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)

There is experimental evidence from radioligand binding experiments for the existence of strong antagonistic interactions between different subtypes of adenosine and dopamine receptors in the striatum, mainly between adenosine A1 and dopamine D1 and between adenosine A2A and dopamine D2 receptors. These interactions seem to be more powerful in the ventral compared to the dorsal striatum, which might have some implications for the treatment of schizophrenia. The binding characteristics of different dopamine and adenosine receptor subtypes were analysed in the different striatal compartments (dorsolateral striatum and shell and core of the nucleus accumbens), by performing saturation experiments with the dopamine D1 receptor antagonist [125I]SCH-23982, the dopamine D2-3 receptor antagonist [3H]raclopride, the adenosine A1 receptor antagonist [3H]DPCPX and the adenosine A2A receptor antagonist [3H]SCH 58261. The experiments were also performed in rats with a neonatal bilateral lesion of the ventral hippocampus (VH), a possible animal model of schizophrenia. Both dopamine D2-3 and adenosine A2A receptors follow a similar pattern, with a lower density of receptors (40%) in the shell of the nucleus accumbens compared with the dorsolateral caudate-putamen. A lower density of adenosine A1 receptors (20%) was also found in the shell of the nucleus accumbens compared with the caudate-putamen. On the other hand, dopamine D1 receptors showed a similar density in the different striatal compartments. Therefore, differences in receptor densities cannot explain the stronger interactions between adenosine and dopamine receptors found in the ventral, compared to the dorsal striatum. No statistical differences in the binding characteristics of any of the different adenosine and dopamine receptor antagonists used were found between sham-operated and VH-lesioned rats.
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PMID:Adenosine and dopamine receptor antagonist binding in the rat ventral and dorsal striatum: lack of changes after a neonatal bilateral lesion of the ventral hippocampus. 1035 90

This article will review the capabilities and accomplishments of radiotracer imaging with single photon emission computed tomography (SPECT) and positron emission tomography (PET) to measure pre-, post-, and "intra-synaptic" aspects of dopaminergic (DAergic) neurotransmission. The presynaptic site can be labeled with probes for the dopamine transporter (DAT) or the synthetic enzyme aromatic L-amino acid decarboxylase ("dopa decarboxylase"). The postsynaptic sites can be labeled with probes for either the dopamine D1 receptor (D1R) or the dopamine D2 receptor (D2R). The "synaptic" measurements are made indirectly by measurements of the interaction/displacement of receptor tracers by endogenous dopamine (DA). Agents are used which either release (e.g., amphetamine) or deplete (e.g., alpha-methyl-paratyrosine (AMPT), an inhibitor of tyrosine hydroxylase) tissue stores of DA. The application of these paradigms will be reviewed with special emphasis to neuropsychiatric diseases such as schizophrenia and idiopathic Parkinson's disease (IPD).
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PMID:Radiotracer imaging of dopaminergic transmission in neuropsychiatric disorders. 1063 81

The present results demonstrate sedative effects of the DA D1 receptor agonist A 68930 (0.9-15 micromol kg(-1), s.c.) on rat spontaneous locomotor activity in an open field. The effects were particularly strong, and dose-dependent, for the ambulatory activity in the open-field arena (forward locomotion) and for rearing activity, whereas the suppression of locomotor activity (i.e. total horizontal activity in the open field) was less conspicuous. The distribution of activity within the open field (activity in center vs periphery) was not consistently affected by the A 68930 treatment. In support for DA D1 receptor mediated effects of A 68930, the effects on locomotor activity, forward locomotion, and on rearing behavior, were partially antagonized by the DA D1 receptor antagonist SCH 23390 (15 nmol kg(-1) s.c.). SCH 23390 by itself produced a modest, but statistically significant, suppression of these different items of open-field behavior. The atypical antipsychotic agent clozapine has previously, in this laboratory, been shown to stimulate DA D1 receptors in vivo. There are a number of clinical and laboratory observations, consistent with the notion of a beneficial role for such effects in schizophrenia. Thus, the sedation, apparently not related to extrapyramidal motor functions, produced by DA D1 receptor agonist A 68930 could reflect an important aspect of the mechanism of action for atypical antipsychotic drugs.
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PMID:Sedative effects of the dopamine D1 receptor agonist A 68930 on rat open-field behavior. 1081 5

Recent studies have shown that medial prefrontal cortex (mPFC) lesions impair performance on a number of rodent tests of attention. Although this evidence clearly suggests a role for the rat mPFC in attentional functions, it is unclear whether subcortical changes associated with mPFC lesions might also be relevant to the neuropsychological deficits observed. Given the ample evidence suggesting increased dopaminergic mechanisms in the basal ganglia following mPFC lesions, we investigated the effects of dopamine receptor agonists and antagonists on the attentional deficits associated with mPFC lesions. Rats trained on a five-choice reaction time task received either complete mPFC lesions or lesions restricted to its ventral subregions, the prelimbic and infralimbic cortices (PRL-IL). Compared with sham-operated rats, animals in both the lesioned groups were impaired at responding correctly to the visual targets, although this deficit was more marked in mPFC-lesioned rats. In addition, both lesions were associated with increased perseverative responding. The accuracy deficits of rats with mPFC lesions were alleviated by systemic administration of the dopamine D2 receptor antagonist sulpiride. In contrast, rats with PRL-IL damage were not affected and control rats were impaired by sulpiride. Administration of either the dopamine D1 receptor antagonist SCH 23390 or of pre-synaptic doses of apomorphine had similar, albeit non-significant effects. Higher doses of any of these drugs non-specifically impaired performance. These results extend previous findings of attentional impairments in rats with mPFC lesions and are compatible with recent hypotheses concerning the role of dopaminergic dysregulation in the pathogenesis of schizophrenia.
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PMID:Sulpiride alleviates the attentional impairments of rats with medial prefrontal cortex lesions. 1249 30

The dopamine (DA) innervation of medial prefrontal cortex (mPFC) regulates cognitive activity in a complex manner. Alterations of DA function, particularly via the DA D1 receptor class (D1R), are implicated in both schizophrenia and drug addiction, yet the precise roles of DA in modulating mPFC excitability remain unclear. We focused on DA modulation of voltage-gated K(+) current (VGKC) in acutely dissociated rat mPFC pyramidal neurons. We defined three components of the whole-cell VGKC according to biophysical and pharmacological properties. The A-type current (I(A)), with rapid activation and inactivation kinetics, was completely inactivated by prolonged holding of the membrane potential at -40 mV and was sensitive to the K(+) channel blocker 4-aminopyridine (4-AP) but not tetraethylammonium (TEA) or dendrotoxin (DTX). The slowly inactivating K(+) current (I(D)), with rapid activation but relatively slow inactivation, was the major contributor to VGKC and was completely inactivated at -40 mV and sensitive to TEA and DTX but less so to 4-AP. The very slowly inactivating K(+) current (I(K)) was elicited by command steps to more depolarized potentials from a prolonged holding potential of -40 mV and was sensitive to all three blockers. Stimulation of DA D2 receptors failed to alter any component of whole-cell VGKC. Stimulation of DA D1Rs selectively suppressed I(D), an effect mimicked by the adenylyl cyclase activator forskolin, the active cAMP analog Sp-cAMP, and the protein phosphatase inhibitor okadaic acid. Inhibition of protein kinase A (PKA) with either PKI or Rp-cAMP abolished D1R modulation. Thus, the DA D1R/cAMP/PKA signaling pathway mediates modulation of I(D) by DA in rat mPFC pyramidal neurons.
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PMID:Dopamine D1-class receptors selectively modulate a slowly inactivating potassium current in rat medial prefrontal cortex pyramidal neurons. 1268 54

Dopaminergic and glutamatergic neurotransmissions in the striatum play an essential role in motor- and reward-related behaviors. Dysfunction of these neurotransmitter systems has been found in Parkinson's disease, schizophrenia, and drug addiction. Cyclin-dependent kinase 5 (CDK5) negatively regulates postsynaptic signaling of dopamine in the striatum. This kinase also reduces the behavioral effects of cocaine. Here we demonstrate that, in addition to a postsynaptic role, CDK5 negatively regulates dopamine release in the striatum. Inhibitors of CDK5 increase evoked dopamine release in a way that is additive to that of cocaine. This presynaptic action of CDK5 also regulates glutamatergic transmission. Indeed, inhibition of CDK5 increases the activity and phosphorylation of N-methyl-d-aspartate receptors, and these effects are reduced by a dopamine D1 receptor antagonist. Using mice with a point mutation of the CDK5 site of the postsynaptic protein DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, molecular mass of 32 kDa), in the absence or in the presence of a dopamine D1 receptor antagonist, we provide evidence that CDK5 inhibitors potentiate dopaminergic transmission at both presynaptic and postsynaptic locations. These findings, together with the known ability of CDK5 inhibitors to prevent degeneration of dopaminergic neurons, suggest that this class of compounds could potentially be used as a novel treatment for disorders associated with dopamine deficiency, such as Parkinson's disease.
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PMID:Cyclin-dependent kinase 5 regulates dopaminergic and glutamatergic transmission in the striatum. 1476 20

Several lines of evidence have pointed to a role of the dopamine system in the pathophysiology of schizophrenia. A recent postmortem study demonstrated a selective decrease of tyrosine hydroxylase fibers on pyramidal neurons in sector CA2 in the hippocampus of schizophrenics. Although both brain imaging and postmortem studies have examined the distribution of the D1 receptor in the prefrontal and cingulate cortex, no study to date has examined its expression of mRNA using a high-resolution autoradiographic approach. In order to further assess whether the regulation of the dopamine D1 receptor is altered in hippocampal neurons in this disorder, we used in situ hybridization (ISH) to measure the expression of messenger RNA for this receptor in the dentate gyrus and sectors CA1-4. Both the number of cells expressing D1 mRNA and the amount of expression per cell were measured in 15 schizophrenic, 15 bipolar disorder, and 15 normal control subjects. The results show a significant (21%) and selective decrease in D1 mRNA expression in sector CA3 of schizophrenic subjects. First-degree relatives of schizophrenics did not show any differences in either the expression of D1 mRNA per cell or the number of cells expressing this mRNA when compared to a separate group of normal controls matched for age and PMI. Subjects with bipolar disorder also showed a significant (25%) and selective increase of D1 mRNA expression in sector CA2. Other hippocampal sectors did not show significant changes. These findings in schizophrenics and bipolars were also associated with inverse changes in the overall number of neurons expressing D1 mRNA in sectors CA3 and CA2, respectively. This study shows diagnosis-specific changes in D1 mRNA expression in the hippocampus of schizophrenic versus bipolar subjects and suggests that this neuromodulatory system may show distinct changes in the pathophysiology of the two disorders.
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PMID:Differences in the cellular distribution of D1 receptor mRNA in the hippocampus of bipolars and schizophrenics. 1545 63

Dopamine (DA) receptor-mediated signal transduction and gene expression play a central role in many brain disorders from schizophrenia to Parkinson's disease to addiction. While trying to evaluate the role of L-type Ca2+ channels in dopamine D1 receptor-mediated phosphorylation of the transcription factor cyclic AMP response element-binding protein (CREB), we found that activation of dopamine D1 receptors alters the properties of L-type Ca2+ channel inhibitors and turns them into facilitators of Ca2+ influx. In D1 receptor-stimulated neurons, L-type Ca2+ channel blockers promote cytosolic Ca2+ accumulation. This leads to the activation of a molecular signal transduction pathway and CREB phosphorylation. In the absence of dopamine receptor stimulation, L-type Ca2+ channel blockers inhibit CREB phosphorylation. The effect of dopamine on L-type Ca2+ channel blockers is dependent on protein kinase A (PKA), suggesting that protein phosphorylation plays a role in this phenomenon. Because of the adverse effect of activated dopamine receptors on L-type Ca2+ channel blocker action, the role of L-type Ca2+ channels in the dopamine D1 receptor signal transduction pathway cannot be assessed with pharmacological tools. However, with antisense technology, we demonstrate that L-type Ca2+ channels contribute to D1 receptor-mediated CREB phosphorylation. We conclude that the D1 receptor signal transduction pathway depends on L-type Ca2+ channels to mediate CREB phosphorylation.
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PMID:L-type Ca2+ channel blockers promote Ca2+ accumulation when dopamine receptors are activated in striatal neurons. 1553 Jun 53

Genetic studies implicating the region of human chromosome 18p11.2 in susceptibility to bipolar disorder and schizophrenia have observed parent-of-origin effects that may be explained by genomic imprinting. We have identified a transcriptional variant of the GNAL gene in this region, employing an alternative first exon that is 5' to the originally identified start site. This alternative GNAL transcript encodes a longer functional variant of the stimulatory G-protein alpha subunit, Golf. The isoforms of Golf display different expression patterns in the CNS and functionally couple to the dopamine D1 receptor when heterologously expressed in Sf9 cells. In addition, there are CpG islands in the vicinity of both first exons that are differentially methylated, a hallmark of genomic imprinting. These results suggest that GNAL, and possibly other genes in the region, is subject to epigenetic regulation and strengthen the case for a susceptibility gene in this region.
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PMID:Alternative transcripts and evidence of imprinting of GNAL on 18p11.2. 1604 73

Genetic variation in antipsychotic drug targets could underlie variability among patients in the time required for antipsychotic effects to be elicited. In a clinical, pharmacogenetic study we focused on the dopamine receptor interacting protein (DRIP) gene family. DRIPs are pivotally involved in regulating dopamine receptor signal transduction. Consecutively hospitalized, acutely psychotic patients with DSM-IV schizophrenia (n=121) were included in the study if they received treatment with typical antipsychotic medication (TYP, n=72) or TYP plus risperidone (TYP-R, n=49) for at least 2 wk. Clinical state and adverse effects were rated at baseline and after 2 wk. Patients improved significantly on both TYP and TYP-R with no significant difference between them. Early responders were defined as patients whose PANSS change scores were greater than the median. Twenty-two single nucleotide polymorphisms (SNPs) were analysed in five DRIP-encoding genes. Two SNPs in NEF3, which encodes the DRIP, neurofilament-medium (NF-M), were associated with early response (rs1457266, p=0.01; rs1379357, p=0.006). A 5 SNP haplotype spanning NEF3 was over-represented in early responders (p=0.015), in the combined patient group and in the TYP group alone. These findings suggest that variation in NEF3, most likely functional variants that are in linkage disequilibrium with the SNPs that we studied, influences rate of response to TYP. Since NEF3 is primarily associated with dopamine D1 receptor function, the evidence for a complementary role of dopamine D1 receptors in antipsychotic effects is considered. The findings reported here open an interesting research avenue in the pharmacogenetics of antipsychotic effects but require replication in larger samples treated in a controlled context.
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PMID:Association of the dopamine receptor interacting protein gene, NEF3, with early response to antipsychotic medication. 1673 40


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