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)

Multiple cortical neuronal responses were elicited by the iontophoretic application of muscarinic receptor agonists and antagonists in the rat cerebral sensorimotor cortex in vivo. (1) The muscarinic receptor agonist, oxotremorine-M induced a biphasic effect on spontaneous firing. This was evident as an early brief increase in the firing rate over the spontaneous discharge followed by secondary inhibition of spontaneous activity. The excitation could be blocked by the muscarinic receptor non-selective antagonist atropine and by both the M1 receptor antagonist pirenzepine and the M2 receptor antagonists gallamine or methoctramine. Oxotremorine-M inhibition of spontaneous activity was not affected by the M1 receptor antagonist pirenzepine, while evaluation of its sensitivity to gallamine and methoctramine was not possible since these two M2 receptor antagonists also depressed spontaneous activity, unlike pirenzepine. Of the other two muscarinic receptor agonists, oxotremorine had inconsistent and weak excitatory effects whilst McN-A-343 had only weak excitatory or inhibitory effects on spontaneous activity. (2) Oxotremorine-M, oxotremorine and McN-A-343 had a depressant action on neuronal discharges evoked by glutamate or acetylcholine. A depressant effect of oxotremorine-M was also demonstrated on the early excitation evoked by subsequent applications of oxotremorine-M itself. Of the three muscarinic receptor agonists tested, oxotremorine-M was the most potent in evoking a long-term depression of evoked discharges, lasting from several minutes (greater than 5 min) to as long as 40 min. Oxotremorine-M-induced depression of evoked responses was most sensitive to the M2 receptor antagonists, whereas oxotremorine-induced depression was more sensitive to the M1 receptor antagonist pirenzepine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Muscarinic receptor agonist-mediated modulation of neuronal activity in rat cerebral cortex. 172 54

Pretreatment of mice with the muscarinic receptor antagonists scopolamine and atropine attenuated the hypermotility (but not the depression of rearing) induced by a low dose of dizocilpine maleate [(+)-MK-801; 0.1 mg/kg, i.p.], a non-competitive NMDA antagonist. In contrast, the muscarinic blockers failed to affect hypermotility induced by equieffective doses of phencyclidine (1 mg/kg, i.p.) or d-amphetamine (2 mg/kg, i.p.). These results suggest differences between the mechanism of behavioral activation produced by dizocilpine and phencyclidine, and demonstrate the potential of muscarinic blockade for diminishing the behavioral toxicity of NMDA antagonists.
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PMID:Muscarinic antagonists attenuate dizocilpine-induced hypermotility in mice. 174 Sep 67

A shortened latency of rapid eye movement (REM) sleep is one of the most stable biological abnormalities described in depressive patients. According to the reciprocal interaction model of non-REM and REM sleep regulation, REM sleep disinhibition at the beginning of the night in depression is a consequence of heightened central nervous system cholinergic transmitter activity in relation to aminergic transmitter activity. A recent study has indicated that muscarinic supersensitivity, rather than quantitatively enhanced cholinergic activity, may be the primary cause of REM sleep abnormalities in depression. The present study tested this hypothesis by treating healthy volunteers for 3 days with a cholinergic antagonist (scopolamine) in the morning, in an effort to induce muscarinic receptor supersensitivity. On the last day of scopolamine administration, RS 86, an orally active cholinergic agonist, was administered before bedtime to test whether this procedure would induce sleep onset REM periods. Whereas scopolamine treatment tended to advance REM sleep and to heighten REM density in healthy controls in comparison to NaCl administration, the additional cholinergic stimulation did not provoke further REM sleep disinhibition. This result underlines the need to take a hypofunction of aminergic transmitter systems into account in attempts to explain the pronounced advance of REM sleep typically seen in depressives.
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PMID:The cholinergic REM induction test with RS 86 after scopolamine pretreatment in healthy subjects. 175 37

Guinea-pig common bile duct preparations were used to quantify the spasmolytic potency of N-butylscopolamine (NBS), papaverine, gallopamil and nifedipine. A method was developed which allowed the measurement of intraluminal pressure changes in vitro. Barium chloride, carbachol and a solution with elevated potassium concentrations were used to stimulate smooth muscles. Concentration-response relationships for the spasmogens as well as for the spasmolytic drugs were evaluated in a cumulative manner. Furthermore, non-cumulative concentration-response curves were constructed for carbachol in the absence and presence of NBS. The -log EC50-values of the spasmogens were found to be 3.28 +/- 0.08 (BaCl2), 6.46 +/- 0.07 (carbachol) and 1.31 +/- 0.08 (KCl), respectively. The Emax values of carbachol and potassium were comparable, and were twice as high as the Emax of BaCl2. Papaverine was less potent than the calcium antagonists gallopamil and nifedipine, but proved capable of completely suppressing elevated muscular tone of the common bile duct preparation, independent of the stimulus used. NBS showed a high potency in suppressing only a carbachol-induced pressure increase, while it was rather ineffective when BaCl2 or a high potassium solution was used as the spasmogen. The concentration-response-curve for carbachol was shifted to the right in a parallel manner by NBS. Only a slight depression of Emax was observed. From the results it is concluded that NBS acts mainly as a muscarinic receptor antagonist. The high potency found for the calcium antagonists, gallopamil and nifedipine, in this model may indicate a possible role for these compounds in the treatment of biliary colic.
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PMID:Comparison of various spasmolytic drugs on guinea-pig isolated common bile duct. 177 88

Arecoline produces a biphasic response in rat left atria, i.e., a depression of basal inotropy at low doses and a positive inotropic effect at higher doses. These present studies were designed to determine whether it can be shown that the two separate responses to arecoline are mediated by two distinct cell surface muscarinic receptors. The antagonists scopolamine, 4-DAMP and AF-DX 116 produced apparent simple competitive antagonism of the negative responses to arecoline. Schild analysis was used to measure the equilibrium dissociation constant of the antagonist-receptor complex for antagonism of this response to arecoline by these antagonists. In atria from rats treated with pertussis toxin, the negative inotropy to arecoline was abolished and only the positive inotropic effects were observed. The antagonism of the positive inotropic response to arecoline by these antagonists was studied separately in atria from rats treated with pertussis toxin by the Schild technique. The pKB estimates made from the Schild regressions indicated no evidence to suggest that the two responses to arecoline (negative and positive inotropy) were mediated by two separate receptors in rat left atria. These data are discussed in terms of a single muscarinic receptor in this tissue mediating these two responses by interaction with two G-proteins in the same cell membrane. These data also are discussed in terms of the use of agonist potency ratios for the classification of receptors.
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PMID:Biphasic dose-response curves to arecoline in rat atria-mediation by a single promiscuous receptor or two receptor subtypes? 194 13

Grayanotoxins are known to occur in the honey produced from the nectar of Rhododendron ponticum growing on the mountains of the eastern Black Sea region of Turkey and also in Japan, Nepal, Brazil, and some parts of North America and Europe. Two cases of honey intoxication are presented here. Both of the patients experienced severe bradycardia and hypotension after ingestion of honey which was brought from Trabzon, Turkey. Microscopical examination showed Rhododendron ponticum pollen tetrades. Anesthetized albino rats were injected intraperitoneally with toxic honey extract doses equivalent to 1 or 5 g honey/kg. Dose-dependent hypotension, bradycardia and respiratory rate depression were observed. When marked bradycardia (approximately 75% of control value) was reached, rats were given atropine sulfate (2 mg/kg, i.p.) or AF-DX 116 (20 mg/kg, i.p.). Atropine sulfate improved both bradycardia and respiratory rate depression. AF-DX 116, which is a selective M2-muscarinic receptor antagonist, restored only heart rate, but not the respiratory rate depression. These results suggest that M2-muscarinic receptors are involved in cardiotoxicity of grayanotoxin.
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PMID:Mad honey poisoning in man and rat. 195 47

The cholinergic rapid eye movement (REM) induction test using arecoline hydrobromide, a cholinergic muscarinic receptor agonist, was studied in patients with affective disorder and in normal controls to determine whether or not depression is associated with enhanced induction of REM sleep by muscarinic agonists. Arecoline induced REM sleep in a dose-dependent fashion in both patients and controls compared with placebo infusions. Compared with normal controls, patients entered REM sleep significantly more rapidly following intravenous administration of 1.0 mg of arecoline hydrobromide than they did following administration of 0.5 mg of arecoline hydrobromide or placebo. These results, as well as those of previous studies, support the hypothesis that patients with affective disorder show a functional supersensitive induction of REM sleep in response to muscarinic receptor agonists and may be consistent with the hypothesis that functional muscarinic receptor "up regulation" is associated with depression.
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PMID:The cholinergic rapid eye movement induction test with arecoline in depression. 199 21

We examined the diurnal rhythm of core body temperature in a strain of rats with an upregulated central muscarinic receptor system. The Flinders-Sensitive Line (FSL) was derived by selectively breeding rats for sensitivity to cholinergic agonists. When compared to control rats, the FSL rats showed a remarkably strong phase advance of the acrophase in body temperature during a standard light-dark schedule. Some patients with some types of depression also show phase advances in a number of circadian rhythms, including temperature. Our finding of a phase advance in a rodent model with a known upregulated muscarinic receptor system is compatible with both the phase advance and the muscarinic overdrive theories of depression. These findings also further validate the usefulness of the FSL rats in the study of depression.
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PMID:Diurnal rhythm of core body temperature is phase advanced in a rodent model of depression. 204 91

Adult Flinders-Sensitive Line (FSL) rats are significantly more sensitive to the behavioral and physiologic effects of muscarinic agonists than are control, Flinders-Resistant Line (FRL) rats; therefore, they resemble humans with depressive disorders. The present study examined the sensitivity of prepubertal and pubertal FSL and FRL rats to the hypothermic and locomotor inhibitory effects of the muscarinic agonist, oxotremorine, and compared these findings to the regional development of muscarinic receptor binding in similarly aged rats. The FSL rats were significantly more sensitive (-1.85 degrees +/- 0.2 degrees C) than the FRL rats (-0.65 degrees +/- 0.15 degrees C) to the hypothermic effect of 0.25 mumol/kg of oxotremorine at the earliest age tested (18 days postpartum) and became progressively more sensitive throughout the period of testing (FSL -2.8 degrees +/- 0.24 degrees C versus FRL -0.5 degrees +/- 0.16 degrees C at 61 days postpartum, data represent the mean +/- SEM of pooled male and female). Significant increases in muscarinic receptor number in FSL rat brain were observed only in older (61 days postpartum) rats. These results are consistent with the suggestion that the FSL rat is a genetic animal model of depression, but also indicate that the differences in muscarinic sensitivity cannot be accounted for exclusively by differences in the number, per se, of muscarinic receptors.
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PMID:Early development of muscarinic supersensitivity in a genetic animal model of depression. 206 20

Bath application of two different concentrations of muscarine produced two different effects on evoked responses in the dentate gyrus of rat hippocampal slices. A concentration of 1 microM muscarine did not affect the evoked population spike or excitatory postsynaptic potential (EPSP), but facilitated the induction of LTP. In contrast, a concentration of 10 microM muscarine depressed both the population spike and EPSP, but had no effect on LTP induction. The M1 muscarinic receptor antagonist pirenzepine (1 microM) blocked the muscarine-induced facilitation of LTP, but had no effect on the depression of evoked responses. These data suggest that activation of M1 receptors can facilitate the induction of LTP.
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PMID:Muscarinic receptor activation facilitates the induction of long-term potentiation (LTP) in the rat dentate gyrus. 225 53


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