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)

The effect of tricyclic antidepressants and monoamine oxidase inhibotors on the Ca(2+)-activated K(+)-efflux was studied using 86Rb-efflux assay in primary cultured mouse spinal cord neurons. Depolarization of the cultured cells with 100 mM KCl increased the 86Rb-efflux significantly in Ca(2+)-containing buffer, but not in Ca(2+)-free buffer. All the antidepressants examined, except the monoamine oxidase inhibitors, inhibited the 86Rb-efflux. Desipramine exhibited additivity with tetraethyl ammonium (TEA) and quinine sulfate (QSO4), but not with GABAB receptor agonist baclofen. The inhibitory action of antidepressants was not mediated through the GABAB receptors, since GABAB receptor antagonist, phaclofen, was unable to antagonize this effect. The ability of tricyclic antidepressants to inhibit calcium ionophore (A 23187)-induced 86Rb-efflux suggests that these drugs do not act at the level of voltage-gated Ca(2+)-channels. Furthermore, this effect does not seem to involve the G-proteins, adenylate cyclase, or protein kinase C systems, since pertussis toxin (PTX) and the activators of adenylate cyclase and protein kinase C did not reverse the effect of tricyclics on 86Rb-efflux. Taken together, these results suggest that antidepressants inhibit Ca(2+)-activated K(+)-channels at a stage subsequent to the voltage-gated Ca(2+)-channels.
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PMID:Tricyclic antidepressants inhibit Ca(2+)-activated K(+)-efflux in cultured spinal cord neurons. 186 61

Ethanol prevents the decrease of the number of beta-adrenoceptors in the cerebral cortex induced by chronic treatment of rats with desipramine. The activation of the adenylate cyclase, the second messenger, by beta-adrenergic agonists is reduced somewhat less than after treatment with desipramine alone. The present paper examined the hypothesis that ethanol inhibits the neuronal adaptation to desipramine chronic treatment at the functional level as well. Desipramine reduced exploratory behavior (crossings, rearings) as did ethanol. Combined treatment attenuated the effect of desipramine. Cognitive performance was investigated using an active avoidance paradigm. Desipramine-treated rats did not learn the task in contrast to control animals. Again, combination treatment with ethanol improved the ability of the rats to perform the task. The activity of cerebral beta-adrenergic mechanisms was assessed by injection of salbutamol, a beta-adrenoceptor agonist in rats pretreated with 5-hydroxytryptophan (5-HTP). The augmentation of the 5-HTP-induced wet dog shake behavior by salbutamol was observed in all animals independent of the chronic treatment. However, rats treated with desipramine were less active than those treated with tap water or ethanol. The effect of desipramine in the presence of a high concentration of salbutamol was attenuated by ethanol. The observed increase of the number of wet dog shakes correlates with the function of these receptors. In two paradigms, spontaneous motility and apomorphine-induced hypothermia, ethanol did not affect the action of desipramine. It is noteworthy that desipramine acted in both situations within a short time period (minutes to hours). The findings strongly suggest that ethanol can prevent adaptive changes in the brain induced by chronic treatment with the antidepressant desipramine. This is of special interest since the adaptation of beta-adrenoceptors is thought to be critical for the antidepressant efficacy of various therapeutic interventions applied in psychiatric practice.
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PMID:Effects of desipramine on rat behavior are prevented by concomitant treatment with ethanol. 254 96

Nonlinear regression analysis of agonist competition binding curves reveals that the [3H]-dihydroalprenolol-labeled receptor population with low affinity for isoproterenol is increased by p-chlorophenylalanine (PCPA) and this increase is abolished by 5-hydroxytryptophan (5-HTP) in vivo. Desipramine (DMI) decreased the beta adrenoceptor population with high agonist affinity to the same degree in PCPA-treated animals as in control animals, thus explaining the reported discrepancy between beta adrenoceptor number and responsiveness of the beta adrenoceptor-coupled adenylate cyclase system. Mianserin also selectively reduced the beta adrenoceptor population with high agonist affinity in membrane preparations of normal animals, whereas fluoxetine selectively abolished the upregulation of the low affinity sites in reserpinized animals and had no effect on either receptor population from brain of normal animals. The results emphasize the importance of nonlinear regression analysis of agonist competition binding for the interpretation of drug action and encourage the pursuit of the molecular neurobiology of the serotonin (5-HT)/norepinephrine (NE) link in brain.
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PMID:Dual aminergic regulation of central beta adrenoceptors. Effect of "atypical" antidepressants and 5-hydroxytryptophan. 256 16

Desipramine (DMI), decreased the maximum number of beta-adrenergic receptors by approximately 10, 20, 30, and 20% in groups of rats treated i.p. with 5 mg/kg for 14 days or 10 mg/kg for 7, 14, or 21 days, respectively. In studies of agonist competition for beta-adrenergic receptors labelled with [125I]-CYP, chronic DMI administration caused a selective decrease in those receptors normally found in the high affinity conformation in proportion to the dose of DMI administered. No change was observed in either the number of receptors in the agonist low affinity conformation or in the affinity of any drug for the high or low affinity conformations of the receptors. Therefore, chronic DMI caused a selective decrease in the beta-adrenergic receptors linked to adenylate cyclase but did not appear to change other properties of the receptors that would be manifested as a change in their ability to interact with adrenergic agonists. Neither iprindole (15 mg/kg i.p., 14 days) nor mianserin (10 mg/kg i.p., 14 days) decreased the number of receptors, the proportions of agonist high or low affinity receptors, or the affinity of competitor drugs for these receptors, suggesting a different mechanism for the reported loss of adenylate cyclase activity following these drugs than the down-regulation of receptors observed with chronic DMI treatment.
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PMID:Agonist interactions with beta-adrenergic receptors following chronic administration of desipramine or the atypical antidepressants, iprindole and mianserin. 286 24

Because both long-term adrenoceptor agonist administration and antidepressant treatment in animals down-regulate CNS beta-adrenoceptors and attenuate brain adenylate cyclase activity, beta-adrenoceptor agonists may also possess antidepressant properties. We compared the effects of the centrally acting beta-adrenoceptor agonist clenbuterol (5, 10 and 35 mg/kg per day), and the combination of propranolol (5 mg/kg per day) and clenbuterol (10 mg/kg per day), with desipramine (15 mg/kg per day) on forced swim test performance and on cortical beta-adrenoceptors in rats following 7 days of drug administration. Desipramine (15 mg/kg per day), and clenbuterol (10 and 35 mg/kg per day, but not 5 mg/kg per day) both significantly reduced immobility in the forced swim test. Frontal cortex beta-adrenoceptors were significantly down-regulated after desipramine and all 3 doses of clenbuterol. The co-administration of propranolol (5 mg/kg per day) blocked both the reduction in immobility and down-regulation of cortical beta-receptors induced by clenbuterol (10 mg/kg per day). Propranolol (5 mg/kg per day) alone up-regulated frontal cortex beta-adrenoceptors, but had no significant effect on swimming performance. These data suggest that the physiological consequences of beta-adrenoceptor down-regulation are important in the mechanism of action of antidepressants. The results also suggest that clenbuterol may be useful in the treatment of depression.
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PMID:A comparison of the neurochemical and behavioral effects of clenbuterol and desipramine. 303 50

In rat brain, the number of beta-adrenoceptors and activity of noradrenaline-dependent adenylate cyclase were examined after treatment with desipramine (7.5 mg kg-1 day-1) for three days alone or in combination with the alpha 2-adrenoceptor antagonist, yohimbine (2 mg kg-1 12 hr-1), or with phenoxybenzamine (7.5 mg kg-1 day-1), which is a more potent inhibitor of alpha 1 than alpha 2-adrenoceptors. The only treatment which significantly decreased the specific binding of the beta-adrenoceptor antagonist, [3H]dihydroalprenolol was the combination of desipramine with yohimbine. Desipramine alone and desipramine with yohimbine also significantly reduced the formation of cyclic AMP in response to incubation with noradrenaline, the response to the drug combination being accounted for by addition of the individual effects of the drugs. The results showed that decreases in the activity of noradrenaline-dependent adenylate cyclase could become apparent before decreases in beta-adrenoceptor numbers. Whether these rapid changes in noradrenaline-dependent adenylate cyclase or in numbers of beta-adrenoceptors which are produced by combination of desipramine with an alpha 2-adrenoceptor antagonist, are of therapeutic value remains to be elucidated.
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PMID:Effect of desipramine, phenoxybenzamine and yohimbine on beta-adrenoceptors and cyclic AMP production in the rat brain. 609 50

The influence of chronic administration of desipramine (16 mg/kg per day for 8 days) or citalopram (1 mg/kg per day for 8 days) on the serotonergic and noradrenergic stimulations of phosphoinositide hydrolysis and cyclic AMP formation was investigated in rat cerebral cortical slices. This was done by means of a prelabelling method allowing the simultaneous measurement of the accumulations of (3H) inositol phosphates ((3H)IP) and of (14C) cyclic AMP. Our results show that neither of the two drugs altered the inhibition of adenylate cyclase activity induced by serotonin1 (5-HT1) receptor agonists nor did they alter 5-HT1A and 5-HT1B receptor densities. Similarly they did not modify the stimulation of the inositol phosphate metabolism induced by 5-HT or norepinephrine (NE). Desipramine treatment decreased both beta-adrenoceptor-elicited cyclic AMP accumulation (-37%) and beta-adrenoceptor density (-29%), whereas citalopram was without effect. These results reinforce the idea that the ability of antidepressants to decrease the activity of the beta-adrenoceptor-adenylate cyclase complex is not common to all antidepressants, and provide no evidence for the involvement of 5-HT1A and/or 5-HT1B in the mechanism of action of these drugs.
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PMID:Cyclic AMP and inositol phosphate accumulations in rat brain cortical slices following chronic citalopram or desipramine administration. 795 21

The effect of subchronic infusion of desipramine, a norepinephrine uptake inhibitor, and clenbuterol, a beta-adrenergic agonist, on the central beta receptor of the rat was determined using in vitro [(3)H]dihydroalprenolol binding. Desipramine produced significant decreases of the receptor in neocortex and hippocampal formation, and clenbuterol effected such decreases in corpus striatum and cerebellum. Both drugs caused a marked decrease in the activity of isoproterenol-sensitive adenylate cyclase in neocortex. The alpha(2) receptor of neocortex and cerebellum was unchanged by either drug as assessed by in vitro[ (3)H ]p- aminoclonidine binding. The results are discussed in terms of the different mechanisms of action of desipramine and clenbuterol, and the efficacy of these two drugs in the treatment of depression.
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PMID:Differential decrease of the central beta-adrenergic receptor in the rat after subchronic infusion of desipramine and clenbuterol. 2048 57

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