Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study, we have applied the brain microdialysis technique to investigate the effect of the stimulation of adenylate cyclase on the extracellular levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in the striatum of freely moving rats. Infusion of 8-bromo-adenosine 3',5'-cyclic monophosphate (8-Br-cAMP), 3-isobutyl-1-methylxanthine, or forskolin produced a significant increase in the release of DA. The effect of 8-Br-cAMP was tetrodotoxin, Ca2+, and dose dependent and was saturable. 8-Br-cAMP also caused an increase in the output of DOPAC and HVA. No effects were seen on the output of 5-HIAA, except at the highest 8-Br-cAMP concentration studied. Infusion of 8-Br-cAMP (25 microM, 1.0 mM, and 3.3 mM) together with infusion of (-)-sulpiride (1 microM) or systemic administration of (+/-)-sulpiride (55 mumol/kg i.p.) produced an additive effect on the release of DA. Infusion or peripheral administration of (-)-N-0437 (1 microM or 1 mumol/kg) both decreased the 8-Br-cAMP-induced increase in the release of DA. These results demonstrate that cyclic AMP may stimulate the release of DA, but it is unlikely that this second messenger is linked to presynaptic D2 receptors controlling the release of DA.
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PMID:Role of adenylate cyclase in the modulation of the release of dopamine: a microdialysis study in the striatum of the rat. 169 44

Postmortem frontal, temporal, and occipital regions of the brain from adult patients who had a diagnosis of Tourette's syndrome were analyzed for neurochemical alterations. In 3 of 4 TS-affected brains, the concentration of adenosine 3',5'-monophosphate (cyclic AMP) was reduced in all brain regions evaluated. This diminution in cyclic AMP was not associated with a significant change in the activity of the synthesizing enzyme, adenylate cyclase. No significant differences were identified for the neurotransmitter-synthesizing enzymes choline acetyltransferase and glutamate decarboxylase. Concentrations of dopamine, norepinephrine, and the serotonin metabolite 5-hydroxyindoleacetic acid were not altered. Postsynaptic receptor-binding activity for muscarinic cholinergic ([3H]quinuclidinyl benzilate) and beta receptors ([125I]iodocyanopindolol) showed no generalized impairment. It is suggested that symptoms of Tourette's syndrome might be related to an abnormality within a second messenger system.
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PMID:Tourette's syndrome: a neurochemical analysis of postmortem cortical brain tissue. 197 20

Triadimefon, a triazole fungicide, has been observed to increase locomotion and induce stereotyped behavior in rodents. The present experiments designed to characterize the stereotyped behavior induced by triadimefon used a computer-supported observational method, and tested the hypothesis that these observed effects involved central dopaminergic systems. Adult male and female Sprague-Dawley rats were injected with triadimefon (0, 50, 100, and 200 mg/kg) in corn oil (2 ml/kg ip) 4 hr prior to behavioral assessment. The two lowest doses of triadimefon increased the frequency of locomotion and rearing, while the highest dose induced highly stereotyped behaviors, including backward locomotion, circling, and head weaving. Immediately after behavioral testing, the rats were sacrificed, and the striata and olfactory tubercles, terminal fields of the nigrostriatal and mesolimbic dopamine systems, respectively, were removed. Steady-state concentrations of the monoamines dopamine and serotonin and their metabolites were determined by HPLC-EC. In independent experiments, the direct effects of triadimefon on dopamine (D1 and D2) receptor binding and dopamine-sensitive adenylate cyclase activity were assessed in vitro using rat striata. Dopamine concentrations were increased in olfactory tubercles, but decreased in striatum. Concentrations of 5-hydroxyindoleacetic acid (the major metabolite of serotonin) were increased only in striatum, and only in animals treated with 200 mg/kg triadimefon. In vitro, triadimefon neither competed with D1 or D2 dopaminergic radioligands nor affected dopamine-stimulated adenylate cyclase activity. Together these behavioral and biochemical data lend support to the hypothesis that triadimefon may have actions similar to those produced by indirect-acting dopamine agonists.
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PMID:Triadimefon, a triazole fungicide, induces stereotyped behavior and alters monoamine metabolism in rats. 231 16

1. Isolated segments of the guinea-pig ileum were vascularly perfused and the release of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) into the portal venous effluent was determined by h.p.l.c. with electrochemical detection. Test substances were applied via the arterial perfusion medium. 2. Isoprenaline (0.1 microM) increased the outflow of 5-HT and 5-HIAA maximally by about 75% and this was antagonized by propranolol (0.1 microM). Forskolin (1-10 microM) increased the outflow of 5-HT by approximately 105% and that of 5-HIAA by approximately 55%. The phosphodiesterase inhibitor AH 21-132 (0.1-1 microM) increased the outflow of 5-HT and 5-HIAA by about 70%. Isoprenaline (1 nM) and AH 21-132 (10 nM), which alone had no effect, increased the outflow of 5-HT and 5-HIAA by 75%, when applied in combination. 3. Clonidine (1 microM) reduced the outflow of 5-HT by 45%, an effect blocked by tolazoline (1 microM), but not by prazosin (0.1 microM). 4. The effects of isoprenaline, forskolin and clonidine were also observed in the presence of tetrodotoxin (1 microM) demonstrating a direct modulation of 5-HT release from the enterochromaffin cells. 5. In conclusion, the release of 5-HT from enterochromaffin cells is facilitated by activation of beta-adrenoceptors and inhibited via alpha 2-adrenoceptors. Enhancing intracellular cyclic AMP, by direct stimulation of adenylate cyclase with forskolin or by inhibition of phosphodiesterase, also facilitates the release of 5-HT. The beta-adrenoceptor-mediated effect on 5-HT release appears to involve an increase in cyclic AMP, as the effect of isoprenaline was potentiated after inhibition of phosphodiesterase.
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PMID:Adrenergic modulation of the release of 5-hydroxytryptamine from the vascularly perfused ileum of the guinea-pig. 246 31

Rats treated with triethyllead (TEL) exhibit a behavioral supersensitivity to challenge with dopamine agonists at 7 days following administration of TEL. In the present series of experiments, some neurochemical mechanisms which may affect this behavioral supersensitivity were detected. Administration of a single dose of TEL chloride (7.88 mg/kg, SC) to male Fischer-344 rats decreased the concentrations of dopamine in hippocampus, and of serotonin in olfactory tubercle, at Day 7 posttreatment. The ratio of 5-hydroxyindoleacetic acid/5-hydroxytryptamine (one estimate of serotonin turnover) was increased in nucleus accumbens (p less than 0.05), with a similar trend in olfactory tubercle and striatum (p less than 0.10). No changes were detected in binding of [3H]spiperone to D2 dopamine receptors in striatum or olfactory tubercle. However, although basal adenylate cyclase activity was unaltered in TEL-treated rats, the Vmax for dopamine-stimulated adenylate cyclase activity was significantly elevated in olfactory tubercle. Conversely, TEL at micromolar concentrations markedly attenuated both basal and dopamine-stimulated adenylate cyclase activity in vitro in striatal homogenates. These data suggest the hypothesis that administration of TEL to rats results in an up-regulation of D1 dopamine receptors in olfactory tubercle, and that the behavioral supersensitivity of TEL-treated animals to dopamine agonists may, in part, be a result of this receptor supersensitivity.
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PMID:Responses of dopaminergic and serotonergic systems to triethyllead intoxication. 246 82

The enantiomers of LY141865, trans(+/-)-4,4a,5,6,7,8a,9-octahydro-5-propyl-2H-pyrazolo[3,4-g]qu inoline, were compared as dopamine D2 agonists by determining their abilities to elevate acetylcholine concentrations in rat corpus striatum. The levorotatory isomer, LY156258, increased striatal acetylcholine concentration at doses of 0.1-1 mg/kg i.p., whereas the dextrorotatory isomer had no effect even at doses as high as 30 mg/kg. The levorotatory isomer also decreased striatal concentrations of the dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, but did not significantly alter dopamine or 5-hydroxyindoleacetic acid concentration. The dextrorotatory isomer had no effect on any of these substances alone and did not alter the effects of the levorotatory isomer. The elevation of striatal acetylcholine levels by LY156258 was mimicked by pergolide, a dopamine agonist, and was totally prevented by pretreatment with haloperidol, a dopamine antagonist. The elevation of striatal acetylcholine concentration by LY157258 was maximal at 0.5 hour and declined thereafter, following a time course similar to that of pergolide. Neither LY141865 nor LY156258 shared with peroglide and dopamine the ability to activate striatal adenylate cyclase in vitro, an effect mediated by D1 receptors. LY141865 and LY156258 (but not the dextrorotatory isomer) inhibited the binding of tritiated apomorphine and spiperone to striatal membrane receptors, but were not as potent as pergolide, they also had less effect, or no effect, on the binding of other tritiated ligands (dopamine, WB4101, clonidine, dihydroalprenolol, pyrilamine or quinuclidinyl benzilate) to their membrane receptors. These results indicate that LY156258 stereospecifically activates dopamine D2 receptors and the studies are the first evidence of sterospecificity of dopamine receptors mediating an increase in striatal acetylcholine concentration.
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PMID:Effect of a stereospecific D2-dopamine agonist on acetylcholine concentration in corpus striatum of rat brain. 665 67

The novel anxiolytic drug buspirone raised striatal levels of the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) 1 hr after oral administration. This effect was dose-dependent with a peak at 60 min. No changes were observed in the levels of 3-methoxytyramine (3MT), the extraneuronal metabolite of dopamine. Noradrenaline, serotonin and its metabolite 5-hydroxyindoleacetic acid (5HIAA) were not affected. Buspirone displaced [3H]spiroperidol from striatal binding sites, with an IC50 (1.8 x 10(-7) M), comparable to that of clozapine (IC50 = 1.4 x 10(-7) M) but considerably lower than that of haloperidol (4.7 x 10(-9) M). Buspirone was only a weak inhibitor of dopamine-stimulated adenyl cyclase. Buspirone was not active on the binding of trifluoperazine to calmodulin and did not modify calmodulin-induced activation of phosphodiesterase (PDE). Repeated administration of buspirone did not increase the number of DA receptors. These data show that, although buspirone has antidopaminergic activity, it can hardly be classified as a classic neuroleptic agent.
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PMID:Dopaminergic effects of buspirone, a novel anxiolytic agent. 683 54

Male Sprague-Dawley rats received injections of cocaine (20 mg/kg/dose, IP) every 12 h for 14 days and were sacrificed on the 15th day. The chronic cocaine treatment caused an increase in the levels of serotonin [5-hydroxytryptamine (5-HT)] and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the hippocampus. 5-HIAA levels in the frontal cortex were also increased, but 5-HT levels were unaltered by the chronic cocaine treatment. Similarly, striatal levels of 5-HT and 5-HIAA were unchanged by repeated administration of cocaine. Chronic cocaine administration did not alter the density of [3H]8-OH(DPAT), [3H]mesulergine, or [3H]ketanserin binding in the hippocampus, choroid plexus, and frontal cortex, respectively. Furthermore, repeated injection of cocaine did not alter serotonergic-mediated inhibition of adenylate cyclase activity. Thus, repeated administration of cocaine causes region-specific alterations in 5-HT levels but does not change the properties of the 5-HT1A, 5-HT1C, or 5-HT2 receptors.
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PMID:Effects of chronic cocaine administration on the serotonergic system in the rat brain. 750 54

The effects of chronic l-dopa treatment on rat striatal adenylate cyclase and dopaminereceptor binding activities were studied using an oral dose of Sinemet (250 mg l-dopa/25 mg carbidopa). The calculated average daily oral intake of l-dopa was 150 mg/rat. A 4-fold increase in the ec(50) for dopamine on adenylate cyclase activity in homogenstes of the caudate nucleus was observed in the oral drug-treated group with no change in the maximal level of enzyme activity. Binding studies using [(3)H]spiroperidol, a dopamine-receptor antagonist, revealed a decrease in the dissociation constant from 0.26 nM in the control group to 0.069 nM in the oral drug-treated group. In addition, the B(max) for [(3)H]spiroperidol specific binding in the animals receiving oral l-dopa increased by 300 fmoles/mg over that observed in the control group. Dopamine-sensitive adenylate cyclase and binding activities in animals receiving a lower dose of l-dopa alone, given intraperitoneally (50 mg/kg) twice daily, were determined to be similar to control values. Analysis of the cerebrospinal fluid biogenic amine metabolites, homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), by gas chromatography/mass spectrometry revealed a 13-fold increase in HVA following oral l-dopa and a 44 per cent increase in MHPG levels. These data, which demonstrate an increased number of dopamine binding sites following long-term l-dopa therapy, are consistent with demonstrations of behavioral hypersensitivity in animals undergoing this particular drug treatment. The results also suggest that the subsensitivity of the adenylate cyclase system may reflect a side effect of this drug, due to prolonged administration.
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PMID:Biochemical alterations of dopamine receptor responses following chronic L-dopa therapy. 2022 43

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