UMLS:C0011570 - FACTA Search

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 inhibitory effect of troxypyrrolidinium (trox) (10(-6) to 2 x 10(-3) M) on responses to carbachol (CCh) and acetylcholine (ACh) was investigated in the electrically stimulated left atrium and longitudinal ileal muscle of the guinea pig. In both tissues, trox exhibited antimuscarinic activity causing parallel shifts of the concentration--response curves to both agonists with no depression of maximum responses. Responses to CCh were inhibited by trox (5 x 10(-4) M) to a greater extent than responses to ACh and this difference was maintained following inhibition of cholinesterases with dyflos. In the guinea-pig atrium using CCh as agonist dose ratios produced by the higher concentrations of trox (greater than 5 x 10(-5) M) were less than expected resulting in a non-linear Arunlakshana--Schild (A-S) plot and this effect of trox was maintained in the presence of mecamylamine (2 x 10(-5) M). In longitudinal ileal muscle flattening of the A-S plot with high concentrations of trox did not occur. Although hemicholinium-3 (HC-3) produces a non-linear A-S plot for antimuscarinic activity in atria the A-S plot obtained with the longitudinal ileal strip using HC-3 (2 x 10(-5) to 2 x 10(-3) M) did not exhibit flattening at high concentrations. The dose ratios obtained with HC-3 (5 x 10(-4) M) using CCh as agonist were significantly greater than those obtained with ACh. It is suggested that trox, like HC-3, acts as a metaffinoid antagonist at the muscarinic receptor.
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PMID:Antagonism of cholinomimetics by troxypyrrolidinium in guinea-pig atria and longitudinal ileal muscle: comparison with hemicholinium-3. 72 41

Atropine (At) and scopolamine (Sc) in low doses intensify basic activity, increase amphetamine stereotypy, and suppress catalepsy induced by injection of haloperidol. High doses lower body temperature, antagonize amphetamine stereotypy, and intensify the hypnotic action of chloral hydrate. Doses of about 1/2 LD50 induce narcotic sleep. Both At and Sc in a wide range of dosage protect against the tonic phase of convulsions produced by electroshock. Sc depresses content of acetylcholine in the brain proportionally to its dosage; At had a similar effect only at the lower of the two doses that were used. Both compounds had no effect on levels of noradrenaline and dopamine in the brain. The results indicate that low doses of blockers of the cholinergic muscarinic receptor, injected intraventricularly, produce strong central stimulation, whereas high doses produce depression of the central nervous system.
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PMID:Central action of drugs acting on the cholinergic muscarinic receptor. III. Influence of atropine and scopolamine injected intraventricularly on behavior and levels of biogenic amines in the rat brain. 117 21

Depression of the electrically-evoked surface-negative field potential (N-Wave) by bath-superfusion of carbachol was measured in guinea-pig olfactory cortex slices maintained in vitro. The possibility that this response, previously proposed to be mediated via a presynaptic M1: muscarinic receptor, might in fact be due to M4 receptor activation, was investigated by testing the effectiveness of himbacine (a proposed M4-selective antagonist) on our cortical preparation. Himbacine (100 nM-1 microM) had no effect on the N-wave potential alone, but it induced a clear competitive-type inhibition of carbachol effects. Schild plot analysis (regression slope constrained to unity) of pooled data yielded a pA2 value of 7.2 for this antagonist (n = 7 slices). This value accords more with that expected for the interaction of himbacine with M1 receptors (approximately 7.2) than with functionally expressed M4 receptors (approximately 8.5-8.5). We therefore conclude that M4-type muscarinic receptors are unlikely to be involved in mediating this presynaptic carbachol response.
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PMID:Carbachol-evoked suppression of excitatory neurotransmission in guinea-pig olfactory cortex slices is unlikely to involve an M4-muscarinic receptor subtype. 131 58

The effect of the muscarinic receptor antagonist AF-DX 116 on the inhibitory action of muscarinic agonists and on responses mediated by nicotinic or muscarinic ganglionic transmission was studied in the superior cervical ganglion of the anesthetized cat. The postganglionic compound action potential evoked by cervical sympathetic trunk stimulation was depressed by methacholine or acetylcholine (ACh) injected into the ganglionic arterial supply. The depression was blocked by AF-DX 116. The compound action potentials evoked by preganglionic stimulus trains were also depressed when the intratrain frequency was 2 Hz or greater. This intratrain depression was, however, insensitive to AF-DX 116. The anticholinesterase drug physostigmine markedly enhanced the intratrain depression of the compound action potential. This effect was reversed by AF-DX 116. During nicotinic receptor block with hexamethonium, preganglionic stimulus trains with intratrain frequencies of 5 Hz or greater produced nicitating membrane contractions that could be blocked by the M1 muscarinic receptor antagonist pirenzepine. The amplitude of the contractions increased with frequency and reached a maximum at 20-40 Hz. AF-DX 116 had no effect on these responses. After administration of physostigmine, the amplitude of the nictitating membrane responses decreased with increasing intratrain frequency. AF-DX 116 reversed this effect. The data suggest that, in the superior cervical ganglion, AF-DX 116 sensitive muscarinic receptors which depress synaptic transmission are activated by exogenous agonists but not by the ACh released by the preganglionic axon terminals unless cholinesterase activity is inhibited.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:An AF-DX 116 sensitive inhibitory mechanism modulates nicotinic and muscarinic transmission in cat superior cervical ganglion in the presence of anticholinesterase. 133 12

Synaptic transmission in developing systems has often been noted to exhibit depression or failure at moderate frequencies of stimulation. While this is often presumed to be a transient, nonspecific inability of developing systems to meet the demands of synaptic transmission, this report demonstrates that such failure in the choroidal neurons of the embryonic ciliary ganglion is due to muscarinically mediated inhibition. Although the ganglion is composed of both choroid and ciliary neurons, only the choroid neurons exhibit the muscarinic depression, and only during embryonic development. The pharmacological properties of the relevant receptor are different from those of the muscarinic receptor involved in presynaptic inhibition in adult autonomic systems. Receptor-mediated, synaptic failure during development may serve to protect immature postsynaptic neurons from potentially toxic overstimulation.
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PMID:Mechanisms of synaptic fatigue in a developing autonomic ganglion. 142 46

Guanine nucleotide binding (G) proteins play a pivotal role in postreceptor information transduction. An important characteristic of G proteins is their increased guanine nucleotide binding following agonist stimulation, which in turn leads to their activation. We have developed a method that enables the measurement of early events in signal transduction beyond receptors, through activated receptor-coupled guanine nucleotide exchange on G proteins. Using this method, lithium was recently demonstrated to inhibit the coupling of both muscarinic cholinergic and beta-adrenergic receptors to pertussis toxin-sensitive and cholera toxin-sensitive G proteins, respectively, thus suggesting alteration of the function of G protein by lithium, as the single site for both the antimanic and antidepressant effects of this drug. One of the most puzzling aspects of the ability of lithium to ameliorate the manic-depressive condition is its relatively selective action upon the central nervous system (CNS). It was previously shown that lithium selectively attenuated the function of Gs proteins in the CNS. In the present study, we show that inhibition by lithium of muscarinic receptor-coupled G protein function is also selective to the CNS. The clinical profile of lithium, carbamazepine, and electroconvulsive treatment (ECT), agents that are effective in the prevention and treatment of bipolar affective disorder, differs from that of purely antidepressant drugs. Antidepressant drugs are effective in the acute treatment and prevention of depression only, and can even precipitate hypomanic or manic "switches," or "rapid cycling" between mania and depression. We have investigated and compared the effects of chronic antibipolar and antidepressant treatments on receptor-coupled G protein function. Antibipolar treatments (lithium, carbamazepine, ECT) attenuate both receptor-coupled Gs and non-Gs (i.e., Gi, Go) proteins function; in contrast, only Gs protein function is inhibited by antidepressant drugs [either tricyclics or monoamine oxidase (MAO) inhibitors]. Moreover, an integral adrenergic neuronal system is required for antidepressant inhibition of Gs protein function, as pretreatment with the noradrenergic neurotoxin DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) specifically abolishes the effects of antidepressant drugs on Gs protein, whereas antibipolar drug effects on G protein function are unaffected by DSP-4. Our results suggest that attenuation of beta-adrenergic receptor-coupled Gs protein function, which is common to both antidepressant and antibipolar treatments, may be the mechanism underlying their antidepressant therapeutic efficacy.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Ziskind-Somerfeld research Award. The involvement of guanine nucleotide binding proteins in the pathogenesis and treatment of affective disorders. 158 23

Slices of human neocortex prelabelled with [3H]choline were superfused and stimulated electrically (3 Hz, 2 ms, 24 mA) in order to investigate the autoreceptor-mediated modulation of acetylcholine (ACh) release. The concentration-response curve of the muscarinic agonist oxotremorine (pKd = 6.76 +/- 0.06), which was equipotent to ACh, was shifted to the right in a parallel manner by atropine (pA2 = 8.56 +/- 0.11), as evaluated by non-linear regression analysis. Calculation of the biophase concentration of ACh showed that no ACh could be assumed to be present under these conditions, whereas following inhibition of the acetylcholinesterase by physostigmine (0.1 microM) a biophase concentration of 10(-6.89 +/- 0.11) M was estimated. The depression of ACh release due to physostigmine and tacrine, another anticholinesterase, was antagonized by atropine. When the autoinhibition was operative atropine and the M2 subtype specific muscarinic antagonists, AF-DX 116 and methoctramine, significantly increased the release of ACh whereas the 'facilitatory' effects of the M1 and M3-specific drugs, pirenzepine and hexahydrosiladifenidol, were not significant. Although different disinhibitory effects of the subtype-specific antagonists were found, they did, however, not show a pattern which would allow a clear characterisation of the subtype of muscarinic receptor associated with the autoreceptor. The release of ACh from neocortex tissue of the (non-demented) neurosurgical patients decreased with their age. This finding is consistent with the hypothesis that the normal aging process resembles a delayed and attenuated disease process of senile dementia of Alzheimer's type.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The autoinhibitory feedback control of acetylcholine release in human neocortex tissue. 161 39

1. Isolated rings of rabbit external jugular vein (RbJV) and rat thoracic aorta (RA) were used to study the effect of the NO synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME) on muscarinic and 5-hydroxytryptamine (5-HT) receptor-stimulated, endothelium-dependent vascular relaxations. 2. In RbJV relaxations produced by the endothelial 5-HT receptor agonist alpha-methyl-5-HT were potently and non-surmountably inhibited by L-NAME (10 microM), whereas acetylcholine relaxations in this tissue were unaffected by this concentration of inhibitor. By contrast, acetylcholine relaxations in RA were virtually abolished by 10 microM L-NAME. In each case an equivalent concentration of D-NAME was without effect on agonist-induced relaxations. 3. The different effect of L-NAME on acetylcholine relaxations in RbJV and RA was not due to muscarinic receptor differences. Affinity estimates for acetylcholine (pKA = 6.12 +/- 0.09; 6.09 +/- 0.08 respectively) and for 4-diphenyl-acetoxy-N-methylpiperidine methobromide (4-DAMP, pKB = 9.01 +2- 0.012; 9.24 +/- 0.16 respectively) indicated that the receptors in both tissues belong to the same M3 class. Tissue differences resulting from the release of a cyclo-oxygenase product or a glibenclamide-sensitive K(+)-channel-linked hyperpolarizing factor were also ruled out by selective inhibition of these pathways. 4. When phenoxybenzamine was used to reduce the efficacy of acetylcholine in RbJV so that it behaved as a partial agonist in this tissue, L-NAME (10 microM) now produced non-surmountable inhibition of relaxation responses. In untreated tissues the same concentration of L-NAME also profoundly inhibited responses produced by butyrylcholine and pilocarpine, both of which behave as partial agonists at the M3 receptor in RbJV. 5. A simple model was developed which describes the theoretical behaviour of receptor-stimulated synthesis and release of NO. The model predicts that competitive inhibition of NO formation results in parallel displacements of the agonist response curve in the case of high efficacy agonist, but right-shift with concomitant depression of the curve maximum in the case of low efficacy agonists. Simulations based on the model showed reasonable agreement with the experimental data. 6. It is concluded that analogues of L-arginine demonstrate tissue- and agonist-dependence in terms of their ability to inhibit receptor-mediated events involving the liberation of NO. This behaviour can reflect differences in agonist efficacy in the receptor systems being studied, a possibility that should be ruled out before apparent resistance to inhibition is taken as evidence for the involvement of heterogeneous endothelium-derived relaxing factors (EDRFs).
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PMID:Inhibition of endothelium-dependent vasorelaxation by arginine analogues: a pharmacological analysis of agonist and tissue dependence. 162 52

Intrathecally administered alpha 2-adrenergic agonists produce analgesia in humans but may also produce hypotension and bradycardia. To further characterize hemodynamic depression produced by intrathecally administered alpha 2-adrenergic agonists, clonidine (100-1,500 micrograms) was injected into the cervical, thoracic, or lumbar intrathecal space of conscious sheep. Only thoracic intrathecal clonidine injection (100 or 300 micrograms) decreased blood pressure, whereas these doses did not affect blood pressure when injected at other sites. A greater clonidine dose (1,500 micrograms) increased blood pressure to a similar degree at all sites. Hypotension after thoracic intrathecal clonidine injection was inhibited by pretreatment with the alpha 2-adrenergic antagonist idazoxan (1 mg, intrathecally) or the depleter of acetylcholine stores hemicholinium-3 (2 mg, intrathecally), suggesting an action at alpha 2-adrenoceptors on cholinergic preganglionic sympathetic neurons. ST-91, a polar clonidine analog, did not decrease blood pressure after thoracic intrathecal injection. Intrathecal injection of the muscarinic receptor agonist carbamylcholine increased blood pressure. These data describe a complex action of intrathecal alpha 2-adrenergic agonists on hemodynamic parameters that is dependent on site of injection, drug dose, and drug lipophilicity; that can be explained by anatomic factors; and that may possibly be exploited to minimize hemodynamic depression from these agents.
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PMID:Site of hemodynamic effects of intrathecal alpha 2-adrenergic agonists. 192 92

Lithium salts are considered the most effective agents used in treating manic-depression. Previous studies in PC12 pheochromocytoma cells indicate that lithium has a dramatic augmenting effect on expression of the fos proto-oncogene, a component of the AP-1 transcription factor. Although fos expression is activated by agonists that function through different signal transduction pathways, the lithium augmenting effect appears to be specific for receptor and post-receptor stimulators of protein kinase C (PKC). In particular, fos induction mediated by the m1 muscarinic receptor linked to PKC activation was found to be exquisitely sensitive to lithium enhancement. We now show that a similar augmenting effect can be demonstrated in rat brain. Following treatment with the muscarinic agonist pilocarpine, fos mRNA accumulates in the cortex, an effect that is blocked by the m1 antagonist pirenzepine. Rats treated with a single intraperitoneal injection of lithium chloride exhibited a substantial increase in pilocarpine-mediated fos expression. In contrast, fos expression induced in several brain regions by a single electroconvulsive shock is not augmented by lithium. The finding that short-term treatment with lithium enhances fos expression in the brain suggests a mechanism for its therapeutic action.
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PMID:Lithium augments pilocarpine-induced fos gene expression in rat brain. 171 37

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