopamine-producing cells link pre- and post-synaptic neurons. Then, in the corpus striatum, the brain area enriched in dopamine, they delineated the enzyme\x{2019}s properties and showed that it was inhibited by antipsychotic drugs, leading to a large body of research on dopamine as a mediator of antipsychotic drug action and putative roles for this transmitter in the pathophysiology of schizophrenia.
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PMID:What dopamine does in the brain. 2210 52

The metabotropic glutamate (mGluRs) receptors are a distinct class of G-protein-coupled receptors that act through activation of phospholipase C and/or inhibition of adenylate cyclase. They encompass seven-transmembrane domain proteins, comprehensively expressed in neuronal and glial cells within the brain, spinal cord and periphery and are involved in controlling pathophysiology of a number of diseases. These receptors may be sorted into three groups based on similarity of amino acid sequence, pharmacology and the transducer pathways they couple. The agonists and antagonists act at the N-terminal glutamate binding site and present a pharmacological strategy to modulate pathogenesis. A number of these compounds are positive or negative allosteric modulators that bind within the receptor transmembrane heptahelical domains. This imparts improved subtype selectivity, improved bioavailability and better drug like properties (e.g. CNS penetration). The mGluRs are presently the focal point of sizeable attention because of their potential as drug targets for the treatment of neurological and psychiatric disorders of the brain including Schizophrenia, Alzheimer's disease, Parkinson's disease, addiction, anxiety, depression, epilepsy and pain. The present review focuses on signal transduction mechanisms implicated to control and functionally upregulate the glutamatergic transmission system. The article also hallmarks agonists and antagonists for mGluRs as pivotal agents to ameliorate an array of neurological and psychiatric disorders.
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PMID:Metabotropic glutamate receptors: a review on prospectives and therapeutic aspects. 2253 May 79

Adrenomedullin (ADM) and nitric oxide (NO) have been implicated in the pathogenesis of certain psychiatric disorders such as schizophrenia and bipolar disorder. ADM induces vasorelaxation by activating adenylate cyclase and stimulating the release of NO. These two molecules are known to influence cerebral activity. In this study, we aimed to examine the serum levels of ADM and NO in patients with major depression (MD). We enrolled 50 patients with MD and 50 healthy control subjects. The diagnosis of MD was established on the basis of a structured clinical interview using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). The severity of depressive symptoms was evaluated using Hamilton's 17-item Depression Rating Scale. The mean serum levels of ADM and NO in patients with MD were significantly higher than those in healthy subjects (p=0.001, for both). The severity of psychomotor retardation in patients with MD was significantly correlated with the ADM (r=0.37, p=0.007) and NO levels (r=0.29, p=0.038). The patients with obvious psychomotor retardation had significantly higher levels of ADM and NO than did the patients with no psychomotor retardation (p=0.025, p=0.030). A significantly positive correlation was found between ADM and NO levels in patients with MD (r=0.79, p=0.001). Serum levels of ADM and NO levels were not correlated with the severity or duration of depression or depressive symptoms (except psychomotor retardation). In conclusion, our study indicates that serum levels of ADM and NO are elevated in patients with MD and that increased serum levels of ADM and NO may be associated with psychomotor retardation. The ADM-NO system may serve as a new target in the treatment of patients with MD and psychomotor retardation.
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PMID:Possible role of adrenomedullin and nitric oxide in major depression. 2386 66


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