Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0036341 (schizophrenia)
60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been suggested that changes in brain 5-hydroxytryptamine3 receptor function may contribute to some behavior disorders, such as anxiety, schizophrenia and drug abuse. We are using the whole-cell version of the patch-clamp technique to study the function of 5-hydroxytryptamine3 channels in neurons freshly dissociated from rat nodose ganglion. In these cells, 5-hydroxytryptamine elicits an inward current over the concentration range of 0.25-100 microM (EC50 = 2.62 microM) by activating 5-hydroxytryptamine3 receptors. The muscarinic cholinergic antagonist atropine reduced the amplitude of 5-hydroxytryptamine activated inward current in a concentration-dependent manner. Other muscarinic antagonists, scopolamine, dexetimide, the M1 muscarinic receptor antagonist pirenzepine, the M2 receptor antagonist methoctramine and the M3 receptor antagonist 4-DAMP methiodide also inhibited 5-hydroxytryptamine-induced inward current. Atropine did not appear to change the reversal potential of this current. In the presence of 5 microM atropine, the concentration-response curve for 5-hydroxytryptamine current was shifted to the right in a parallel fashion. The EC50 value for 5-hydroxytryptamine was increased from 2.62 to 8.76 microM. Schild plots of increasing atropine and 5-hydroxytryptamine concentrations revealed a pA2 value of 5.74 for atropine (apparent KD = 1.8 microM). These observations suggest that atropine competitively antagonizes the activation of a receptor for the neurotransmitter serotonin, a novel action of muscarinic antagonists in the nervous system. This effect of atropine may contribute to the clinical symptoms seen in severe atropine intoxication.
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PMID:The effect of atropine on the activation of 5-hydroxytryptamine3 channels in rat nodose ganglion neurons. 753 5

Disinhibition of rapid eye movement (REM) sleep (e.g. shortening of REM latency, heightened REM density) is frequently encountered in patients with a major depressive disorder (MDD). Administration of cholinomimetics prior to or during sleep leads to a more pronounced advance of REM sleep in depressed patients compared to healthy controls and patients with other psychiatric disorders. The present study tested whether the cholinergic REM induction test (CRIT) with 1.5 mg RS 86 (an orally acting muscarinic agonist) differentiates patients with MDD (n = 40) from those with schizophrenia (n = 43) and healthy controls (n = 36). The most pronounced shortening of REM latency after cholinergic stimulation occurred in patients with MDD. However, a significant number of patients with schizophrenia also displayed short REM latencies (REM latency < 25 minutes) under placebo conditions and after cholinergic stimulation. REM density measures more clearly differentiated patients with MDD from those with schizophrenia. It is concluded that a subgroup of patients suffering from schizophrenia displays signs of a muscarinic receptor supersensitivity.
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PMID:Cholinergic REM induction test: muscarinic supersensitivity underlies polysomnographic findings in both depression and schizophrenia. 793 82

(5R,6R)6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3 .2.1]octane (PTAC) is a potent muscarinic receptor ligand with high affinity for central muscarinic receptors and no or substantially less affinity for a large number of other receptors or binding sites including dopamine receptors. The ligand exhibits partial agonist effects at muscarinic M2 and M4 receptors and antagonist effects at muscarinic M1, M3 and M5 receptors. PTAC inhibited conditioned avoidance responding, dopamine receptor agonist-induced behavior and D-amphetamine-induced FOS protein M5 expression in the nucleus accumbens without inducing catalepsy, tremor or salivation at pharmacologically relevant doses. The effect of PTAC on conditioned avoidance responding and dopamine receptor agonist-induced behavior was antagonized by the acetylcholine receptor antagonist scopolamine. The compound selectively inhibited dopamine cell firing (acute administration) as well as the number of spontaneously active dopamine cells (chronic administration) in the limbic ventral tegmental area (A10) relative to the non-limbic substantia nigra, pars compacta (A9). The results demonstrate that PTAC exhibits functional dopamine receptor antagonism despite its lack of affinity for the dopamine receptors and indicate that muscarinic receptor partial agonists may be an important new approach in the medical treatment of schizophrenia.
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PMID:Unexpected antipsychotic-like activity with the muscarinic receptor ligand (5R,6R)6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane . 977 40

The alpha 7-nicotinic receptor (nAChR)-selective agonist choline and nAChR-subtype-selective antagonists led to the discovery that activation of both alpha 7 and alpha 4 beta 2 nAChRs located in CA1 interneurons in slices taken from the rat hippocampus facilitates the tetrodotoxin (TTX)-sensitive release of gamma-aminobutyric acid (GABA). Experiments carried out in cultured hippocampal neurons not only confirmed that preterminal alpha 7 and alpha 4 beta 2 nAChRs modulate the TTX-sensitive release of GABA, but also demonstrated that evoked release of GABA is reduced by rapid exposure of the neurons to acetylcholine (ACh, 10 microM-1 mM) in the presence of the muscarinic receptor antagonist atropine (1 microM). This effect of ACh, which is fully reversible and concentration-dependent, is partially blocked by superfusion of the cultured neurons with external solution containing either the alpha 7-nAChR-selective antagonist methyllycaconitine (MLA, 1 nM) or the alpha 4 beta 2-nAChR-selective antagonist dihydro-beta-erythroidine (DH beta E, 100 nM). A complete blockade of ACh-induced reduction of evoked release of GABA was achieved only when the neurons were perfused with external solution containing both MLA and DH beta E, suggesting that activation of both alpha 7 and alpha 4 beta 2 nAChRs modulates the evoked release of GABA from hippocampal neurons. Such mechanisms may account for the apparent involvement of nAChRs in the psychological effects of tobacco smoking, in brain disorders (e.g., schizophrenia and epilepsy), and in physiological processes, including cognition and nociception.
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PMID:Contribution of nicotinic receptors to the function of synapses in the central nervous system: the action of choline as a selective agonist of alpha 7 receptors. 978 29

While increased dopamine activity is central to our current understanding of the pathophysiology of schizophrenia, dysregulation of a single neurotransmitter is unlikely to explain the disorder adequately. It is argued here that the muscarinic aspects of schizophrenia should be reassessed for a number of reasons. These include current evidence that cholinergic modulation affects both positive and negative symptoms, and neuroendocrine and polysomnographic data that suggest an increased muscarinic cholinergic activity in schizophrenia. In addition, the interactions between the dopaminergic and cholinergic systems are becoming better understood and appear to occur especially in regions that are thought to be relevant is schizophrenia. The fact that the highest affinity of clozapine, with its unique therapeutic profile, is to the muscarinic receptor encourages further evaluation. Finally, the use of anticholinergic agents to treat extrapyramidal side-effects and the fact that many antipsychotic agents have intrinsic anticholinergic activity suggest that the role of the cholinergic system in schizophrenia needs to be more clearly delineated.
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PMID:Cholinergic aspects of schizophrenia. 1021 Nov 33

Clinical studies of cholinergic pharmacotherapy, together with the putative role of the muscarinic receptor system in the neurophysiology of human behavior, support a possible muscarinic cholinergic involvement in schizophrenia. The present study has measured the density of [3H]AF-DX 384 labelled receptors (muscarinic M2 and M4) in the caudate-putamen, obtained at autopsy, from 19 subjects who had schizophrenia, and 20 subjects who did not have schizophrenia. [3H]AF-DX 384 binding was reduced in caudate-putamen from schizophrenic subjects (104 +/- 10.3 vs 145 +/- 901 fmol mg(-1) TE; mean +/- s.e.; p = 0.007). Preliminary analysis of patient drug data as well as rat studies suggest that the reduced [3H]AF-DX 384 binding in caudate-putamen of schizophrenic subjects is not wholly due to antipsychotic drug treatment, or anticholinergic medication for the treatment of extrapyramidal effects. These data suggest that the muscarinic cholinergic system may be involved in the pathology of schizophrenia.
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PMID:The binding of [3H]AF-DX 384 is reduced in the caudate-putamen of subjects with schizophrenia. 1035 30

Xanomeline is an M(1)/M(4) preferring muscarinic receptor agonist which decreased psychotic behaviors in patients with Alzheimer's disease, suggesting that xanomeline might be useful in the treatment of psychotic symptoms in patients with schizophrenia. The purpose of the present studies was, therefore, to compare the pharmacologic profile of xanomeline with that of known antipsychotic drugs. Electrophysiologically, xanomeline, after both acute and chronic administration in rats, inhibited A10 but not A9 dopamine cells in a manner which was blocked by the muscarinic receptor antagonist scopolamine. Behaviorally, xanomeline, like haloperidol, clozapine and olanzapine, blocked dopamine agonist-induced turning in unilateral 6-hydroxydopamine-lesioned rats, as well as apomorphine-induced climbing in mice. However, unlike the dopamine antagonist antipsychotic haloperidol, xanomeline did not produce catalepsy in rats. Moreover, xanomeline, like haloperidol, clozapine and olanzapine, inhibited conditioned avoidance responding in rats, an effect which also was blocked by scopolamine. The present results thus demonstrate that xanomeline has a pharmacologic profile which is similar to that of the atypical antipsychotics clozapine and olanzapine, thus indicating that xanomeline has the potential to be a novel approach in the treatment of psychotic symptoms in patients with schizophrenia.
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PMID:Xanomeline, an M(1)/M(4) preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice. 1078 83

Olanzapine is an atypical antipsychotic with potent antimuscarinic properties in vitro (K(i) = 2-25 nM). We studied in vivo muscarinic receptor occupancy by olanzapine at both low dose (5 mg/dy) and high dose (20 mg/dy) in several regions of cortex, striatum, thalamus and pons by analyzing [I-123]IQNB SPECT images of seven schizophrenia patients. Both low-dose and high-dose olanzapine studies revealed significantly lower [I-123]IQNB binding than that of drug-free schizophrenia patients (N = 12) in all regions except striatum. [I-123]IQNB binding was significantly lower at high-dose than low-dose in the same regions. Muscarinic occupancy by olanzapine ranged from 13% to 57% at 5 mg/dy and 26% to 79% at 20 mg/dy with an anatomical pattern indicating M(2) subtype selectivity. The [I-123]IQNB data indicate that olanzapine is a potent and subtype-selective muscarinic antagonist in vivo, perhaps explaining its low extrapyramidal side effect profile and low incidence of anticholinergic side effects.
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PMID:In vivo olanzapine occupancy of muscarinic acetylcholine receptors in patients with schizophrenia. 1086 86

Heterotrimeric G proteins play a pivotal role in post-receptor information transduction and were previously implicated in the pathophysiology and treatment of mood disorders. Changes previously detected in G protein levels in post-mortem brain of patients with schizophrenia could reflect effects of antipsychotic medication. The present study aims at quantitatively and functionally evaluating receptor-coupled G proteins in mononuclear leukocytes obtained from 23 untreated patients with schizophrenia and 30 healthy subjects in an attempt to unravel a pattern of G protein measures in schizophrenia distinctive from patterns previously obtained in mood disorders. Dopamine-enhanced guanine nucleotide binding capacity to G(s) protein through D1/D5 receptor in mononuclear leukocytes of untreated patients with schizophrenia was significantly increased in comparison with healthy subjects, and positively correlated with both the total PANSS score and the positive subscale. beta-Adrenergic and muscarinic receptor-coupled G protein functions, as well as G(s)alpha, G(i)alpha and Gbeta immunoreactivities, were similar to healthy subjects. These findings, distinctive for schizophrenia, unrelated to drug treatment, and differential from previous findings in mania and depression, may potentially help to differentially diagnose, after the first psychotic episode, between the major psychoses: schizophrenia and manic-depressive illness.
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PMID:Elevated dopamine receptor-coupled G(s) protein measures in mononuclear leukocytes of patients with schizophrenia. 1116 43

Dopamine D3 receptors have been implicated in the aetiology of schizophrenia and the actions of antipsychotic drugs. The initial studies reported here assessed the involvement of such receptors in the in vivo actions of the atypical antipsychotic clozapine and the putative D3-preferring antagonist PNU-99194A in drug discrimination assays. Rats trained to discriminate clozapine consistently generalized to PNU-99194A in two separate studies. However, four other putative D3-preferring antagonists (PD 152255, (+)-S14297, nafadotride and (+)-AJ 76) did not induce generalization to clozapine. In rats trained to discriminate PNU-99194A, which has been suggested to induce a stimulus mediated specifically by D3 antagonism, the D3-preferring antagonist (+)-UH 232 and clozapine both induced full generalization. However, the PNU-99194A-trained animals also generalized fully to the muscarinic antagonists scopolamine and trihexyphenidyl. A possible explanation for the symmetrical generalization observed between clozapine and PNU-99194A is that these drugs have common muscarinic antagonist actions, since muscarinic antagonists have been reported to substitute for clozapine in numerous prior studies. However, in vitro receptor binding studies with M1-M5 receptors indicated that (with the possible exception of the M4 receptor), no muscarinic receptor subtype had high affinity for both clozapine, PNU-99194A and scopolamine. In addition, other binding studies indicated that whereas clozapine and PNU-99194A had high affinity for the D3 receptor, scopolamine did not. It is therefore concluded that: (1) The generalization seen between clozapine, PNU-99194A and muscarinic antagonists may be mediated by common effects 'downstream' from either muscarinic or D3 receptors; (2) D3 antagonism does not play a critical role in the clozapine stimulus (since D3-preferring antagonists did not consistently induce generalization to clozapine); (3) although D3 antagonism plays a role in the PNU-91994A stimulus (since the D3-preferring antagonist (+)-UH 232 induced full generalization, in accord with results from prior studies with other D3-preferring antagonists, the PNU-99194A stimulus also has commonalities with that induced by muscarinic antagonists and clozapine. The in vivo differences observed between PNU-99194A and other D3-preferring antagonists should be borne in mind when this agent is used as a tool to study D3 receptor functioning in vivo. The similarities between the PNU-99194A and clozapine stimuli suggest tentatively that compounds with a profile like PNU-99194A may have antipsychotic actions similar to clozapine. Some preclinical data are suggestive of such effects of PNU-99194A.
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PMID:Common discriminative stimulus properties in rats of muscarinic antagonists, clozapine and the D3 preferring antagonist PNU-99194a: an analysis of possible mechanisms. 1171 Jul 45


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