Phencyclidine-induced Disruption Of Prepulse Inhibition Research Articles

Sex differences in psychotomimetic-induced behaviours in rats

Animal model studies using equal numbers of males and females are sparse in psychiatry research. Given the marked sex differences observed in psychiatric disorders, such as schizophrenia, using both males and females in research studies is an important requirement. Thus the aim of this study was to examine sex differences in psychotomimetic-induced behavioural deficits relevant to psychosis. We therefore compared the acute effect of amphetamine or phencyclidine on locomotor activity and prepulse inhibition in adult male and female Sprague-Dawley rats. The results of this study were that: (1) amphetamine-induced distance travelled was greater in female rats than in male rats, (2) phencyclidine-induced locomotor hyperactivity was similar in male and female rats; (3) there were no sex differences in amphetamine- or phencyclidine-induced disruption of prepulse inhibition; (4) male rats had an increased startle response after amphetamine. These findings suggest that sensitivity to amphetamine, but not phencyclidine, differs between male and female rats, and that this sex difference is selective to locomotor hyperactivity and startle, but not prepulse inhibition. This study used two widely-used, validated preclinical assays relevant to psychosis; the results of this study have implications for psychiatry research, particularly for disorders where marked sex differences in onset and symptomology are observed.

Egis-11150: A candidate antipsychotic compound with procognitive efficacy in rodents

Classical antipsychotics, e.g. haloperidol, chlorpromazine, are potent at controlling the positive symptoms of schizophrenia but frequently elicit extrapyramidal motor side-effects. The introduction of atypical antipsychotics such as risperidone, olanzapine and clozapine has obviated this problem, but none of the current drugs seem to improve the cognitive deficits accompanying schizophrenia. Thus there is an unmet need for agents that not only suppress the psychotic symptoms but also ameliorate the impairment of cognition. Here, we report the preclinical properties of a candidate antipsychotic, Egis-11150, that shows marked pro-cognitive efficacy. Egis-11150 displayed high affinity for adrenergic α1, α2c, 5-HT2A 5-HT7, moderate affinity for adrenergic α2a and D2 receptors. It was a functional antagonist on all of the above receptors, with the exception of 5-HT7 receptors, where it was an inverse agonist. Phencyclidine-induced hypermotility in mice and inhibition of conditioned avoidance response in rats were assessed to estimate efficacy against the positive and social withdrawal test in rats was used to predict efficacy against the negative symptoms of schizophrenia. Passive-avoidance learning, novel object recognition and radial maze tests in rats were used to assess pro-cognitive activity, while phencyclidine-induced disruption of prepulse inhibition in mice was examined to test for effects on attention. Egis-11150 (0.01–0.3 mg/kg, ip.) was effective in all of the preclinical models of schizophrenia examined. Moreover, a robust pro-cognitive profile was apparent. In summary, work in preclinical models indicates that Egis-11150 is a potential treatment for controlling the psychosis as well as the cognitive dysfunction in schizophrenia.This article is part of a Special Issue entitled ‘Cognitive Enhancers’.

Antipsychotic property of EGIS 11150 (S 36549) in phencyclidine-induced disruption of prepulse inhibition in rats and mice

Event Abstract Back to Event Antipsychotic property of EGIS 11150 (S 36549) in phencyclidine-induced disruption of prepulse inhibition in rats and mice Krisztina Moricz1*, Gabor Gigler1, Hajnalka Kompagne1, Szabolcs Kertesz1, Marta Agoston1, Katalin Nagy1, Jozsef Barkoczy1, Gabor Szenasi1 and Istvan Gacsalyi1 1 EGIS Pharmaceuticals Plc., CTCN, Hungary Prepulse inhibition (PPI) is disrupted in schizophrenic patients and the degree of reflex inhibition is an operational measure of sensorimotor gating. NMDA antagonist such as phencyclidine (PCP) also disrupts PPI in animals when administrated acutely, and this effect can be prevented by antipsychotics (preferentially atypical ones). EGIS-11150 is a new atypical antipsychotic agent developed by EGIS Pharmaceutical Plc. Earlier we demonstrated that the compound possessed strong procognitive and neuroprotective effects and exerted strong antipsychotic activity in a series of animal models of the negative and positive symptoms of schizophrenia. (Gacsályi et al. 2007) The aim of the present study was to examine the effects of EGIS 11150 in phencyclidine-induced disruption of prepulse inhibition in rats and mice. In rats EGIS 11150 restored the deficit of PPI - induced by 2 mg/kg PCP - in 0.1, 0.3 and 1 mg/kg i.p. administrated at 30 min before the test. In mice the PPI was disrupted by 10 mg/kg PCP sac. (-30 min). EGIS 11150 was effective in 0.01, 0.03 and 0.1 mg/kg doses i.p. The compound decreased the startle magnitudes in all studied doses in rats and the largest dose in mice. If we administrated EGIS 11150 alone, although it reduced the startle amplitudes in largest doses, it did not show effect on PPI. This result suggests that the startle amplitude reducing effect of the compound is separate from the PPI deficit-restoring efficacy.In the present studies EGIS 11150 processed a remarkable properties to restore the PPI deficit induced by PCP, which confirmed that it may be a potential therapeutic agent in the treatment of schizophrenia. Conference: 41st European Brain and Behaviour Society Meeting, Rhodes Island, Greece, 13 Sep - 18 Sep, 2009. Presentation Type: Poster Presentation Topic: Poster presentations Citation: Moricz K, Gigler G, Kompagne H, Kertesz S, Agoston M, Nagy K, Barkoczy J, Szenasi G and Gacsalyi I (2009). Antipsychotic property of EGIS 11150 (S 36549) in phencyclidine-induced disruption of prepulse inhibition in rats and mice. Conference Abstract: 41st European Brain and Behaviour Society Meeting. doi: 10.3389/conf.neuro.08.2009.09.239 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 11 Jun 2009; Published Online: 11 Jun 2009. * Correspondence: Krisztina Moricz, EGIS Pharmaceuticals Plc., CTCN, Budapest, Hungary, moricz.krisztina@egis.hu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Krisztina Moricz Gabor Gigler Hajnalka Kompagne Szabolcs Kertesz Marta Agoston Katalin Nagy Jozsef Barkoczy Gabor Szenasi Istvan Gacsalyi Google Krisztina Moricz Gabor Gigler Hajnalka Kompagne Szabolcs Kertesz Marta Agoston Katalin Nagy Jozsef Barkoczy Gabor Szenasi Istvan Gacsalyi Google Scholar Krisztina Moricz Gabor Gigler Hajnalka Kompagne Szabolcs Kertesz Marta Agoston Katalin Nagy Jozsef Barkoczy Gabor Szenasi Istvan Gacsalyi PubMed Krisztina Moricz Gabor Gigler Hajnalka Kompagne Szabolcs Kertesz Marta Agoston Katalin Nagy Jozsef Barkoczy Gabor Szenasi Istvan Gacsalyi Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Inactivation of the 5-HT 7 Receptor Partially Blocks Phencyclidine-Induced Disruption of Prepulse Inhibition

Studies have implicated the serotonin (5-HT)(7) receptor in physiological and pathophysiological phenomena, including thermoregulation, central control of micturition and locomotion, regulation of circadian rhythm, sleep, and depression. Further, several antidepressant and antipsychotic drugs have high affinity for the 5-HT(7) receptor.We examined the role of 5-HT(7) receptors in a rodent analogue of sensorimotor gating deficits in schizophrenia: phencyclidine (PCP)-induced disruption of prepulse inhibition (PPI) of acoustic startle. We used mice lacking the 5-HT(7) receptor due to a targeted inactivation of this receptor gene and the selective 5-HT(7) receptor antagonist SB-269970.SB-269970 did not affect either baseline PPI or PCP-disrupted PPI. There was no difference between 5-HT(7)(+/+) and 5-HT(7)(-/-) mice in startle reactivity or PPI regardless of prepulse intensity (74-82 dB), interstimulus interval (25-500 msec), or pulse intensity (90-120 dB). Nevertheless, disruption of PPI produced by PCP (10 mg/kg) in wild-type mice was reduced in 5-HT(7)(-/-) mice, although it was not affected by the 5-HT(7) antagonist SB-269970. By contrast, the PPI-disruptive effects of apomorphine (5 mg/kg) and amphetamine (7.5 mg/kg) were comparable in both genotypes.The results indicate a partial role for the 5-HT(7) receptor in the glutamatergic PPI model of sensorimotor gating deficits in schizophrenia that is sensitive to atypical antipsychotics and no involvement of this receptor in the dopaminergic PPI model that is sensitive to typical antipsychotics. Thus, the 5-HT(7)(-/-) mice may provide a useful tool to study the role of 5-HT(7) receptor in the action of atypical antipsychotic drugs and schizophrenia.

The atypical antipsychotic, aripiprazole, blocks phencyclidine-induced disruption of prepulse inhibition in mice

The psychotomimetic drug, phencyclidine, induces schizophrenia-like behavioural changes in both humans and animals. Phencyclidine-induced disruption of sensory motor gating mechanisms, as assessed by prepulse inhibition of the acoustic startle, is widely used in research animals as a screening model for antipsychotic properties in general and may predict effects on negative and cognitive deficits in particular. Dopamine (DA) stabilizers comprise a new generation of antipsychotics characterized by a partial DA receptor agonist or antagonist action and have been suggested to have a more favourable clinical profile. The aim of the present study was to investigate the ability of first, second and third generation antipsychotics to interfere with the disruptive effect of phencyclidine on prepulse inhibition in mice. Aripiprazole blocked the phencyclidine-induced disruption of prepulse inhibition. The atypical antipsychotic clozapine was less effective, whereas olanzapine, and the typical antipsychotic haloperidol, failed to alter the effects of phencyclidine on prepulse inhibition. The somewhat superior efficacy of clozapine compared to haloperidol may be explained by its lower affinity and faster dissociation rate for DA D2 receptors possibly combined with an interaction with other receptor systems. Aripiprazole was found to be more effective than clozapine or olanzapine, which may be explained by a partial agonist activity of aripiprazole at DA D2 receptors. In conclusion, the present findings suggest that partial DA agonism leading to DA stabilizing properties may have favourable effects on sensorimotor gating and thus tentatively on cognitive dysfunctions in schizophrenia.

The nitric oxide synthase inhibitor, L-NAME, block phencyclidine-induced disruption of prepulse inhibition in mice.

Schizophrenia is a major public health problem that affects approximately 1% of the population worldwide. Schizophrenia-like syndromes can be induced in humans by phencyclidine (PCP), a drug with marked psychomimetic properties. Recent studies show that the behavioural and biochemical effects of PCP in rats are blocked by nitric oxide synthase (NOS) inhibitors, suggesting that NO plays an important role in the pharmacological effects of PCP. The aim of this study was to investigate if PCP-induced disruption of prepulse inhibition of acoustic startle could be blocked by the NOS inhibitor, L-NAME, in mice. The present study shows that PCP readily disrupts prepulse inhibition in mice normally without affecting pulse-alone trials. Furthermore, L-NAME blocked the PCP-induced disruption of prepulse inhibition in a dose-related manner. The PCP-induced disruption of prepulse inhibition and the ability of L-NAME to block this effect in both rats and mice suggest that this is a general and not a species-specific effect. The results of the present study further suggest that PCP exerts at least some of its actions in the central nervous system by a NO-dependent mechanism.

Effects of σ 1 receptor ligand, MS-377 on apomorphine- or phencyclidine-induced disruption of prepulse inhibition of acoustic startle in rats

To evaluate the antipsychotic property of a σ 1 receptor ligand, ( R)-(+)-1-(4-chlorophenyl)-3-{4-(2-methoxyethyl)piperazin-1-yl}methyl-2-pyrrolidinone- l-tartrate (MS-377), an antagonistic effect of MS-377 on the disruption of prepulse inhibition (PPI) of the acoustic startle by apomorphine or phencyclidine (PCP) was investigated in rats. MS-377 antagonized the PCP-induced disruption of PPI. The ED 50 value of MS-377 for this effect was 0.66 mg/kg. In contrast, apomorphine-induced disruption of PPI was not attenuated by MS-377. These data indicate that the PCP-induced disruption of PPI in rats would be, at least partially, mediated by σ receptors and MS-377 could be a novel anti-psychotic agent with clinical efficacy for the sensorimotor-gating deficit in schizophrenia.

Involvement of serotonin 2A receptors in phencyclidine-induced disruption of prepulse inhibition of the acoustic startle in rats

Background: The disruption of prepulse inhibition of acoustic startle (PPI) is an animal model for some aspects of schizophrenia. Phencyclidine causes psychotomimetic symptoms in human and disrupts PPI in animals, however, the mechanism underlying this disruption remains unclear. The present experiment tested the hypothesis that serotonin 2A receptor blocking property of drugs reverses the phencyclidine-induced PPI disruption. Methods: The ED 50 value of spiperone, haloperidol, chlorpromazine, clozapine, risperidone, olanzapine, seroquel, pipamperone, mianserin, or desipramine to reverse the phencyclidine- or apomorphine-induced PPI disruption in rats was determined. Then the correlation between the ED50 value and the affinity for the serotonin 2A, 2C, dopamine D 2, or α-1 receptor of each drug was examined. Results: The ED 50 value of the drugs to reverse the phencyclidine-induced PPI disruption was significantly correlated with the affinity for the serotonin 2A receptor, but not for the dopamine D 2, serotonin 2C, or α-1 receptor of each drug. In contrast, the ED 50 value of the drugs to reverse the apomorphine-induced PPI disruption was significantly correlated with the affinity for the dopamine D 2 receptor, but not for the serotonin 2A receptor. Conclusions: An activation of serotonin 2A receptors would mediate the phencyclidine-induced PPI disruption.

Nitric oxide synthase inhibitors attenuate phencyclidine-induced disruption of prepulse inhibition.

Glutamate stimulation of N-methyl-D-aspartate (NMDA) receptors results in release of nitric oxide which may mediate the effects of NMDA receptor stimulation and/or may result in feedback inhibition of the presynaptic neuron. Results of a previous study showed that nitric oxide synthase (NOS) inhibitors blocked dizocilpine-induced behavior in mice. In the present study, NOS inhibitors were tested in combination with phencyclidine (PCP), a drug which typically dose-dependently disrupts prepulse inhibition of the acoustic startle response in rats. Alone, NOS inhibitors and promoters do not affect prepulse inhibition; however, when tested in combination with PCP, the NOS inhibitors, L-NOARG, 7-nitroindazole and arcaine--but not the NR2B-selective polyamine site NMDA antagonist, eliprodil--attenuated PCP-induced disruption of prepulse inhibition of the acoustic startle response. These effects are similar to those produced by many atypical antipsychotics and suggests that this class of drugs should be investigated further for their potential utility as antipsychotics and as treatments for PCP abuse.

Nitric oxide synthase inhibition blocks phencyclidine-induced behavioural effects on prepulse inhibition and locomotor activity in the rat.

The ability of the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), to block the behavioural effects of the potent psychotomimetic, phencyclidine, was tested in rats using two different behavioural models. L-NAME was found to block both phencyclidine-induced disruption of prepulse inhibition of acoustic startle and phencyclidine-induced stimulation of locomotor activity. A selective action of L-NAME on the effects of phencyclidine was indicated, since L-NAME did not alter the effects of amphetamine, another potent psychotomimetic, in these behavioural models. These observations suggest that a nitric oxide-dependent mechanism may be involved in the effects of phencyclidine in the central nervous system.

Clozapine's effects on phencyclidine-induced disruption of prepulse inhibition of the acoustic startle response

The reduction in magnitude of the startle reflex in response to a loud noise produced by prior presentation of a stimulus of lower intensity is known as prepulse inhibition (PPI). PPI may be disrupted by a variety of drugs, most notably by dopaminergic agonists such as apomorphine and by phencyclidine (PCP), and related noncompetitive N- methyl- D- aspartate (NMDA) antagonist. Apomorphine-induced disruption of PPI is antagonized by both typical and atypical neuroleptics. The present study examined the effects of the atypical neuroleptic, clozapine, alone and in combination with PCP, on PPI in rats. The results of previous studies suggest that disruption of PPI by PCP and similar drugs is not sensitive to antagonism by typical neuroleptics such as haloperidol. The results of the present study show that clozapine's effect on PCP-induced disruption of PPI is also limited. The failure of clinically effective antipsychotics of diverse chemical classes to block the effects of PCP on PPI of acoustic startle suggest that the effects of PCP in this procedure may represent a model of attentional deficits observed in treatment-resistant schizophrenia.