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)

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

The mode of action by which the atypical antipsychotic drug clozapine exerts its superior efficacy to ameliorate both positive and negative symptoms is still unknown. In the present in vivo electrophysiological study, we investigate the effects of haloperidol (a typical antipsychotic drug) and clozapine on ventral tegmental area (VTA) dopamine (DA) neurons in a situation of hyperdopaminergic activity in order to mimic tentatively a condition similar to that seen in schizophrenia. Increased DA transmission was induced by elevating endogenous levels of the N-methyl-D-aspartate receptor and alpha7(*) nicotinic receptor antagonist kynurenic acid (KYNA; by means of PNU 156561A, 40 mg /kg, i.v.). In control rats, i.v. administered haloperidol (0.05-0.8 mg/kg) or clozapine (1.25-10 mg/kg) was associated with increased firing rate and burst firing activity of VTA DA neurons. However, in rats displaying hyperdopaminergia (induced by elevated levels of KYNA), the effects of clozapine on VTA DA neurons were converted into pure inhibitory responses, including decrease in burst firing activity. In contrast, haloperidol still produced an excitatory action on VTA DA neurons in rats with elevated levels of endogenous brain KYNA. The results of the present study suggest that clozapine facilitates or inhibits VTA DA neurotransmission, depending on brain concentration of KYNA. Such an effect of clozapine may be related to its unique effect in also ameliorating negative symptoms of schizophrenia.
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PMID:Inhibitory action of clozapine on rat ventral tegmental area dopamine neurons following increased levels of endogenous kynurenic acid. 1286 92

In recent years the "dopamine (DA) hypothesis of schizophrenia", has been modified into a more diversified view where an attenuated glutamatergic neurotransmission is believed to participate in the pathogenesis of the disease. Thus, schizophrenia may be regarded as a glutamate deficiency disorder. Kynurenic acid (KYNA) is an endogenous glutamate antagonist with a preferential action at the glycinesite of the N-methyl D-aspartate (NMDA)-receptor. Mounting evidence indicates that the compound is significantly involved in basal neurophysiological processes in the brain. Thus, in anaesthetized rats, pharmacologically elevated KYNA concentration (by means of PNU 156561A) was associated with increased firing rate and burst firing activity of midbrain DA neurons. Similar alterations in basal firing characteristics are also observed following systemic administration of PCP or ketamine, indicating per se that elevated levels of brain KYNA is associated with psychotomimetic effects. Indeed, cerebrospinal fluid (CSF) level of kynurenic acid was elevated in 28 male first episode schizophrenic patients (1.67 +/- 0.27 nM) as compared to 17 male healthy controls (0.97 +/- 0.07 nM. Elevated brain KYNA concentration was also found to dramatically affect the responsivity of rat midbrain DA neurons to the atypical antipsychotic drug clozapine. Thus, whereas clozapine produced increased firing rate and burst firing activity of these neurons in untreated rats, elevation of brain KYNA levels was found to reverse the action of clozapine into a pure inhibitory response. The present study suggests a contribution of KYNA in the pathogenesis of schizophrenia and link the dopamine hypothesis of schizophrenia together with the idea of a deficiency of glutamate function in this disease.
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PMID:Kynurenic acid and schizophrenia. 1520 28

Schizophrenic patients are thought to have an impaired ability to process sensory information. This deficit leads to disrupted auditory gating measured electrophysiologically as a reduced suppression of the second of paired auditoryevoked responses (P50) and is proposed to be associated with decreased function and/or expression of the homomeric alpha7 nicotinic acetylcholine receptor (nAChR). Here, we provide evidence that N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride (PNU-282987), a novel selective agonist of the alpha7 nAChR, evoked whole-cell currents from cultured rat hippocampal neurons that were sensitive to the selective alpha7 nAChR antagonist methyllycaconitine (MLA) and enhanced GABAergic synaptic activity when applied to hippocampal slices. Amphetamine-induced sensory gating deficit, determined by auditory-evoked potentials in hippocampal CA3 region, was restored by systemic administration of PNU-282987 in chloral hydrate-anesthetized rats. Auditory gating of rat reticular thalamic neurons was also disrupted by amphetamine; however, PNU-282987 normalized gating deficit only in a subset of tested neurons (6 of 11). Furthermore, PNU-282987 improved the inherent hippocampal gating deficit occurring in a subpopulation of anesthetized rats, and enhanced amphetamine-induced hippocampal oscillation. We propose that the alpha7 nAChR agonist PNU-282987, via modulating/enhancing hippocampal GABAergic neurotransmission, improves auditory gating and enhances hippocampal oscillatory activity. These results provide further support for the concept that drugs that selectively activate alpha7 nAChRs may offer a novel, potential pharmacotherapy in treatment of schizophrenia.
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PMID:The selective alpha7 nicotinic acetylcholine receptor agonist PNU-282987 [N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride] enhances GABAergic synaptic activity in brain slices and restores auditory gating deficits in anesthetized rats. 1552 1

The major brain noradrenergic nucleus locus coeruleus (LC) has long been thought to be involved in states of alertness and cognitive processes. These functional characteristics make this nucleus interesting with regard to the signs of schizophrenia, especially the negative symptoms of the disease. In the present in-vivo electrophysiological study we analyse a putative interaction between endogenous kynurenic acid (KYNA) and the antipsychotic drugs clozapine and haloperidol on noradrenergic LC neurons. Previous studies have shown that systemically administered antipsychotic drugs increase the neuronal activity of LC noradrenaline (NA) neurons. In line with these findings, our results show that clozapine (1.25-10 mg/kg i.v.) and haloperidol (0.05-0.08 mg/kg i.v.) increased the firing rate of LC NA neurons in anaesthetized rats. Pretreatment with PNU 156561A (40 mg/kg i.v., 3 h), a potent inhibitor of kynurenine 3-hydroxylase, produced a 2-fold increase in rat brain KYNA levels. This treatment prevented the increase in firing rate of LC NA neurons induced by haloperidol (0.05-0.08 mg/kg i.v.) and clozapine in high doses (2.5-10 mg/kg i.v.). However, the excitatory action of the lowest dose of clozapine (1.25 mg/kg i.v.) was not abolished by elevated levels of brain KYNA. Furthermore, pretreatment with L-701,324 (4 mg/kg i.v.) a selective antagonist at the glycine site of the NMDA receptor prevented the excitatory effects of both clozapine and haloperidol. The present results suggest that the excitation of LC NA neurons by haloperidol and clozapine involves a glutamatergic component.
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PMID:Activation of noradrenergic locus coeruleus neurons by clozapine and haloperidol: involvement of glutamatergic mechanisms. 1573 50

Several lines of evidence suggest a link between the alpha7 neuronal nicotinic acetylcholine receptor (nAChR) and brain disorders including schizophrenia, Alzheimer's disease, and traumatic brain injury. The present work describes a novel molecule, 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596), which acts as a powerful positive allosteric modulator of the alpha7 nAChR. Discovered in a high-throughput screen, PNU-120596 increased agonist-evoked calcium flux mediated by an engineered variant of the human alpha7 nAChR. Electrophysiology studies confirmed that PNU-120596 increased peak agonist-evoked currents mediated by wild-type receptors and also demonstrated a pronounced prolongation of the evoked response in the continued presence of agonist. In contrast, PNU-120596 produced no detectable change in currents mediated by alpha4beta2, alpha3beta4, and alpha9alpha10 nAChRs. PNU-120596 increased the channel mean open time of alpha7 nAChRs but had no effect on ion selectivity and relatively little, if any, effect on unitary conductance. When applied to acute hippocampal slices, PNU-120596 increased the frequency of ACh-evoked GABAergic postsynaptic currents measured in pyramidal neurons; this effect was suppressed by TTX, suggesting that PNU-120596 modulated the function of alpha7 nAChRs located on the somatodendritic membrane of hippocampal interneurons. Accordingly, PNU-120596 greatly enhanced the ACh-evoked inward currents in these interneurons. Systemic administration of PNU-120596 to rats improved the auditory gating deficit caused by amphetamine, a model proposed to reflect a circuit level disturbance associated with schizophrenia. Together, these results suggest that PNU-120596 represents a new class of molecule that enhances alpha7 nAChR function and thus has the potential to treat psychiatric and neurological disorders.
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PMID:A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo characterization. 1585 66

It is considered that activation of nicotinic alpha7 receptors (alpha7 nAChR) is useful for the treatment of cognitive disturbances in schizophrenia and Alzheimer's disease. Recently, selective alpha7 nAChR agonists have been discovered and are used to validate the alpha7 nAChR as a drug target for the treatment of cognitive disturbances in schizophrenia. One important feature shared by all known antipsychotics is their capacity to induce expression of the neuronal immediate-early gene c-fos in the limbic forebrain. Using two novel and selective alpha7 nAChR agonists, PNU-282987 and SSR180711, we investigated their ability to induce c-Fos expression in the limbic forebrain with particular emphasis on the same regions reported to be activated by antipsychotics. Both alpha7 nAChR agonists increased c-Fos dose-dependently in the prefrontal cortex and the shell of nucleus accumbens, while leaving the core of nucleus accumbens and the dorsolateral striatum unaffected. The accumbal and cortical effect of SSR180711 was blocked completely by pre-administration of the alpha7 nAChR antagonist methyllycaconitine. Also, SSR180711 displayed no c-Fos-inducing effect in alpha7 nAChR knock-out mice. In conclusion, these results show that selective pharmacologic stimulation of alpha7 nAChR function results in activation of forebrain regions similar to conventional antipsychotics.
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PMID:Alpha-7 nicotinic acetylcholine receptor agonists selectively activate limbic regions of the rat forebrain: an effect similar to antipsychotics. 1745 7

Selective modulation of alpha7 nicotinic acetylcholine receptors (nAChRs) is thought to regulate processes impaired in schizophrenia, Alzheimer's disease, and other dementias. One approach to target alpha7 nAChRs is by positive allosteric modulation. Structurally diverse compounds, including PNU-120596, 4-naphthalene-1-yl-3a,4,5,9b-tetrahydro-3-H-cyclopenta[c]quinoline-8-sulfonic acid amide (TQS), and 5-hydroxyindole (5-HI) have been identified as positive allosteric modulators (PAMs), but their receptor interactions and pharmacological profiles remain to be fully elucidated. In this study, we investigated interactions of these compounds at human alpha7 nAChRs, expressed in Xenopus laevis oocytes, along with genistein, a tyrosine kinase inhibitor. Genistein was found to function as a PAM. Two types of PAM profiles were observed. 5-HI and genistein predominantly affected the apparent peak current (type I) whereas PNU-120596 and TQS increased the apparent peak current and evoked a distinct weakly decaying current (type II). Concentration-responses to agonists [ACh, 3-[(3E)-3-[(2,4-dimethoxyphenyl)methylidene]-5,6-dihydro-4H-pyridin-2-yl]pyridine dihydrochloride (GTS-21), and N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride (PNU-282987)] were potentiated by both types, although type II PAMs had greater effects. When applied after alpha7 nAChRs were desensitized, type II, but not type I, PAMs could reactivate alpha7 currents. Both types of PAMs also increased the ACh-evoked alpha7 window currents, with type II PAMs generally showing larger potentiation. None of the PAMs tested increased nicotine-evoked Ca(2+) transients in human embryonic kidney 293 cells expressing human alpha4beta2 or alpha3beta4 nAChRs, although some inhibition was noted for 5-HI, genistein, and TQS. In summary, our studies reveal two distinct alpha7 PAM profiles, which could offer unique opportunities for modulating alpha7 nAChRs in vivo and in the development of novel therapeutics for central nervous system indications.
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PMID:Distinct profiles of alpha7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes. 1756 4

Positive allosteric modulators of alpha7 nicotinic acetylcholine receptors (nAChRs) have attracted considerable interest as potential tools for the treatment of neurological and psychiatric disorders such as Alzheimer's disease and schizophrenia. However, despite the potential therapeutic usefulness of these compounds, little is known about their mechanism of action. Here, we have examined two allosteric potentiators of alpha7 nAChRs (PNU-120596 and LY-2087101). From studies with a series of subunit chimeras, we have identified the transmembrane regions of alpha7 as being critical in facilitating potentiation of agonist-evoked responses. Furthermore, we have identified five transmembrane amino acids that, when mutated, significantly reduce potentiation of alpha7 nAChRs. The amino acids we have identified are located within the alpha-helical transmembrane domains TM1 (S222 and A225), TM2 (M253), and TM4 (F455 and C459). Mutation of either A225 or M253 individually have particularly profound effects, reducing potentiation of EC(20) concentrations of acetylcholine to a tenth of the level seen with wild-type alpha7. Reference to homology models of the alpha7 nAChR, based on the 4A structure of the Torpedo nAChR, indicates that the side chains of all five amino acids point toward an intrasubunit cavity located between the four alpha-helical transmembrane domains. Computer docking simulations predict that the allosteric compounds such as PNU-120596 and LY-2087101 may bind within this intrasubunit cavity, much as neurosteroids and volatile anesthetics are thought to interact with GABA(A) and glycine receptors. Our findings suggest that this is a conserved modulatory allosteric site within neurotransmitter-gated ion channels.
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PMID:Potentiation of alpha7 nicotinic acetylcholine receptors via an allosteric transmembrane site. 1879 Oct 69

Alpha7 nicotinic acetylcholine receptor channels are important ligand-gated ion channels that are fast desensitizing, cation selective and have been implicated in the pathophysiology of schizophrenia and Alzheimer's disease. We report here high quality alpha7 parallel patch clamp recordings using the QPatch automated patch clamp system. The QPatch patch clamps up to 48 cells in parallel with the same high fidelity as conventional patch clamp. EC(50) and IC(50) values were comparable to values obtained with conventional patch clamp. The EC(50) value for acetylcholine (ACh) on the QPatch with area under the curve (AUC) analysis was 26microM compared to a value of 29microM determined from conventional patch clamp experiments. Sequential additions of ACh can be made with minimal decay of the peak amplitude. The competitive alpha7 antagonist methyllycaconitine (MLA) blocked currents with an IC(50) value of 0.25nM which is similar to published IC(50) values for MLA. Finally, two different classes of positive allosteric modulators represented by PNU-120596 and NS-1738 elicited characteristic responses, thus allowing accurate characterization of modulation and measurements of potency. These results demonstrate that alpha7 nicotinic acetylcholine receptor channels can be studied reliably in a higher throughput, parallel manner with the QPatch automated patch clamp system.
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PMID:Characterization of compounds on nicotinic acetylcholine receptor alpha7 channels using higher throughput electrophysiology. 1900 Jul 13


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