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)

Polymorphism of serum cholinesterase (SCE, acylcholinacylhydrolase, EC 3.1.1.8) for the E1 locus was studied in the groups of the patients affected with schizophrenia, peptic ulcer, hereditary erythrocytopathies, tuberculosis, thyreotoxicosis, essential hypertension and rheumatic disease. Increased frequencies of I phenotypes (E1uE1a genotype) were found among patients with peptic ulcer (12.3%), hereditary erythrocytopathies (23.2%), and UF phenotypes (E1uE1f genotype) were observed among patients with schizophrenia (2.8%) and tuberculosis (5.4%). The increased frequencies of E1a and E1f alleles in these groups of patients were, as compared to the control group, statistically significant. The value of relative risk for peptic ulcer was 3.39 in individuals of the E1uE1a genotype, those being 3.62 for schizophrenia and 6.92 for tuberculosis in individuals of the E1uE1f genotype. The nature of the other associations is discussed.
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PMID:[Association of mutant alleles of serum cholinesterase with various multi-factorial and infectious diseases]. 347 79

Cholinergic processes were measured in plasma and red blood cells (RBC) obtained from patients with mania, depression, and schizophrenia. RBC choline levels were elevated in manic patients, and lithium treatment led to a further increase. RBC choline transport was below normal in manic patients, and lithium treatment further reduced choline transport in addition to reducing the apparent affinity for choline. RBC acetylcholinesterase was low in depressed and schizophrenic patients, but not in manic patients, whereas plasma acetylcholinesterase was reduced only in depressed patients. Plasma nonspecific cholinesterase was below normal in all groups of patients. These results indicate unique patterns of differences from controls in the cholinergic system in blood samples from patients with different psychiatric illnesses.
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PMID:Cholinergic processes in blood samples from patients with major psychiatric disorders. 406 16

More than a decade of scientific inquiry into the biochemistry of schizophrenia has been organized by the dopamine hypothesis. The evidence that neuroleptics reduce brain dopamine activity is compelling and derives from both human and animal studies. In addition, agents which enhance brain dopamine activity, such as amphetamine or cocaine, can cause a syndrome that can be indistinguishable from acute paranoid schizophrenia. However, a major problem with the dopamine hypothesis is the lack of strong direct evidence of altered dopamine concentrations or metabolism when measured in large groups of schizophrenic subjects. The idea that schizophrenia is more than one illness is an old concept, but it finds increasing support in new studies of the clinical phenomenology, genetics, and biochemistry of schizophrenic patients. The revival of the concept of multiple forms of schizophrenia, in turn, has fostered the development of new biochemical hypotheses of the disorder. These hypotheses propose that neurotransmitters, other than dopamine, may be involved in schizophrenic symptoms. Reports of elevated concentrations of norepinephrine is specific areas of the brain and in the spinal fluid have led to the hypothesis that norepinephrine may be involved in schizophrenia. At least two groups of investigators have suggested that phenylethylamine might be involved in schizophrenia. In part, this proposal is based on the structural and pharmacological similarities of phenylethylamine and amphetamine. gamma-Aminobutyric acid (GABA) is an important inhibitory neurotransmitter. Evidence for the inhibitory influence of GABA-ergic neurons on dopaminergic neurons has led to the hypothesis that decreased GABA-ergic activity may be involved in producing schizophrenic symptoms. Studies with the reversible acetylcholinesterase inhibitor physostigmine and the dopamine agonist methylphenidate have led to the suggestion that acetylcholine and dopamine imbalance may be involved in schizophrenia. This hypothesis is one example of the idea that altered balance between several neurotransmitters may underlie schizophrenia. The recent discovery of the endorphins has led to speculations about the possible role of these substances in schizophrenia. Both an excess and a deficiency of endorphin activity have been implicated in schizophrenia, and speculative evidence has been used to support both hypotheses. The ultimate aim of the search for biochemical defects in schizophrenia is the development of rational drug treatments which will correct these defects and in doing so, these drugs will provide effective treatments for patients with schizophrenic symptoms.
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PMID:Biochemistry and the schizophrenia. Old concepts and new hypothesis. 700 86

We report a 60-yr-old woman with schizophrenia, who manifested a neuroleptic malignant (NM)-like syndrome after acute organophosphate poisoning (OPP). She attempted suicide by ingesting 40% emulsions of DMTP (S-2,3-dihydro-5-methoxy-2-oxo-1,3,4-thiadizol-3-yl-methyl O,O-dimethyl phosphorodithioate) 100 ml. On admission, she was unconscious and demonstrated convulsions, depressed respiratory movements, miosis and profuse salivation. Plasma cholinesterase concentration (842 IU.L-1) was very low and OPP was diagnosed. She was treated with gastric lavage, atropine and pralidoxime (PAM). By the seventh day after admission, symptoms of OPP disappeared and serum ChE had recovered to a sub-normal level. On the 13th day, she demonstrated coma, high fever (41.0 degrees C) and lead-pipe rigidity. Serum CPK was increased (1631 IU.L-1). Dantrolene sodium iv was administered for three days. Body temperature began to decrease in 24 hr, and her consciousness, muscle rigidity and other neurological symptoms returned to normal by the 16th day after admission. She was discharged from the hospital without sequelae 55 days after admission. We conclude that OPP can predispose to an NM-like syndrome and that dantrolene may be effective in the management.
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PMID:Neuroleptic malignant-like syndrome: a complication of acute organophosphate poisoning. 859 Apr 92

The primary pathology in Alzheimer's disease (DAT) occurs in the basal forebrain cholinergic system (BFCS), which provides the major cholinergic innervation to the neocortex, hippocampus and amygdala. Consistent with the 'cholinergic hypothesis' of dementia in DAT, the most effective treatments so far developed for DAT are drugs which act to boost the functions of the BFCS. These include the centrally acting cholinesterase inhibitor tacrine, and the cholinergic agonist nicotine, acute administration of which leads to an improvement in attentional functions, in line with recent animal studies of the role of the BFCS in cognition. We conclude that future research should include the development of more potent, longer-lasting, less toxic cholinergic agents, which appear to be the best candidates for alleviating the cognitive symptomatology of DAT. Such drugs may also be useful in the treatment of a number of other cognitive disorders, including Lewy body dementia, attention deficit/hyperactivity disorder, and schizophrenia.
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PMID:The cognitive psychopharmacology of Alzheimer's disease: focus on cholinergic systems. 956 19

1. Extracellular single-unit recording and iontophoresis were used to examine the effects of different cholinoceptor agonists and antagonists on the firing rate and firing pattern of A9 and A10 presumed dopaminergic neurones in the anaesthetized rat. 2. Administration of low currents (1-5 nA) of the selective muscarinic agonists oxotremorine M (Oxo M) and muscarine and of the non-selective muscarinic/nicotinic agonist carbamylcholine (CCh) produced a dose-dependent increase in firing rate in most of the A9 and A10 presumed dopaminergic neurones tested. Oxo M-induced activation could be completely blocked by iontophoretic application of the muscarinic antagonist butyl-scopolamine or systemic administration of the muscarinic antagonist scopolamine (300 microg kg(-1), i.v.). 3. Iontophoretic application of the selective nicotinic agonist methylcarbamylcholine (MCCh), but not nicotine, induced a consistent increase in firing rate. Surprisingly, the excitatory effect of MCCh was significantly reduced by the selective muscarinic antagonist scopolamine (300 microg kg(-1), i.v.), but not by the selective nicotinic antagonist mecamylamine (2.2 mg kg(-1), i.v.). Mecamylamine (3 mg kg(-1), i.v.) was also ineffective in reducing the CCh-induced activation of presumed dopamine neurones, suggesting that both CCh and MCCh increased the activity of dopamine neurones via an interaction with muscarinic receptors. 4. Iontophoretic application of the endogenous agonist acetylcholine (ACh) had no or little effect on the firing activity of A10 presumed dopaminergic neurones. However, concomitant application of neostigmine, a potent cholinesterase inhibitor, with acetylcholine induced a substantial activation of these neurones. This activation consisted of two components; one, which was prevalent, was scopolamine (300 microg kg(-1), i.v.)-sensitive, and the other was mecamylamine (2 mg kg(-1), i.v.)-sensitive. 5. In addition to their effect on firing activity, Oxo M, muscarine and concomitant neostigmine/ACh caused a significant increase in burst firing of A10 neurones, but not of A9 neurones. 6. These data suggest that dopamine cells, both in the A9 and A10 regions, possess functional muscarinic receptors, the activation of which can increase their firing rate and, for A10 neurones, their amount of burst activity. These cholinoceptors would be able to influence the activity of the midbrain dopamine system greatly and may play a role in, and/or be a therapeutic target for, brain disorders in which dopamine is involved (e.g., Parkinson's disease, drug addiction and schizophrenia).
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PMID:Activation of midbrain presumed dopaminergic neurones by muscarinic cholinergic receptors: an in vivo electrophysiological study in the rat. 964 68

There is recognition that the cognitive symptoms of schizophrenia have the most substantial impact on illness outcome. Domains of cognition reported to be significantly affected include serial learning, executive function, vigilance, and distractibility, to name a few. Dopamine activity at D1 receptors mediates many cognitive processes subserved by the prefrontal cortex (PFC), particularly working memory. The number of D1 receptors in the PFC is decreased in schizophrenics and is unaffected by chronic administration of typical neuroleptics. Therefore, medications that increase dopamine in the PFC, such as atypical neuroleptics, or that directly activate the D1 receptor may prove useful in the remediation of prefrontal-dependent cognitive deficits in schizophrenia. Decreased levels of cortical norepinephrine (NE) are associated with impaired learning and working memory in animal models, and can be reversed by drugs that restore NE activity. More specifically, alpha-2 adrenergic receptor agonists have been particularly effective in improving delayed response performance in young monkeys with localized 6-hydroxydopamine lesions in the PFC. Furthermore, human postmortem studies have demonstrated decreased NE in the frontal cortex of demented schizophrenic patients. Therefore, alpha-2 receptor agonists hold promise as drugs to improve cognitive performance on tasks dependent upon PFC function in schizophrenics. Finally, the finding that cortical choline acetyl transferase activity correlates with Clinical Dementia Rating scores in schizophrenic patients and that cholinomimetic drugs enhance cognition in healthy subjects suggests that cholinergic drugs may also treat cognitive symptoms in schizophrenia. Two potential types of cholinomimetics for use in schizophrenics are the acetylcholinesterase inhibitors and M1/M4 muscarinic agonists, both of which increase cortical cholinergic activity.
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PMID:Pharmacologic strategies for augmenting cognitive performance in schizophrenia. 989 70

Latent inhibition consists of a decrement in conditioning to a stimulus as a result of its prior non-reinforced pre-exposure. Based on evidence pointing to the involvement of the hippocampus and the nucleus accumbens in latent inhibition disruption, it has been proposed that latent inhibition depends on the integrity of the subicular input to the nucleus accumbens. Since fibers originating in the subiculum and destined for the nucleus accumbens run through the fimbria-fornix, we assessed the effects of radiofrequency lesion or transection of the fimbria-fornix, on latent inhibition. The effectiveness of both lesions was demonstrated by the total disappearance of acetylcholinesterase staining in the hippocampus and of retrogradely labeled cells in the hippocampus/subiculum following the injection of the retrograde tracer biotin-dextran amine into the shell subregion of the nucleus accumbens. Likewise, in accord with previously documented behavioral effects of lesions to the hippocampus and related structures, both lesions increased spontaneous activity and disrupted performance in Morris water maze, and the radiofrequency lesion facilitated the acquisition of two-way active avoidance. In spite of the above, latent inhibition remained unaffected by both fimbria-fornix lesions, indicating that the critical projections subserving latent inhibition are not those traversing the fimbria-fornix from the hippocampus/subiculum to the nucleus accumbens. The implications of these results for the neural circuitry of latent inhibition and the latent inhibition model of schizophrenia are discussed.
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PMID:The effects of radiofrequency lesion or transection of the fimbria-fornix on latent inhibition in the rat. 1039 42

The role of noradrenergic neurotransmission in normal cognitive functions has been extensively investigated, however, the involvement of noradrenergic functions in the cognitive impairment associated with schizophrenia and Alzheimer's disease has not been as intensively considered. The limited ability of atypical antipsychotics to treat the cognitive impairment of schizophrenia, and cholinomimetics to treat the cognitive impairment of Alzheimer's disease, may be related to the influence of a multiplicity of neurotransmitter abnormalities including noradrenergic dysfunction, which these treatments do not address. The evidence of noradrenergic dysfunction occurring concomitantly with dopamine dysfunction in schizophrenia and acetylcholine dysfunction in Alzheimer's disease supports therapeutic approaches using noradrenergic drugs in combination with neuroleptics and cholinesterase inhibitors, respectively, to enhance the treatment of cognitive impairment. Given the results of animal and human studies, it appears that alpha-2A agonists may be the optimal choice for this purpose.
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PMID:The role of norepinephrine in the pathophysiology of cognitive disorders: potential applications to the treatment of cognitive dysfunction in schizophrenia and Alzheimer's disease. 1056 29

Because of the demonstration of a selective alpha nicotinic receptor abnormality in patients with schizophrenia, galantamine was added to the stable regimen of atypical and other antipsychotic medications in a 43-year-old man manifesting severe and persistent positive and negative symptoms, as well as mood disturbance and cognitive dysfunction. Galantamine is an inhibitor of acetylcholinesterase and a positive allosteric modulator of nicotinic cholinergic receptors (with a FDA-approved indication for the treatment of patients with mild to moderate Alzheimer disease (AD) under the trade name Reminyl). Galantamine HBr was initiated at a dose of 4 mg po BID, which was maintained for the first week of adjuvant therapy, and eventually was increased to 12 mg po BID during the final weeks of his 2-month trial. Remarkably, within 1 week of its initiation, there was a dramatic and clinically significant decrease of negative symptoms, as reflected in formal ratings on the Scale for the Assessment of Negative Symptoms. Moreover, within a few days of galantamine discontinuation, negative symptoms worsened, returning to the baseline level of severity. In addition to targeting memory dysfunction in AD, acetylcholinesterase inhibitors may have an expanded range of targets and clinical indications, including behavioral and psychotic symptoms. Galantamine is distinguished from other acetylcholinesterase inhibitors by its positive allosteric modulatory properties, improving the efficiency of transduction of the acetylcholine signal at nicotinic receptors. This latter property may have contributed to the observed improvement in negative symptoms observed in this patient. Importantly, positive symptoms were unchanged during this 2-month trial.(7)
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PMID:Adjuvant galantamine administration improves negative symptoms in a patient with treatment-refractory schizophrenia. 1241 61


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