Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The predominant consequences of mu-opioid-receptor activation are depression of both neuronal activity and transmitter release. Mu-Opioid agonists have previously been observed to increase a potassium conductance and to inhibit adenylate cyclase. We now report that activation of mu-opioid receptors directly decreases the N-type calcium-channel current in a differentiated, human neuroblastoma cell line (SH-SY5Y). The coupling between the mu-opioid receptor and the calcium channel involves a pertussis toxin-sensitive G protein and is independent of changes in adenylate cyclase activity. The inhibition of the calcium-channel current is voltage dependent because it is largely overcome by strong membrane depolarization. It is not associated with changes in the kinetics of current inactivation. Therefore, the mu-receptor belongs to the superfamily of G-protein-coupled, inhibitory neurotransmitter receptors which modulate the activity of calcium and potassium channels and adenylate cyclase.
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PMID:Mu-opioid-receptor-mediated inhibition of the N-type calcium-channel current. 167 47

Quantitative autoradiography was used to examine the effect of lesioning a well-defined glutamatergic system (retinofugal fibres) on [3H]forskolin binding to Gs-adenylate cyclase and [3H]PDBu (phorbol-12,13-dibutyrate) binding to protein kinase C (PKC) in the rat visual system at 1, 5, 10 and 20 days after unilateral orbital enucleation. Local cerebral glucose utilisation was determined in the same animals using quantitative [14C]2-deoxyglucose autoradiography. At 5 days post-lesion, [3H]forskolin binding sites were significantly reduced in the visually-deprived superior colliculus (-14 +/- 1%) and dorsal lateral geniculate body (-8 +/- 2%), and these reductions persisted until 20 days post-lesion. There were no significant alterations in the amount of [3H]PDBu binding in any region in the visually-deprived hemisphere following enucleation. Function-related glucose use was significantly reduced throughout the visual pathway after enucleation. In this study, there was no conclusive evidence of plastic modifications of second messenger systems in the rat visual system despite a general depression of visual function following lesion of retinofugal fibres.
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PMID:Alterations of functional glucose use and ligand binding to second messenger systems following unilateral orbital enucleation. 188 25

Fetal lung beta-receptors become effectively coupled to lung fluid reabsorption and enzymes involved in surfactant synthesis on the day before birth, a period when circulating catecholamine levels are high. Accordingly, we examined the effects of repeated maternal terbutaline exposure on beta-receptor binding capabilities and beta-receptor-mediated processes in the fetal rat lung. Administration of terbutaline to pregnant rats on gestational day 17-20 produced significant reductions in beta-receptor binding to membrane preparations. Similarly, beta-receptor-mediated stimulation of adenylate cyclase activity and ornithine decarboxylase activity showed marked desensitization in the terbutaline-exposed fetuses. However, the linkage of beta-receptors to lung fluid reabsorption and phosphatidic acid phosphatase, an enzyme involved in surfactant synthesis, did not desensitize with chronic terbutaline pretreatment; both of these processes displayed the normal onset of responsiveness on gestational day 21 in the treated animals, as well as a normal magnitude of response. Hence, beta-receptor-mediated events in the developing lung may be differentially regulated during exposure to agonists, allowing the selective expression or depression of function when circulating catecholamine levels are high.
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PMID:Regulation of beta-adrenergic receptor-mediated processes in fetal rat lung: selective desensitization caused by chronic terbutaline exposure. 196 39

The functional status of platelet alpha 2-adrenoceptors in patients with major depression has been assessed by simultaneously measuring both a biochemical mechanism of transduction of receptor activation (inhibition of adenylate cyclase activity) and a physiologic response of the receptor (induction of aggregation). The inhibitory effects induced by epinephrine and UK 14304 on adenylate cyclase activity were unchanged, while the aggregation responses induced by the same alpha 2-adrenoceptor agonists were potentiated, which indicated receptor supersensitivity. In depressed (n = 30) and euthymic (n = 11) patients as well as in control subjects (n = 66), there was a clear dissociation between inhibition of adenylate cyclase activity and induction of aggregation, indicating that the two responses represent different phenomena of alpha 2-adrenoceptor activation. alpha 2-Adrenoceptor-mediated platelet aggregation could represent a better marker than inhibition of adenylate cyclase to assess functional changes of the receptor in depression. Both of these functional responses are desensitized after long-term antidepressant treatment.
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PMID:Alpha 2-adrenoceptor-mediated inhibition of platelet adenylate cyclase and induction of aggregation in major depression. Effect of long-term cyclic antidepressant drug treatment. 196 26

Preclinical neurochemical studies indicate that buspirone and gepirone bind selectively to presynaptic (dorsal raphe) and postsynaptic (hippocampus, cortex) 5-hydroxytryptamine1A (5-HT1A) receptor binding sites. Furthermore, in functional neurochemical and electrophysiologic receptor studies, azapirones in general display partial agonist activity at postsynaptic 5-HT1A receptors linked negatively to adenyl cyclase and appear to demonstrate a similar profile on hippocampal CA1 pyramidal neurons sensitive to the effects of 5-HT. Through their action at presynaptic 5-HT1A receptors, these agents have been shown to dose-dependently inhibit cortical and hippocampal 5-HT synthesis while inhibiting the firing of 5-HT--containing dorsal raphe neurons, both in vitro and in vivo. These results suggest that the efficacy seen in clinical trials of anxiety and depression may be related to buspirone's and gepirone's complex interaction with presynaptic and postsynaptic 5-HT1A receptors, which initiate long-term changes in central 5-HT neurotransmission.
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PMID:Neurochemistry and neurophysiology of buspirone and gepirone: interactions at presynaptic and postsynaptic 5-HT1A receptors. 197 41

The selective 5-HT1A receptor ligand ipsapirone (IPS) induces corticotropin (ACTH) and cortisol secretion in humans. To explore 5-HT1A receptor-mediated hypothalamic-pituitary-adrenal (HPA) system activation in depression, 24 subjects (12 patients with unipolar depression and 12 individually matched controls) were given 0.3 mg/kg IPS or placebo in random order. Compared with controls, the depressed patients exhibited significantly decreased ACTH and cortisol responses to IPS in association with increased basal cortisol secretion. The impaired HPA response following 5-HT1A receptor challenge in unipolar depression could have resulted from glucocorticoid-dependent subsensitivity of the (post-synaptic) 5-HT1A receptor itself and/or from a defective postreceptor signaling pathway [inhibitory guanine nucleotide-binding protein (Gi)-adenylate cyclase complex function], thus supporting the hypothesis that a disintegrated 5-HT and HPA system interaction may be present in depression. Future studies of the HPA response to direct-acting 5-HT1A ligands, such as IPS, should facilitate the assessment of 5-HT/HPA system integrity in various affective disorders and its involvement in psychotropic drug effects.
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PMID:5-HT1A receptor responsivity in unipolar depression. Evaluation of ipsapirone-induced ACTH and cortisol secretion in patients and controls. 197 79

This study tests the hypothesis that atrial natriuretic factor (ANF) and C-ANF(4-23)-NH2 (C-ANF) augment cGMP generation and inhibit both cAMP generation and depolarization-induced catecholamine release in nerve growth factor treated pheochromocytoma cells by a pertussis toxin (PTX)-sensitive mechanism. Synthetic rat ANF(99-126) and the clearance receptor antagonist C-ANF (10(-12)-10(-9) M) inhibited basal and 5 microM vasoactive intestinal peptide (VIP)-induced cAMP generation in a concentration-dependent manner. These actions of ANF and C-ANF were blocked by 12-18 h pretreatment with PTX (100 ng/ml), suggesting ANF receptor coupling to adenylate cyclase via an inhibitory guanine nucleotide-binding protein. Both ANF (10(-11)-10(-9) M) and C-ANF (10(-11)-10(-8) M) also inhibited K(+)-induced catecholamine release in a concentration-dependent manner. ANF (10(-11)-10(-8) M) increased cGMP generation in a concentration-dependent manner but C-ANF did not. The accumulation of cGMP in response to ANF was not altered by treatment with PTX. Therefore, PTX dissociated the increased concentrations of cGMP from the ANF-mediated depression of evoked catecholamine release. C-ANF also dissociated elevations in cGMP concentrations from an ANF-mediated attenuation of evoked catecholamine release. The results of this study indicate that ANF inhibits adrenergic neurotransmission independent of guanylate cyclase.
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PMID:Neuromodulatory effects of atrial natriuretic factor are independent of guanylate cyclase in adrenergic neuronal pheochromocytoma cells. 197 29

This study was aimed at investigating the effects of treatment with a lithium-imipramine combination on the activity of adenylate cyclase in membranes from the cerebral cortex of the rat. Treatment with (1) lithium for 2 weeks, yielding a level of lithium in serum of 0.54 +/- 0.12 mmol/l, (2) imipramine for 4 weeks (10 mg/kg i.p. twice per day) and (3) a combination of the two drugs reduced isoprenaline-induced stimulation of adenylate cyclase by GTP, with a greater decrement with the combined treatment. None of the treatments exerted any effect on the activity of the enzyme stimulated by GTP alone. Lithium ex vivo inhibited the calcium (Ca2+)- and Gpp(NH)p-stimulated activity of adenylate cyclase, but imipramine ex vivo did not affect the activity of adenylate cyclase, stimulated by these activators. The lithium-imipramine treatment reduced Ca2(+)- and Gpp(NH)p-stimulated activity of adenylate cyclase, but this was not different from that observed in the lithium-treated group. In conclusion, the beta-adrenoceptor-stimulated adenylate cyclase was affected markedly by administration of lithium and imipramine together. In contrast to lithium ex vivo, imipramine ex vivo did not impair the activity of either the guanine nucleotide regulatory protein or the catalytic subunit, since no change in activity was observed in the presence of beta,gamma-imidoguanosine-5' triphosphate (Gpp(NH)p) or Ca2+. Furthermore, lithium ex vivo exerted its post-receptor effects on the adenylate cyclase, independent of imipramine. The decrement in activity of beta-adrenergic adenylate cyclase, induced by administration of the two drugs together may partly be involved in the therapeutic action of the augmentation of antidepressants by lithium in refractory depression.
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PMID:Effects of treatment with a lithium-imipramine combination on components of adenylate cyclase in the cerebral cortex of the rat. 210 75

The effects of chronic administration of desimipramine (DMI, 10 mg/kg i.p. daily for 4 or 5 weeks), short-term administration of lithium (Li, 0.2% in food for 10 days) and a combination of these treatments on serotonergic receptors and second messengers were studied in the rat brain. DMI alone had no effect on [3H]5-HT binding but reduced [3H]ketanserin binding in cortical membranes, 5-HT-stimulated inositol phosphate (IP) formation in cortical slices and the degree of inhibition of forskolin-stimulated adenylate cyclase by 5-HT in hippocampal membranes. Li alone reduced [3H]5-HT binding and the degree of inhibition of forskolin-stimulated adenylate cyclase by 5-HT in hippocampal membranes, and also reduced [3H]ketanserin binding and 5-HT-stimulated IP formation in the cortex. The two treatments combined in general produced effects similar to those of Li alone, but the decrease in [3H]ketanserin binding in cortical membranes was significantly greater than that given by Li alone, whereas the reduction in the degree of inhibition of forskolin-stimulated adenylate cyclase by 5-HT in hippocampal membranes was significantly greater than that produced by DMI alone. It is concluded that the therapeutic action of Li when added to tricyclic antidepressants in the treatment of refractory depression may partly have its basis in potentiation of effects on the serotonergic system in the brain.
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PMID:Single and combined effects of desimipramine and lithium on serotonergic receptor number and second messenger function in rat brain. 213 25

Li inhibition of noradrenergic adenylate cyclase may be due to inhibition by Li of agonist-induced increases in GTP binding to G-protein. Such inhibition by Li of G-protein function could have effects on phosphatidyl-inositol-mediated second messenger systems as well as on cyclic AMP-mediated systems. However, Sherman, Berridge and others have proposed that Li affects phosphatidylinositol metabolism by inhibiting inositol-1-phosphatase. We recently have been able to measure inositol-1-phosphatase in human red blood cells. Preliminary data on patients treated with Li compared with controls suggests that the enzyme is indeed inhibited in vivo in patients undergoing Li treatment. However, a series of experiments in rats on addition of inositol to Li treatment did not find that inositol could reverse Li effects. Chronic oral high dose inositol does not reverse Li-induced polyuria (measured by polydipsia), Li-induced weight loss or Li-induced depression of exploratory behavior. These results suggest that Li inhibition of inositol-1-phosphatase indeed occurs in vivo. However, the physiological significance of inositol-1-phosphatase inhibition is not yet established.
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PMID:Role of inositol-1-phosphatase inhibition in the mechanism of action of lithium. 215 51


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