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 neurotoxic effects of long-term, low-level exposure to the commercially available insecticide, Fenthion, were examined in the present study. Young (2 month) adult, male Long-Evans rats were dermally exposed to Fenthion (25 mg/kg, 3X week) and sampled after 2 and 10 months exposure to assess neurotoxic damage in the hippocampus using morphological and biochemical endpoints. Histopathology, consisting of gliosis, swollen and necrotic neurons, and cell dropout, occurred in the dentate gyrus (DG), CA4 (hilus), and CA3 sectors as early as 2 months postexposure. Acetylcholinesterase (AChE) staining of brain tissues taken at this time was severely reduced in the septal nuclei, the DG molecular layer, the CA4, and the hippocampus proper. After 10 months exposure to Fenthion, cellular necrosis and gliosis intensified in the CA4 and CA3 regions and occasionally involved the CA2. Radiometric assays of AChE activity in the hippocampus indicated a 65 and 85% depression after 2 and 10 months exposure, respectively. Quinuclidinyl benzilate binding for the hippocampal muscarinic receptor was reduced by 6 and 15%, after 2 and 10 months exposure, respectively. A separate group of older (12 month) rats was exposed to the same dosing regimen of Fenthion and examined for neuropathological damage after 2 and 10 months exposure. Aged animals exposed for only 2 months expressed severe hippocampal degeneration in a pattern similar to that seen in the young adult after 10 months exposure (viz., DG, CA4, CA3). Aged animals exposed for 10 months showed more extensive histopathology of the CA4-2 and occasionally CA1. These observations indicate that in both young adult and aged animals, subchronic, low-level exposure to anticholinesterase compounds can result in serious neurotoxic consequences to the mammalian hippocampus.
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PMID:The neurotoxicity of subchronic acetylcholinesterase (AChE) inhibition in rat hippocampus. 238 36

3,7-Dihydro-7-[2-hydroxy-3-[4-[3-(phenylthio) propyl]-1-piperazinyl]propyl]-1,3-dimethyl-1H-purine-2,6-dione dihydrochloride (tazifylline, RS-49014) potently inhibited contractions evoked by stimulation of histamine H1-receptors in isolated guinea pig ilea and exhibited high affinity for these receptors in radioligand binding studies in vitro. In rats, guinea pigs and dogs the antihistaminic effect of tazifylline was rapid in onset and long-lived. In anesthetized guinea pigs, tazifylline markedly inhibited histamine-induced bronchoconstriction and protected conscious animals from the lethal effect of large doses of the amine. In conscious rats, tazifylline was more potent in reducing the inflammatory effects of intradermal histamine than that evoked by anaphylactic reaction. In conscious dogs, orally administered tazifylline inhibited histamine-induced skin inflammation for long periods of time and in anesthetized animals attenuated that portion of the histamine-evoked hypotension attributable to stimulation of H1-receptors. Results obtained from a variety of in vitro and in vivo experimental preparations showed that tazifylline had much lower affinity for histamine H2-receptors, alpha- and beta-adrenoceptors, 5-hydroxytryptamine and muscarinic receptor subtypes. Tazifylline poorly inhibited the release of histamine from rat peritoneal mast cells. Large oral doses of tazifylline did not reduce spontaneous locomotor activity in mice, nor did they produce overt symptoms of behavioral depression in conscious rats. Therefore, tazifylline is a potent, selective and long-acting histamine H1-receptor antagonist that does not appear to produce central depression in animals.
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PMID:Animal pharmacology of the selective histamine H1-receptor antagonist tazifylline. 242 63

The technique of microelectrophoresis was used to investigate the cholinoceptor pharmacology of spontaneously active single neurones in the parietal cortex of the rat. Acetylcholine, carbachol and the selective M1-muscarinic receptor agonist, McN-A-343, were each potent excitants (rank order of apparent potency: carbachol greater than acetylcholine greater than McN-A-343). When measured in vitro, the apparent mobilities of carbachol and acetylcholine were similar although significantly less than that of McN-A-343, suggesting that the lower potencies of acetylcholine and McN-A-343 probably reflect a genuine biological phenomenon. In addition to excitation, carbachol also evoked biphasic (excitation/depression) and depressant responses. In contrast to the other cholinoceptor agonists, nicotine produced weak and inconsistent excitations. Excitatory responses to acetylcholine and carbachol were significantly attenuated by the selective M1-muscarinic receptor antagonist, pirenzepine, at a time when the excitatory response to McN-A-343 was also significantly reduced. Responses to phenylephrine were not diminished. On several cells an excitatory response to carbachol was converted to a depression by pirenzepine. These results suggest that the excitatory responses of cortical neurones to cholinoceptor agonists are mediated predominantly by M1-muscarinic receptors. The identity of the receptor mediating the depressant response to carbachol remains uncertain, although nicotinic cholinoceptors do not appear to be involved.
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PMID:Involvement of M1-muscarinic receptors in the excitation of neocortical neurones by acetylcholine. 244 71

Neuronal nucleic acid responses were examined within the rat thalamic ventrobasal nuclear complex (VBC) and nucleus reticularis (NR) following single intraperitoneal injections of the central muscarinic-cholinergic (M2) receptor agonist oxotremorine (0.1, 0.7, or 1.0 mg/kg). After stoichiometric azure B and Feulgen staining of brain sections, scanning-integrating cytophotometry was used to quantify azure B-ribonucleic acid (RNA) content, Feulgen-DNA levels, and changes in the susceptibility of chromatin to Feulgen acid hydrolysis (F-DNA yield) of neurons on an individual basis. Changes in neuronal nucleolar volume were also determined histometrically. Within the VBC, oxotremorine produced marked dose-dependent elevations in neuronal RNA content and nucleolar volume with increased F-DNA yield (chromatin activation) in a proportion of VBC neurons. In contrast, within the NR, oxotremorine elicited reductions in RNA levels, F-DNA yield and nucleolar volume. The data demonstrate that oxotremorine-induced central muscarinic receptor stimulation is associated with metabolic correlates of thalamic VBC neuroexcitation and NR neuron depression. The overall study lends further credence to the hypothesis that muscarinic-cholinergic mechanisms are operative within the mammalian thalamus.
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PMID:Effects of oxotremorine on neuronal RNA and chromatin in thalamic cholinoceptive sites. 246 66

Intracellular recording from hippocampal CA1 pyramidal cells was used to characterize the pharmacological properties of muscarinic responses. Results obtained with the M1 antagonist pirenzepine and the M2 antagonist gallamine suggest that an M1 muscarinic receptor is involved in the muscarinic-induced membrane depolarization and blockade of the afterhyperpolarization (AHP). On the other hand, an M2 receptor may be involved in the cholinergic depression of the EPSP and the blockade of the potassium current termed the M-current. Pretreatment of hippocampi with pertussis toxin did not prevent any of the muscarinic responses suggesting that a pertussis toxin-sensitive G-protein is not involved. The M-current, in contrast to the other muscarinic actions, was unaffected by muscarinic agonists which are weak at increasing phosphoinositide (PI) turnover and actually blocked the action of full agonists. This finding suggests that stimulation of PI turnover may be involved in the blockade of the M-current. Although activation of protein kinase C with phorbol esters has little effect on the M-current, intracellular application of inositol trisphosphate did reduce the M-current. We were unable to establish any clear relationship between biochemical effector systems and the muscarinic receptor subtypes.
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PMID:Pharmacological characterization of muscarinic responses in rat hippocampal pyramidal cells. 253 6

The effects of lethal (2.0 mg/kg) and high sublethal (1.3 mg/kg) dosages of the organophosphate acetylcholinesterase (AChE) inhibitor paraoxon on FR10 performance rate was determined 1 and 2 days after intoxication. The lethal doses were antidoted with either centrally acting atropine sulfate (AS), or atropine methyl bromide (AMB) or atropine methyl nitrate (AMN), both quaternary salts and not expected to act centrally. AChE inhibition in the brain was about 35-60% on the second day after treatment. AS yielded a small transient depression in performance, while AMB and AMN yielded severe deficits, with incomplete recovery. Performance was depressed by 1.3 mg/kg paraoxon by 52% and 34% on days 1 and 2, respectively, while performance was more greatly depressed by the lethal dose, especially with the noncentrally acting antidotes: AS, 67 and 48%; AMB, 81 and 55%; AMN, 91 and 78%. However, a low dose of AS with 2 mg/kg paraoxon resulted in very severe, nonrecovering deficits. A lethal dose of the nonpersistent anti-AChE eserine sulfate, antidoted with a low dose of AS, yielded no deficits. Thus, a high level, acute intoxication with paraoxon yields behavioral deficits which are attenuated by high levels of a centrally acting muscarinic receptor antagonist. The paraoxon-induced performance deficits or their recovery do not correlate directly with AChE inhibition.
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PMID:Short-term effects of paraoxon and atropine on schedule-controlled behavior in rats. 259 81

The ability of physostigmine (PHY) and pyridostigmine (PYR) to protect against the segmental synaptic depression caused by sarin was examined in isolated spinal cords from neonatal rats. The monosynaptic reflex was unaffected at concentrations up to 0.1 microM PHY or 0.3 microM PYR but raising the concentrations of either drug produced a concentration-dependent depression of the monosynaptic reflex which could be completely antagonized by atropine. The monosynaptic reflex was depressed by 50% at 0.45 microM PHY and 2 microM PYR with maximal depression occurring at 1 microM PHY (to about 10% of control) and 10 microM PYR (to about 35% of control). Pretreating the cords with 0.1 microM PHY and PYR for 30 min failed to protect against the depressant effects of sarin even though they inhibited total cholinesterase (ChE) by 27 and 21%, respectively. Both PHY and PYR depressed total ChE activity of the spinal cord in a concentration-dependent manner with 50% inhibition of ChE occurring at 0.8 microM. These results suggest that the carbamates affect segmental transmission by activation of a muscarinic receptor, that protective carbamylation of ChE is ineffective against organophosphorus-induced segmental depression, and that inhibition of ChE is unrelated to both carbamate- and organophosphorus-induced depression of the monosynaptic reflex.
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PMID:Interaction of reversible and irreversible cholinesterase inhibitors on the monosynaptic reflex in neonatal rats. 272 98

The effects of mescaline and LSD on the flash-evoked cortical potential (FEP) were determined in unrestrained rats with chronically-implanted electrodes. Systemic administration of mescaline or LSD significantly attenuated the primary component of the FEP at three stimulus intensities with the greatest effect observed 60-90 minutes following drug administration. The magnitude and specificity of the effects of these agents on the primary response suggest that they produce deficits in conduction through the retino-geniculato-cortical system. The serotonin receptor antagonists, cyproheptadine and methysergide, antagonized the mescaline-induced depression of the FEP in accordance with neurochemical and behavioral evidence that mescaline acts as a partial agonist on serotonin receptors. Topical or intraocular administration of atropine antagonized the actions of systemically-administered mescaline. In addition, intraocular administration of mescaline or LSD attenuated the FEP indicative of an action of these hallucinogens on visual processing in the retina which is modulated by muscarinic receptor activity.
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PMID:Effects of intraocular mescaline and LSD on visual-evoked responses in the rat. 273 30

A relationship between psychological and neurobiological predisposition factors for affective disorders has been suggested. The aim of the present study was to test this hypothesis. As predisposition measures of affective disorders, muscarinic and beta-adrenergic receptors densities on blood cells and personality traits were determined in 16 male volunteers. The Minnesota Multiphasic Personality Inventory (MMPI), Freiburger Personality Inventory (FPI), and Premorbid Personality Inventory (PPI) were used for personality assessment. The erythrocyte muscarinic receptor density (mainly M1 subtype) correlated highly significantly negatively with depression on the MMPI (r = -0.71; P less than 0.001) as well as significantly positively with reactive aggressiveness (dominance) on the FPI (r = 0.48; P less than 0.05) and extraversion on the PPI (r = 0.46; P less than 0.05). The beta-adrenoceptor density on lymphocytes correlated significantly negatively with spontaneous aggressiveness (r = -0.51; P less than 0.05) on the FPI. These results are the first evidence that premorbid personality traits of depressives are related to M1-muscarinic and beta-adrenergic receptors densities. It is speculated that decreased beta-adrenergic receptor densities might predispose an individual to major depression whereas a decrease of M1-muscarinic receptor densities could play a role in the development of minor depressions. The findings of the present study are compatible with the postulated relationship between personality and neurobiological predisposition factors of depressive disorders. They suggest the participation of neurobiological factors in the development of personality traits predisposing to depression. However, they seem to be nonspecific for depression and are probably neither a sufficient nor a necessary cause of this disorder. Additional biological or psychological factors seem to be required for the development of clinical depressions.
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PMID:Personality factors predisposing to depression correlate significantly negatively with M1-muscarinic and beta-adrenergic receptor densities on blood cells. 284 46

Activation of M2-muscarinic receptors alters the configuration of the action potential due to depression of the calcium-dependent components, the shoulder in the falling phase and the afterhyperpolarization, in isolated superior cervical ganglionic neurons of rabbits. This effect was inhibited by preincubation of the cells with pertussis toxin, or by the intracellular administration of guanosine 5'-O-(2-thiodiphosphate) (GDP-beta-S). The muscarinic effect persisted in the cells loaded with guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S). Intracellular application of cAMP and 3-isobutyl-l-methylxanthine did not change the muscarinic effect. The results suggest that a GTP-binding protein is involved in the cAMP-independent, M2-muscarinic receptor-mediated regulation of action potential firing in sympathetic neurons.
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PMID:GTP-binding proteins mediate the M2-muscarinic effect on the action potential in isolated sympathetic neurons of rabbits. 285 47


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