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)

In order to define the modulatory role played by gamma-aminobutyric acid (GABA) in corticopetal cholinergic projections, the effect of this amino acid and related drugs on gross behaviour, the EEG and the release of acetylcholine (ACh) from the cerebral cortex in freely moving guinea-pigs was studied. gamma Aminobutyric acid, injected intracerebroventricularly (20-50 mumol) induced a three-phase picture: first (5-15 min) behavioural activation and increased release of ACh, then (30-90 min) depression, EEG synchronization and reduced release of ACh, and finally "rebound" stimulation. Ethanolamine-O-sulphate (EOS) injected intraventricularly (28 mumol/kg) or intraperitoneally (14 mmol/kg) reproduced the first two phases of the effects of GABA (i.e. stimulation followed by inhibition), while diazepam (0.7 and 3.5 mumol/kg, i.p.) and flurazepam (32 mumol/kg, i.p.) caused, at first, only depression. Muscimol and 4,5,6,7-tetrahydroisoxazolo(4,5-c)pyridine-3-ol (THIP) injected intraventricularly (in the nmol range) or intraperitoneally (in the mumol range) produced behavioural activation and increased release of ACh; the depressant signs appeared only after very large, toxic doses. Picrotoxin and bicuculline, at sub-convulsive doses, reduced the symptomatology caused by GABA and antagonized the sedation produced by diazepam. Methysergide (8-16 mumol/kg, i.p.) prevented the behavioural activation and the increased release of ACh by GABA, unmasked the depression due to subthreshold doses of diazepam (i.c.v., 7-70 nmol) and reversed the stimulation induced by muscimol into sedation and reduced the outflow of ACh. Pretreatment with 5,7-HT also dampened and shortened the stimulation by muscimol.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The modulation of cortical acetylcholine release by GABA, GABA-like drugs and benzodiazepines in freely moving guinea-pigs. 286 May 90

The effects of tryptamine (TRM) on behavior were investigated in mice. TRM at a dose of 50 mg/kg i.p. induced an inhibition of locomotor activity and, at doses ranging from 150 to 300 mg/kg, induced peculiar behaviors such as head twitch, head weaving, forepaw treading, hindlimb abduction and Straub tail. These behavioral effects were continuous, although TRM rapidly disappeared from the brain. Methysergide, a 5-hydroxytryptamine (5-HT) receptor antagonist, completely abolished TRM-induced excitatory behaviors and p-chlorophenylalanine, a 5-HT depleter, significantly inhibited the behaviors. Our results show that TRM induced both the depression and excitation in the behavior of mice depending on the dosage and TRM-induced excitatory behaviors may be attributed to both its direct stimulation of 5-HT receptors and facilitation of 5-HT release.
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PMID:Effect of tryptamine on the behavior of mice. 294 Mar 57

The mode of action of tryptamine was investigated on strips of left circumflex coronary artery of calf. 1) Exposure to (-)-deprenyl, an irreversible inhibitor of monoamine oxidase B, markedly potentiated the contractions caused by tryptamine but not those by 5-hydroxy-tryptamine (5-HT). Experiments were therefore carried out on arteries treated with (-)-deprenyl. 2) Tryptamine, administered non-cumulatively, elicited fast developing contractions, which partially faded. The intrinsic activity for the peak response to tryptamine was 0.8 compared to 5-HT. Ketanserin competitively antagonized the tryptamine-induced contractions with a KB of (-log mol/l) 9.9. Methysergide antagonized the effects of tryptamine in a noncompetitive manner by depressing the maximum response with an IC50 (-log mol/l) greater than 9.0. 3) Tryptamine caused unsurmountable depression of 5-HT-induced contractions with an IC50 (-log mol/l) of 6.4. Ketanserin also competitively antagonized the depressant effects of tryptamine on 5-HT-induced contractions with a KB of (-log mol/l) 9.9. 4) At high concentrations of tryptamine (0.2-1 mmol/l), the fast developing contractions were followed by slowly developing contractions. Methysergide 1 nmol/l enhanced maximally the slow developing contractions. 5) These findings are consistent with an interaction of tryptamine at different sites of the allosteric 5-HT2-receptor system: (I) Tryptamine competes with ketanserin for the 5-HT2-receptor in the highly active R state. Binding of tryptamine to the R state would cause the fast contraction. (II) Tryptamine competes with ketanserin for the allosteric sites.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of tryptamine mediated through 2 states of the 5-HT2 receptor in calf coronary artery. 313 78

Methysergide depresses the contractile effects of 5-hydroxytryptamine (5-HT) in bovine large coronary arteries devoid of endothelium. The IC50 of methysergide for depression of the response to 5-HT was (-log mol/l) 9.8. A low sensitivity contractile effect of 5-HT was not influenced by 1-1,000 nmol/l methysergide. The maximum force of this residual response is approximately 1/3 of the maximum force elicited by 5-HT in the absence of methysergide. Ketanserin restored the 5-HT-induced contraction depressed by methysergide. In the presence of 0.1 mumol/l ketanserin, methysergide caused depression of the 5-HT-induced effects with an IC50 (-log mol/l) of 6.5 without affecting the residual response. We propose that methysergide depresses 5-HT-induced contractions by acting on an allosteric site. The effect of binding of methysergide to the allosteric site would lead to a conformational change of the 5-HT2-receptor, thereby only allowing the production of a residual 5-HT-induced contraction. Ketanserin competes with high affinity not only with 5-HT for the 5-HT2-receptor but also with methysergide for the allosteric site, thus shifting the receptor back into its original conformation. The affinity estimate of ketanserin for the allosteric site yielded a KB (-log mol/l) of 10.3. Ketanserin (1-1,000 nmol/l) antagonized the contractile effects of 5-HT with a potency expected from its affinity for 5-HT2-receptors (-log KB, mol/l 9.4). However, micromolar concentrations of ketanserin antagonized the effects of 5-HT less than expected from its affinity for 5-HT2-receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A paradox: the 5-HT2-receptor antagonist ketanserin restores the 5-HT-induced contraction depressed by methysergide in large coronary arteries of calf. Allosteric regulation of 5-HT2-receptors. 315 64

The mode of action of ICI 169,369, a novel 5-hydroxytryptamine2 (5-HT2) receptor antagonist, was investigated in arterial muscle. Isolated preparations from calf coronary artery and from rat tail artery with the endothelium rubbed off were set up to contract isometrically with 5-HT. ICI 169,369 (1-3000 nM) antagonized surmountably and competitively the contractile effects of 5-HT in coronary artery (pKB, 9.1) and tail artery (pKB, 8.8). Methysergide antagonized unsurmountably 5-HT-induced contractions by reducing maximum effects to 25% (coronary artery: pIC50, 9.8) and 60% (tail artery: pIC80, 9.0). ICI 169,369 (100-300 nM) restored the maximum effects of 5-HT that had been depressed by methysergide (20 nM coronary artery, 100 nM tail artery). Preincubation with ICI 169,369 also prevented the methysergide-induced depression of the maximum effects of 5-HT. The protective effect of ICI 169,369 was overcome by high methysergide concentrations (up to 3 microM), suggesting competition between the two drugs for a common site. The data are consistent with an allosterically modulated interconversion of the 5-HT2 receptor between two states (R in equilibrium R'). ICI 169,369 competes with 5-HT for the 5-HT2 receptor. ICI 169,369 and methysergide also compete for an allosteric site of the 5-HT2 receptor system, thereby facilitating the highly active R-state and low active R'-state, respectively.
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PMID:ICI 169,369 is both a competitive antagonist and an allosteric activator of the arterial 5-hydroxytryptamine2 receptor system. 338 35

A theory of excessive transmission of serotonin (5-HT) in depression has been previously proposed. The purpose of the present study was to test this theory further by using the model of depression in rats induced by L-5-hydroxytryptophan (5-HTP), the precursor of 5-HT. The drug effects on 5-HTP (25 mg/kg) induced behavioral depression were tested by chronic administration using methysergide which is a postsynaptic blocker of 5-HT, or by comparable clinical doses of antidepressant drugs. Methysergide (2 mg/kg) blocked 5-HTP induced depression on days 8 and 22 after initiation of medication by 70% and 83%, respectively. Among antidepressants, mianserin (2 mg/kg) was the first to produce an effect, displaying a 38% effect as early as 1 day after the start of medication and having blocking effects of 52% and 72% on days 8 and 22. Desipramine (5 mg/kg), doxepine (5 mg/kg), imipramine (5 mg/kg) and trazodone (10 mg/kg) showed no significant effect on days 1 and 8, and on day 22, 64, 36, 33 and 32% blocking, respectively. Amitriptyline had an initial effect of 41% at a dose of 10 mg/kg. Clomipramine (5 mg/kg), zimelidine (6 mg/kg) and chlorpromazine (2.5 mg/kg), which is a neuroleptic, showed no effect. Considering these results in light of recent data reported on the 5-HT synapse, it was suggested that 5-HTP induced depression may be induced by excessive transmission of 5-HT and that some antidepressant drugs may produce their effect by blocking this postsynaptic transmission. Based on these results, the mechanisms of human depression were discussed.
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PMID:Action of chronically administered antidepressants on the serotonergic postsynapse in a model of depression. 349 69

Recently, Kaumann and Frenken (1985) proposed an allosteric model of vascular 5-HT2-receptors. We now present experiments in both bovine coronary and pulmonary artery, using the method of irreversible receptor occlusion, that support and extend the model. 1) Phenoxybenzamine was found to cause irreversible antagonism of the effects of 5-hydroxytryptamine (5-HT). Maximal contractile effects induced by 5-HT were depressed and, with further receptor occlusion, concentration-effect curves for 5-HT became biphasic. The high-sensitivity and the low-sensitivity component of the curve for 5-HT consisted of quickly and slowly developing contractions, respectively. 2) Biphasic concentration-effect curves for 5-HT after receptor occlusion were shifted to the right in non-parallel manner by ketanserin and became monophasic with an unexpected partial restoration of maximal responses to 5-HT. The magnitude of the shift of the partially restored concentration-effect curve for 5-HT by ketanserin after receptor occlusion by phenoxybenzamine is consistent with an interaction of ketanserin with 5-HT2-receptors. 3) Preincubation with methysergide before phenoxybenzamine-treatment followed by washout of both drugs, and subsequent incubation with ketanserin completely prevented a depression of 5-HT-induced effects by phenoxybenzamine. 4) Estimates for the equilibrium dissociation constant of 5-HT for the 5-HT2-receptor derived from fast developing contractions range from 0.1 mumol/l to 0.4 mumol/l. 5) The results are consistent with a model of two interconvertible states of the 5-HT2-receptor. Phenoxybenzamine occludes the 5-HT2-receptor in the R-state but not in the R'-state. The low active R'-state of the 5-HT2-receptor appears to pre-exist in the absence of drugs and is not affected by phenoxybenzamine. By converting R' into R ketanserin restores partially the response to 5-HT after occlusion of the R-state by phenoxybenzamine. Methysergide prevents the 5-HT2-receptor occlusion induced by phenoxybenzamine indirectly by favouring isomerisation into the R'-state.
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PMID:Interconversion into a low active state protects vascular 5-HT2-receptors against irreversible antagonism by phenoxybenzamine. 361 85

The effect of somatostatin on lateral hypothalamic self-stimulation was investigated in atropine- and methysergide-pretreated rats. Somatostatin markedly decreased the self-stimulation rate of the animals. Atropine in a dose which had no action on self-stimulation partly antagonized the effect of somatostatin. Methysergide potentiated the somatostatin-induced depression of self-stimulation behavior. These results suggest that the central cholinergic and serotoninergic systems may play a role in the somatostatin-induced inhibition of self-stimulation.
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PMID:The effect of somatostatin on self-stimulation behavior in atropine- and methysergide-pretreated rats. 613 93

The effects of lysergic acid diethylamide (LSD), methysergide, and cyproheptadine on activity in classical primary pathways of the visual and somatosensory systems were compared with their effects on activity in sensory convergent (association) regions in alpha-chloralose-anesthetized cats. Those effects were blocked by cyproheptadine whereas methysergide potentiated the actions of LSD on visual primary activity. In contrast, LSD depressed the primary somatic pathway, at small doses (25 to 50 micrograms/kg) and facilitated the response at larger doses (200 micrograms/kg). Cyproheptadine and methysergide did not agonize these actions of LSD. The anterior marginal cortex, nucleus central median-parafascicularis, nucleus lateral posterior, and the superior colliculus, all sites of heterosensory convergence, were depressed by LSD. The depression of responses at heterosensory sites by LSD was blocked by cyproheptadine. Methysergide potentiated the LSD-induced depression of visual-evoked activity but not somatosensory activity. These results suggest that LSD depresses sensory activity in regions which integrate multiple sensory modalities independently of actions on sensory-specific pathways. These effects appear to involve a cyproheptadine-sensitive system.
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PMID:Differential effects of lysergic acid diethylamide, methysergide, and cyproheptadine on modality-specific and nonspecific sensory evoked potentials. 662 26

To further test the new hypersensitive postsynaptic serotonin (5-HT) receptor theory of depression bases on or animal model, it was necessary to demonstrate that some of the currently used antidepressive drugs can block D,L-5-hydroxytryptophan (5-HTP) induced depression acting through postsynaptic rather than presynaptic mechanisms. Rats working for milk reinforcement and exhibiting behavioral depression following administration of 5-HTP (IP) were pretreated (1 hour before the 5-HTP injection) with fluoxetine (5 mg/kg IP) or methysergide (5 mg/kg IP) to establish a behavioral basis for distinguishing between pre- and postsynaptic events, respectively. Fluoxetine, a known specific uptake blocker of 5-HT, potentiated the depressive effect of 12.5 mg/kg 5-HTP by 200%. Methysergide, a postsynaptic blocker of 5-HT, almost completely (93%) abolished the depressive effect of 50 mg/kg 5-HTP. Since acute pretreatment with comparable clinical doses of the antidepressive drugs, mianserin, amitriptyline, imipramine, or iprindole, resulted in blockade of the 5-HTP induced depression by 70, 50, 40, and 20% respectively, these drugs can act as antagonists of 5-HT at the postsynaptic serotonin receptor. When these results are viewed in terms of recent data reported from CNS binding studies, the therapeutic effects of some antidepressants may be explained by their postsynaptic rather than presynaptic effects at central serotonergic receptors.
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PMID:Postsynaptic action by four antidepressive drugs in an animal model of depression. 697 69


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