UMLS:C0036341 - FACTA Search

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

1 Kryptopyrrole (2, 4-dimethyl, 3-ethylpyrrole) inhibited conduction in rat sciatic nerve by a local anaesthetic action. 2 Tone and both spontaneous and electrically-induced contractions of guinea-pig ileum were also inhibited by kryptopyrrole. The concentration of kryptopyrrole required for 50% inhibition of a maximum twitch tension (ID50) was 0.085 mM. 3 Oxidation products of kryptopyrrole with chromatographic properties similar to those of urinary constituents reported in schizophrenia and hepatic porphyrias had little or no effect at similar concentrations. 4 Dose-response curves to exogenous acetylcholine in guinea-pig ileum were shifted to the right by kryptopyrrole, with loss of parallelism and reduction in the maximum contraction. 5 Acetylcholine overflow from ileal segments at rest and during electrical stimulation was reduced by kryptopyrrole. 6 These results on ileal segments are consistent with kryptopyrrole having both a post-junctional site of action, presumably directly on the muscle, and a pre-junctional site reducing the output of acetylcholine from the myenteric plexus. 7 The significance of these findings is discussed in relation to a possible clinical pathological role for these compounds.
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PMID:Pharmacological properties of kryptopyrrole and its oxidation products on isolated sciatic nerve of rat and on guinea-pig ileum. 76 Aug 88

Based on the implication of increased muscarinic ACh activity in the production of negative symptoms, the association of decreasing cholinergic activity with positive symptoms, and the covariance of positive and negative symptoms in the psychotic phase of schizophrenia, a model of (DA) dopaminergic/(ACh) cholinergic interactions in schizophrenia was recently formulated. It suggests that DA/ACh balance is of central importance in schizophrenic pathophysiology and that muscarinic ACh activity increases in an attempt to maintain this balance in the face of increasing DA activity that occurs in the psychotic phase of the illness. The model further suggests that the muscarinic system exerts a damping influence on the emergence of positive symptoms associated with DA hyperactivity, but that this compensatory increase in muscarinic activity is accompanied by an intensification of negative symptoms. In the present study, we tested two important postulates of this model. We tested the prediction that muscarinic activity is increased in schizophrenia by comparing the effect of biperiden, an antimuscarinic M-1 agent, on REM latency in 12 drug-free schizophrenic inpatients and matched normal controls. We found that biperiden caused a smaller increase in REM latency in schizophrenic patients, suggesting that muscarinic activity is increased in schizophrenia. We tested the prediction that an anticholinergic agent would increase positive symptoms and decrease negative symptoms by studying the effect of 8 mg of biperiden/day for 2 days on positive and negative symptoms (assessed by the BPRS) in 30 medication-free schizophrenic inpatients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Muscarinic cholinergic hyperactivity in schizophrenia. Relationship to positive and negative symptoms. 200 53

The present review deals with the molecular mechanisms and elementary phenomena underlying the activation of the voltage- and chemo-sensitive membrane macromolecules: sodium- and potassium-ion channels and nicotinic ACh receptors and their associated ion channel. To achieve an understanding of their various kinetics and conformational states, a number of novel alkaloids, BTX, HTXs, gephyrotoxins, and certain psychotomimetic drugs such as phencyclidine, and many other pharmacologically active agents have been used. Biochemical assays and various electrophysiological techniques have been used in a number of biological preparations--e.g., Torpedo membranes, brain synaptosomes, amphibian and mammalian neuromuscular preparations--to describe the action of such agents. The availability of BTX and scorpion toxins together with aconitine and veratridine as activators and TTX and STX as antagonists of the voltage-sensitive sodium channels, made possible the identification and the physiological and pharmacological characterization of these channels. These studies provided the basis for understanding the mechanisms underlying electrical excitability and culminated, more recently, in the purification and reconstitution of sodium channels from rat brain and in the successful cloning of these channels with the elucidation of their primary structure. We now know that the sodium channel has a molecular mass of 316,000 daltons, consists of five subunits, and has multiple sites for various ligands. In contrast to sodium channels, various classes of potassium channels (inward and outward rectifier potassium channels and Ca(2+)-activated potassium channels) have been described. Unlike the sodium channels, there are no known specific activators for potassium channels. However, a number of potassium channel blockers such as 4-aminopyridine, HTX, histamine, and norepinephrine have been identified which complement the varying types of potassium channels in different neurons. One class of potassium channel blockers with profound medical and social implications comprises PCP and its analogues. The blockade of the potassium-induced 86Rb+ efflux from brain cells, the resulting prolongation of muscle and nerve action potentials, and the increase in transmitter release observed with PCP and some analogues are all highly suggestive of a role for the potassium channel in the behavioral effects of these drugs and its potential involvement in schizophrenia. A number of toxic principles of both plant and animal origin played a significant role in the development of our knowledge about the nAChR.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Macromolecular sites for specific neurotoxins and drugs on chemosensitive synapses and electrical excitation in biological membranes. 248 4

Acetylcholine is a neurotransmitter that has been implicated in the pathophysiology of major depression. This is supported by the enhanced growth hormone (GH) release in response to pyridostigmine (PYD) challenge in depressed subjects relative to healthy comparison subjects. The aim of this study is to examine the specificity of the PYD/GH challenge in the diagnosis of depression. Pyridostigmine 120 mg orally, was administered to a total of 116 physically healthy subjects. Growth hormone responses were studied in 38 patients with (DSM-III-R) major depression, 13 subjects with panic disorder, 9 subjects with schizophrenia, 10 recently detoxified alcoholics, and a comparison group of 46 healthy volunteers. Mean delta GH (the difference between basal and maximal GH following PYD) was significantly greater than comparison subjects in patients with major depression. Responses observed in patients with schizophrenia and alcohol dependence syndrome did not differ from the comparison group. Those patients with panic disorder and a high Hamilton depression score had an enhanced delta GH. The sensitivity of the PYD/GH test was 63% for major depression. These results indicate that the PYD/GH test may help distinguish depression from schizophrenia, alcohol-dependence syndrome, or panic disorder with a low Hamilton depression score.
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PMID:Specificity of the pyridostigmine/growth hormone challenge in the diagnosis of depression. 934 32

Nicotine is a very widely used drug of abuse, which exerts a number of neurovegetative, behavioural and psychological effects by interacting with neuronal nicotinic acetylcholine receptors (NAChRs). These receptors are distributed widely in human brain and ganglia, and form a family of ACh-gated ion channels of different subtypes, each of which has a specific pharmacology and physiology. As human NAChRs have been implicated in a number of human central nervous system disorders (including the neurodegenerative Alzheimer's disease, schizophrenia and epilepsy), they are suitable potential targets for rational drug therapy. Much of our current knowledge about the structure and function of NAChRs comes from studies carried out in other species, such as rodents and chicks, and information concerning human nicotinic receptors is still incomplete and scattered in the literature. Nevertheless, it is already evident that there are a number of differences in the anatomical distribution, physiology, pharmacology, and expression regulation of certain subtypes between the nicotinic systems of humans and other species. This review will attempt to survey the major achievements reached in the study of the structure and function of NAChRs by examining the molecular basis of their functional diversity viewed mainly from pharmacological and biochemical perspectives. It will also summarize our current knowledge concerning the structure and function of the NAChRs expressed by other species, and the newly discovered drugs used to classify their numerous subtypes. Finally, the role of NAChRs in behaviour and pathology will be considered.
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PMID:Human neuronal nicotinic receptors. 936 11

Nicotinic cholinergic systems are involved with several important aspects of cognitive function including attention, learning and memory. Nicotinic cholinergic receptors are located in many regions of the brain, including areas important for cognitive function such as the hippocampus and frontal cortex. Nicotinic agonists have been found in rodent and non-human primate studies to improve performance on a variety of memory tasks. In a complementary fashion, nicotinic antagonists such as mecamylamine impair working memory function. In humans, similar effects have been seen. Nicotinic agonist treatment can improve attention, learning and memory and nicotinic antagonist treatment can cause deficits. To define the neural substrates of nicotinic involvement in cognitive function, three areas of investigation are underway. 1) Critical neuroanatomic loci for nicotinic effects are beginning to be determined. The hippocampus, frontal cortex and midbrain dopaminergic nuclei have been found to be important sites of action for nicotinic involvement in memory function. 2) Nicotinic receptor subtype involvement in cognitive function is being studied. There has been considerable recent work identifying nicotinic receptor subunit conformation including alpha and beta subunits. Nicotinic receptor subtypes appear to be associated with different functional systems; however, much remains to be done to determine the precise role each subtype plays in terms of cognitive function. 3) Nicotinic interactions with other transmitter systems are being assessed. Nicotine receptors interact in important ways with other systems to affect cognitive functioning, including muscarinic ACh, dopamine, norepinepherine, serotonin, glutamate, and other systems. Nicotinic function in clinical populations and potential for therapeutics has been investigated for Alzheimer's disease, Parkinson's disease, schizophrenia and attention deficit/hyperactivity disorder. Areas which need to receive greater attention are the exact anatomical location and the specific receptor subtypes critically involved in nicotine's effects. In addition, more work needs to be done to develop and determine the efficacy and safety of novel nicotinic ligands for use in the long-term treatment of human cognitive disorders.
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PMID:Nicotinic acetylcholine involvement in cognitive function in animals. 972 45

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

Phencyclidine (PCP) is a drug of abuse that produces schizophrenia-like symptoms in humans and increases locomotor activity and stereotypic behavior in rodents. PCP-induced alteration in rat locomotor activity is thought to be mediated by an inhibition of N-methyl-D-aspartate (NMDA) receptors in the striatum and other brain regions. In this study, rats treated chronically with PCP (20 mg/kg once per day for 5 days) showed a marked increase in locomotor activity following a PCP challenge (3.2 mg/kg) administered after either 3 or 8 days of withdrawal. In biochemical assays, the release of striatal [14C]GABA by NMDA was enhanced by about 77% by chronic PCP treatment, whereas [3H]ACh release was increased by about 31% in tissue from PCP-treated rats. Even though binding experiments with 1-[1-(2-thiethyl)cyclohexyl]piperidyl-3,4 3H(N) ([3H]TCP) showed no alteration in the Kd or Bmax in whole striatum, quantitative immunocytochemical experiments found an upregulation in the NR1 subunit in the cell bodies and neuropil of cortical and striatal regions of the forebrain following chronic PCP treatment. An increase in the size of NR1-immunoreactive cells in the forebrain was also observed following chronic PCP treatment. Together, these data may help in understanding the mechanisms underlying the adaptive response to chronic reduction in glutamatergic NMDA transmission that has been postulated to be involved in the etiology of schizophrenia.
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PMID:Augmentation of locomotor activity by chronic phencyclidine is associated with an increase in striatal NMDA receptor function and an upregulation of the NR1 receptor subunit. 1002 41

The present report describes the participation of nicotinic receptors (nAChRs) in controlling the excitability of local neuronal circuitries in the rat hippocampus and in the human cerebral cortex. The patch-clamp technique was used to record responses triggered by the non-selective agonist ACh and the alpha7-nAChR-selective agonist choline in interneurons of human cerebral cortical and rat hippocampal slices. Evidence is provided that functional alpha7- and alpha4beta2-like nAChRs are present on somatodendritic and/or preterminal/terminal regions of interneurons in the CA1 field of the rat hippocampus and in the human cerebral cortex and that activation of the different nAChR subtypes present in the preterminal/terminal areas of the interneurons triggers the tetrodotoxin-sensitive release of GABA. Modulation by nAChRs of GABAergic transmission, which can result either in inhibition or disinhibition of pyramidal neurons, depends both on the receptor subtype present in the interneurons and on the agonist acting upon these receptors. Not only do alpha7 nAChRs desensitize faster than alpha4beta2 nAChRs, but also alpha7 nAChR desensitization induced by ACh lasts longer than that induced by choline. These mechanisms, which appear to be retained across species, might explain the involvement of nAChRs in cognitive functions and in such neurological disorders as Alzheimer's disease and schizophrenia.
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PMID:Neuronal nicotinic receptors in synaptic functions in humans and rats: physiological and clinical relevance. 1094 40

Patients with chronic schizophrenia suffer from alterations in cholinergic functioning due to several factors, including the disease diathesis and pharmacologic treatments. Acetylcholine-cognition relationships are well explored in normals but are unclear in schizophrenia. Prior work indicated serum anticholinergicity does not cause global cognitive impairment in this group (Tracy et al., 1998a), raising the possibility that anticholinergicity normalizes an abnormal hyperactive cholinergic state. Serum anticholinergic levels were determined in 38 chronic schizophrenia patients using an established radioreceptor assay method. Six cognitive functions associated with cholinergic tone in normals were tested. The potential role of autonomic arousal and cigarette smoking were also assessed as both have been linked to cholinergic functioning. Regression analyses showed measures of inhibitory executive control and effortful memory accounted for a greater proportion of the variance in the anticholinergicity measure compared to the other variables. The data demonstrate a relationship between high anticholinergicity and worse performance on two types of attention-resource demanding cognitive processes and do not support the notion that reduced cholinergic tone normalizes a hyperactive cortical acetylcholine substrate. Relevant neuroanatomic structures and implications for models of cognitive deficits in schizophrenia are discussed.
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PMID:Anticholinergicity and cognitive processing in chronic schizophrenia. 1124 Mar 12

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