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Kenji Hashimoto - One of the best experts on this subject based on the ideXlab platform.
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improvement of Dizocilpine induced social recognition deficits in mice by brexpiprazole a novel serotonin dopamine activity modulator
European Neuropsychopharmacology, 2015Co-Authors: Takashi Futamura, Noriko Yoshimi, Kenji HashimotoAbstract:Abstract Cognitive impairment, including impaired social cognition, is largely responsible for the deterioration in social life suffered by patients with psychiatric disorders, such as schizophrenia and major depressive disorder (MDD). Brexpiprazole (7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one), a novel serotonin–dopamine activity modulator, was developed to offer efficacious and tolerable therapy for different psychiatric disorders, including schizophrenia and adjunctive treatment of MDD. In this study, we investigated whether brexpiprazole could improve social recognition deficits (one of social cognition deficits) in mice, after administration of the N-methyl- d -aspartate (NMDA) receptor antagonist MK-801 (Dizocilpine). Dosing with Dizocilpine (0.1 mg/kg) induced significant impairment of social recognition in mice. Brexpiprazole (0.01, 0.03, 0.1 mg/kg, p.o.) significantly ameliorated Dizocilpine-induced social recognition deficits, without sedation or a reduction of exploratory behavior. In addition, brexpiprazole alone had no effect on social recognition in untreated control mice. By contrast, neither risperidone (0.03 mg/kg, p.o.) nor olanzapine (0.03 mg/kg, p.o.) altered Dizocilpine-induced social recognition deficits. Finally, the effect of brexpiprazole on Dizocilpine-induced social recognition deficits was antagonized by WAY-100,635, a selective serotonin 5-HT1A antagonist. These results suggest that brexpiprazole could improve Dizocilpine-induced social recognition deficits via 5-HT1A receptor activation in mice. Therefore, brexpiprazole may confer a beneficial effect on social cognition deficits in patients with psychiatric disorders.
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minocycline attenuates hyperlocomotion and prepulse inhibition deficits in mice after administration of the nmda receptor antagonist Dizocilpine
Neuropsychopharmacology, 2007Co-Authors: Lin Zhang, Yukihiko Shirayama, Kenji HashimotoAbstract:The present study was undertaken to examine whether the second generation antibiotic drug minocycline attenuates behavioral changes (eg, acute hyperlocomotion and prepulse inhibition (PPI) deficits) in mice after the administration of the N-methyl-D-aspartate (NMDA) receptor antagonist (+)-MK-801 (Dizocilpine). Dizocilpine (0.1 mg/kg)-induced hyperlocomotion was significantly attenuated by pretreatment with minocycline (40 mg/kg). Furthermore, the PPI deficits after a single administration of Dizocilpine (0.1 mg/kg) were attenuated by pretreatment with minocycline (10, 20, or 40 mg/kg), in a dose-dependent manner. Moreover, in vivo microdialysis study in the free-moving mice revealed that pretreatment with minocycline (40 mg/kg, i.p.) significantly attenuated the increase of extracellular dopamine (DA) levels in the frontal cortex and striatum after administration of Dizocilpine (0.1 mg/kg), suggesting that the inhibition of Dizocilpine-induced DA release by minocycline may, at least in part, be implicated in the mechanism of action of minocycline with respect to Dizocilpine-induced behavioral changes in mice. These findings suggest that minocycline could attenuate behavioral changes in mice after the administration of the NMDA receptor antagonist Dizocilpine. Therefore, it is possible that minocycline would be a potential therapeutic drug for schizophrenia.
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adenosine a1 receptor agonists block the neuropathological changes in rat retrosplenial cortex after administration of the nmda receptor antagonist Dizocilpine
Neuropsychopharmacology, 2004Co-Authors: Naoe Okamura, Chikara Kumakiri, Naoya Komatsu, Eiji Shimizu, Kenji Hashimoto, Masaomi IyoAbstract:Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist Dizocilpine ((+)-MK-801) is known to induce neurotoxicity in rat retrosplenial cortex after systemic administration. The present study was undertaken to examine the effects of adenosine A(1) receptor agonists on the neurotoxicity in rat retrosplenial cortex after administration of Dizocilpine. Pretreatment with adenosine A(1) receptor agonists, 2-chloro-N(6)-cyclopentyladenosine (CCPA) (0.1, 0.3, 1, or 3 mg/kg, intraperitoneally (i.p.)), or N(6)-cyclopentyladenosine (CPA) (1, 3, or 10 mg/kg, i.p.), attenuated neurotoxicity by Dizocilpine (0.5 mg/kg, i.p), in a dose-dependent manner. Coadministration with adenosine A(1) receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 3 mg/kg, i.p.) significantly blocked the protective effects of CCPA for Dizocilpine-induced neurotoxicity. Furthermore, pretreatment with CCPA (3 mg/kg) attenuated significantly the Dizocilpine-induced expression of HSP-70 protein, which is known as a sensitive marker of reversible neuronal damage, and coadministration with DPCPX (3 mg/kg) blocked the inhibitory effects of CCPA for marked expression of HSP-70 protein by administration of Dizocilpine. Moreover, pretreatment with CCPA (3 mg/kg, i.p.) significantly suppressed the increase of extracellular acetylcholine (ACh) levels in the retrosplenial cortex by administration of Dizocilpine (0.5 mg/kg). In contrast, local perfusion of CCPA (1 microM) into the retrosplenial cortex via the dialysis probe did not alter the ACh levels by administration of Dizocilpine (0.5 mg/kg), suggesting that the locus of action of CCPA is not in the retrosplenial cortex. These findings suggest that adenosine A(1) receptors agonists could protect against neuropathological changes in rat retrosplenial cortex after administration of the NMDA receptor antagonist Dizocilpine.
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Protective effect of LY379268, a selective group II metabotropic glutamate receptor agonist, on Dizocilpine-induced neuropathological changes in rat retrosplenial cortex.
Brain research, 2003Co-Authors: Naoe Okamura, Chikara Kumakiri, Naoya Komatsu, Eiji Shimizu, Kenji Hashimoto, Kaori Koike, Shintaro Ohgake, Hiroki Koizumi, Masaomi IyoAbstract:In the present study, we examined the effects of LY379268, the group II metabotropic glutamate receptor (mGluR) agonist, on the neuropathological changes in the rat retrosplenial cortex induced by noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist Dizocilpine ((+)-MK-801). Administration of LY379268 (1, 3, 10 mg/kg, i.p.) reduced Dizocilpine (0.5 mg/kg, i.p.)-induced neuropathological changes in the retrosplenial cortex, in a dose-dependent manner. Co-administration of LY379268 (10 mg/kg, i.p.) with group II mGluR antagonist LY341495 (5 mg/kg, i.p.) blocked the effects of LY379268. Furthermore, LY379268 (10 mg/kg, i.p.) significantly reduced the expression of heat shock protein HSP-70, a marker of reversible neuronal injury, in the rat retrosplenial cortex after administration of Dizocilpine (0.5 mg/kg, i.p.). Moreover, pretreatment with LY379268 (10 mg/kg, i.p.) significantly suppressed the increase in extracellular acetylcholine (ACh) levels in the retrosplenial cortex induced by administration of Dizocilpine (0.5 mg/kg, i.p.). These results suggest that LY379268 has a protective effect on the neurotoxicity in the rat retrosplenial cortex after administration of NMDA receptor antagonists such as Dizocilpine.
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protective effect of the antipsychotic drug zotepine on Dizocilpine induced neuropathological changes in rat retrosplenial cortex
European Journal of Pharmacology, 2003Co-Authors: Naoe Okamura, Nobuhisa Kanahara, Chikara Kumakiri, Eiji Shimizu, Kenji Hashimoto, Naoya KomatsuAbstract:An atypical antipsychotic drug, zotepine, which is pharmacologically and clinically related to clozapine, has unique therapeutic effects on patients with schizophrenia. It has been demonstrated that clozapine blocks neurotoxicity in the rat retrosplenial cortex induced by administration of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist Dizocilpine ((+)-MK-801). We examined whether or not zotepine has the ability to block neurotoxicity in the rat retrosplenial cortex induced by administration of Dizocilpine. Female Sprague– Dawley rats were injected intraperitoneally (i.p.) with vehicle (1 mg/kg), zotepine (5, 10 or 20 mg/kg) or clozapine (20 mg/kg). Fifteen minutes later, animals were injected intraperitoneally (i.p.) with vehicle (1 ml/kg) or Dizocilpine (0.5 mg/kg). Neuropathological changes (neuronal vacuolization) were assessed 4 h after administration of Dizocilpine. Immunohistochemical analysis of heat shock protein HSP-70, a marker of reversible neuronal injury, was performed 24 h after administration of Dizocilpine. The pretreatment with zotepine (5, 10 or 20 mg/kg) significantly decreased the number of vacuolized neurons in the rat retrosplenial cortex 4 h after the administration of Dizocilpine (0.5 mg/kg), in a dose-dependent manner. The potency of zotepine (20 mg/kg) for Dizocilpine-induced neurotoxicity was similar to that of clozapine (20 mg/kg). Furthermore, similar to the case with clozapine (20 mg/kg, i.p.), zotepine (20 mg/kg, i.p.) significantly attenuated the expression of HSP-70 in the rat retrosplenial cortex induced by Dizocilpine (0.5 mg/kg, i.p.). The present study suggests that the neuroprotective effects of zotepine- on Dizocilpine-induced neurotoxicity are equipotent to those of clozapine. Based on the NMDA receptor hypofunction hypothesis of schizophrenia, the efficacy of zotepine in this study may partly contribute to the unique therapeutic effects of zotepine in patients with schizophrenia. D 2003 Elsevier Science B.V. All rights reserved.
Toshitaka Nabeshima - One of the best experts on this subject based on the ideXlab platform.
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Molecular mechanisms in Dizocilpine-induced attenuation of development of morphine dependence: an association with cortical Ca2+/calmodulin-dependent signal cascade
Behavioural brain research, 2004Co-Authors: Moustafa Mahmoud Hamdy, Yukihiro Noda, Masayuki Miyazaki, Takayoshi Mamiya, Ayumu Nozaki, Atsumi Nitta, Merfat Sayed, Abdel-azim Assi, Adel A. Gomaa, Toshitaka NabeshimaAbstract:Abstract We investigated how Dizocilpine, a non-competitive N -methyl- d -aspartate (NMDA) receptor antagonist, affects the development of morphine dependence in mice. Co-administration of Dizocilpine (0.25 mg/kg) and morphine (10 mg/kg) for 5 days attenuated the development of tolerance to the antinociceptive effects of morphine. The withdrawal manifestation induced by the naloxone-challenge (5 mg/kg) was significantly reduced in mice that were treated with a combination of Dizocilpine and morphine, compared to the mice treated with morphine and saline. The present study revealed a significant increase in c-Fos protein expression in the cortex and thalamus of mice showing naloxone-precipitated withdrawal syndrome. The combination of Dizocilpine and morphine prevented the increase of c-Fos protein expression in the cortex and thalamus. Interestingly, repeated co-administration of Dizocilpine and morphine prevented the withdrawal-induced phosphorylation of Ca 2+ /calmodulin kinase II (p-CaMK II) in the cortex, but not in the thalamus. Acute Dizocilpine treatment prior to the naloxone-challenge and repeated treatment with Dizocilpine alone had no effect on analgesia, withdrawal manifestations, p-CaMK II levels or c-Fos protein levels. These results showed that co-administration of Dizocilpine and morphine prevented the development of morphine tolerance and dependence and suggested that the preventive effect of Dizocilpine results from the regulation of c-Fos protein expression, which is possibly involved in the activation of the Ca 2+ /calmodulin-dependent signal cascade in the cortex.
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σ Receptor ligands (+)-SKF10,047 and SA4503 improve Dizocilpine-induced spatial memory deficits in rats
European journal of pharmacology, 1998Co-Authors: Li Bo Zou, Kiyofumi Yamada, Toshitaka NabeshimaAbstract:This study examined the effects of the sigma receptor ligands (+)-N-allylnormetazocine ((+)-SKF10,047) and 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) on Dizocilpine-induced impairment of working and reference memory in a radial arm maze task in rats. Dizocilpine, a non-competitive NMDA receptor antagonist, significantly impaired both reference and working memory, an effect which was accompanied by ataxia and impairment of food intake. The Dizocilpine-induced impairment of reference memory was dose-dependently attenuated by (+)-SKF10,047 and SA4503. SA4503 also attenuated the Dizocilpine-induced working memory impairment, although (+)-SKF10,047 had no effect. Neither sigma receptor ligand affected the behavioral symptoms such as ataxia and impairment of food intake induced by Dizocilpine. The ameliorating effects of both (+)-SKF10,047 and SA4503 on Dizocilpine-induced spatial memory impairment were completely antagonized by a sigma1 receptor antagonist N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine-mon ohydrochloride. These results suggest that the interaction of sigma1 receptors with NMDA receptors modulates spatial memory in rats.
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σ receptor ligands skf10 047 and sa4503 improve Dizocilpine induced spatial memory deficits in rats
European Journal of Pharmacology, 1998Co-Authors: Li Bo Zou, Kiyofumi Yamada, Toshitaka NabeshimaAbstract:This study examined the effects of the sigma receptor ligands (+)-N-allylnormetazocine ((+)-SKF10,047) and 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) on Dizocilpine-induced impairment of working and reference memory in a radial arm maze task in rats. Dizocilpine, a non-competitive NMDA receptor antagonist, significantly impaired both reference and working memory, an effect which was accompanied by ataxia and impairment of food intake. The Dizocilpine-induced impairment of reference memory was dose-dependently attenuated by (+)-SKF10,047 and SA4503. SA4503 also attenuated the Dizocilpine-induced working memory impairment, although (+)-SKF10,047 had no effect. Neither sigma receptor ligand affected the behavioral symptoms such as ataxia and impairment of food intake induced by Dizocilpine. The ameliorating effects of both (+)-SKF10,047 and SA4503 on Dizocilpine-induced spatial memory impairment were completely antagonized by a sigma1 receptor antagonist N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine-mon ohydrochloride. These results suggest that the interaction of sigma1 receptors with NMDA receptors modulates spatial memory in rats.
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role of nitric oxide and cyclic gmp in the Dizocilpine induced impairment of spontaneous alternation behavior in mice
Neuroscience, 1996Co-Authors: Kiyofumi Yamada, Yukihiro Noda, Takayoshi Mamiya, Masayuki Hiramatsu, Masaaki Murai, T Kameyama, Yumiko Komori, Toshiaki Nikai, Hisayoshi Sugihara, Toshitaka NabeshimaAbstract:Abstract The activation of N -methyl- d -aspartate receptors induces the synthesis of nitric oxide, which activates soluble guanylate cyclase and leads to the formation of cyclic GMP in the brain. The inhibition of nitric oxide production, as well as the blockade of N -methyl- d -aspartate receptors, has been reported to prevent the induction of hippocampal long-term potentiation and learning and memory formation in vivo , although the effects of inhibitors of nitric oxide synthase are still controversial. We investigated the putative role of nitric oxide and cyclic GMP in Dizocilpine-induced memory impairment in mice. The nitric oxide synthase inhibitors, N G -nitro- l -arginine methyl ester and 7-nitro indazole, as well as Dizocilpine, a non-competitive N -methyl- d -aspartate receptor antagonist, dose-dependently impaired spatial working memory in mice, assessed by their spontaneous alternation behavior in a Y-maze. The inhibitory effects of both N G -nitro- l -arginine methyl ester and Dizocilpine on their behavior were completely reversed by 8-bromo-cyclic GMP. Cyclic GMP levels in the cerebellum were reduced by treatment with Dizocilpine. N G -Nitro- l -arginine methyl ester and 7-nitro indazole reduced cyclic GMP levels in the cerebral cortex/hippocampus and cerebellum, and the suppressive effect of N G -nitro- l -arginine methyl ester on cyclic GMP levels in the cerebral cortex/hippocampus was reversed by co-treatment with l -arginine. Cyclic AMP levels in the brain were not affected by treatment with either Dizocilpine, N G -nitro- l -arginine methyl ester, or 7-nitro indazole. Neither N G -nitro- l -arginine methyl ester nor l -arginine had any effect on monoamine and acetylcholine metabolism in the brain. These results suggest that the reduction in nitric oxide/cyclic GMP production in the brain may be responsible for Dizocilpine-induced impairment of spontaneous alternation behavior in a Y-maze.
Edward D. Levin - One of the best experts on this subject based on the ideXlab platform.
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effects of azd3480 a neuronal nicotinic acetylcholine receptor agonist and donepezil on Dizocilpine induced attentional impairment in rats
Psychopharmacology, 2012Co-Authors: Amir H. Rezvani, Marty Cauley, Edwin C Johnson, Gregory J Gatto, Edward D. LevinAbstract:Nicotinic acetylcholine systems play major roles in cognitive function. Nicotine and a variety of nicotinic agonists improve attention, and nicotinic antagonist exposure impairs it. This study was conducted to investigate the effect of a novel nicotinic receptor agonist at α4β2 nicotinic receptors (AZD3480) on attention and reversal of pharmacologically induced attentional impairment produced by the NMDA glutamate antagonist Dizocilpine (MK-801). Adult female Sprague-Dawley rats were trained to perform an operant visual signal detection task to a stable baseline of accuracy. The rats were then injected subcutaneously following a repeated measures, counter-balanced design with saline, AZD3480 (0.01, 0.1, and 1 mg/kg), Dizocilpine (0.05 mg/kg), or their combinations 30 min before the test. The effect of donepezil on the same pharmacologically induced attentional impairment was also tested. A separate group of rats was injected with donepezil (0.01, 0.1, and 1 mg/kg), Dizocilpine (0.05 mg/kg), or their combinations, and their attention were assessed. Saline was the vehicle control. Dizocilpine caused a significant (p < 0.0005) impairment in percent correct performance. This attentional impairment was significantly (p < 0.0005) reversed by 0.01 and 0.1 mg/kg of AZD3480. AZD3480 by itself did not alter the already high baseline control performance. Donepezil (0.01–1.0 mg/kg) also significantly (p < 0.005) attenuated the Dizocilpine-induced attentional impairment. AZD3480, similar to donepezil, showed significant efficacy for counteracting the attentional impairment caused by the NMDA glutamate antagonist Dizocilpine. Low doses of AZD3480 may provide therapeutic benefit for reversing attentional impairment in patients suffering from cognitive impairment due to glutamatergic dysregulation and likely other attentional disorders.
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idazoxan blocks the nicotine induced reversal of the memory impairment caused by the nmda glutamate receptor antagonist Dizocilpine
Pharmacology Biochemistry and Behavior, 2008Co-Authors: Olga Timofeeva, Edward D. LevinAbstract:Abstract Rationale Alpha2-adrenoreceptor (α 2 -AR) antagonists have been shown to improve, while α 2 -AR agonists impair cognitive function in subjects with functioning NMDA receptors (NMDAR). In subjects with inhibited NMDAR (a model of schizophrenia) α 2 -AR agonists attenuate the cognitive impairments. The effect with α 2 -AR antagonists remains unclear. Objectives We investigated the effects of the α 2 -AR antagonist idazoxan on memory function in rats treated/not treated with NMDAR antagonist Dizocilpine or a combination of Dizocilpine and nicotine to clarify noradrenergic/cholinergic regulation of memory function. Methods Female Sprague–Dawley rats ( n = 12) were trained for food reward on the radial maze. Working and reference memory errors and response latency were assessed after injections of idazoxan (0.5, 1.0 mg/kg), Dizocilpine (0.05 mg/kg), nicotine (0.2, 0.4 mg/kg) or vehicle, alone or in combination. Results Dizocilpine potently impaired memory. Nicotine (0.4 mg/kg) reversed this impairment. Idazoxan at the doses tested did not affect performance when given alone or with Dizocilpine, but it did block the nicotine reversal of the Dizocilpine-induced memory impairment. Three rats after 10–12 drug treatments developed limbic seizures. Our findings suggest that combination of drugs which block α 2 -AR with nicotinic agonists in schizophrenia may prevent therapeutic effect of nicotinic agonists and increase risk for convulsive activity with repeated administration.
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chronic nicotine and Dizocilpine effects on nicotinic and nmda glutamatergic receptor regulation interactions with clozapine actions and attentional performance in rats
Progress in Neuro-psychopharmacology & Biological Psychiatry, 2008Co-Authors: Amir H. Rezvani, Yousef Tizabi, Bruk Getachew, Sheketha R Hauser, Patrick D Caldwell, Christopher Hunter, Edward D. LevinAbstract:Blockade of NMDA glutamate receptors with Dizocilpine (MK-801) has been shown to cause substantial cognitive deficits and has been used to model symptoms of schizophrenia. Nicotine or nicotinic agonists, in contrast, may enhance cognitive or attentional functions and be of therapeutic potential in schizophrenia. Nicotinic-glutamatergic interactions, therefore, may have important implications in cognitive functions and antipsychotic treatments. Clozapine, a widely used antipsychotic drug, has been shown in some studies to be effective in ameliorating the cognitive deficits associated with schizophrenia. However, there is some evidence to suggest that clozapine similar to haloperidol may impair sustained attention in rats. In this study, we sought to determine whether chronic nicotine or Dizocilpine may modify the effects of acute clozapine on attentional parameters and whether the behavioral effects would correlate with nicotinic or NMDA receptor densities in discrete brain regions. Adult female rats trained on an operant visual signal detection task were given 4 weeks of nicotine (5 mg/kg/day), Dizocilpine (0.15 mg/kg/day), the same doses of both nicotine and Dizocilpine as a mixture, or saline by osmotic minipump. While on chronic treatment, rats received acute injections of various doses of clozapine (0, 0.625, 1.25, 2.5 mg/kg, sc) 10 min prior to tests on attentional tasks. The pumps were removed on day 28 and 24 h later the animals were sacrificed for measurements of receptor densities in specific brain regions. The percent correct hit as a measure of sustained attention was significantly impaired by clozapine in a dose-related manner. Neither chronic nicotine nor Dizocilpine affected this measure on their own or modified the effects of clozapine. Both nicotine and Dizocilpine affected the receptor bindings in a region specific manner and their combination further modified the effects of each other in selective regions. Attentional performance was inversely correlated with alpha-bungarotoxin binding in the frontal cortex only. In conclusion, the data suggest attentional impairments with clozapine alone and no modification of this effect with nicotine or Dizocilpine. Moreover, cortical low affinity nicotinic receptors may have a role in attentional functions.
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Chronic nicotine and Dizocilpine effects on regionally specific nicotinic and NMDA glutamate receptor binding.
Brain research, 2005Co-Authors: Edward D. Levin, Yousef Tizabi, Amir H. Rezvani, D. Patrick Caldwell, Ann Petro, Bruk GetachewAbstract:Chronic nicotine administration has long been known to increase the number of high-affinity alpha4beta2 nicotinic receptors with lesser effects on low-affinity alpha7 nicotinic receptors. Nicotine has been shown to promote the release of a variety of neurotransmitters including glutamate. Nicotine may also interact directly with the glutamatergic receptors. Nicotinic-glutamate interactions may be critical to the long-term effects of nicotine. Conversely, glutamatergic drugs may interact with the nicotinic system. Such interactions have important implications in interpretation of the mechanism of drug actions, especially when the drugs are given together. The current study examined the effects of chronic administration of nicotine (5 mg of the nicotine base/kg/day for 28 days), Dizocilpine (MK-801) (0.3 mg/kg/day for 28 days), an NMDA receptor antagonist, as well as the combination of the two drugs on nicotinic and NMDA receptor densities in discrete brain regions. The chronic dose of Dizocilpine used was behaviorally active causing a dramatic reduction in prepulse inhibition (PPI) of acoustic startle response. The nicotine dose used did not significantly affect PPI but previously we have found it to be behaviorally active in improving working memory function. High-affinity nicotinic receptor binding, as has been seen previously, was significantly increased by chronic nicotine in most areas. Chronic Dizocilpine alone did not affect high-affinity nicotinic receptor binding, but it did modify the effects of chronic nicotine, attenuating nicotine-induced increases in the frontal cortex and striatum. Low-affinity nicotinic binding was significantly increased by chronic nicotine in only one area, the cerebellum. Chronic Dizocilpine significantly increased low-affinity nicotinic binding in several brain areas, the colliculi, hippocampus, and the hypothalamus. The combination of nicotine and Dizocilpine attenuated the effects of each with diminished nicotine-induced increased nicotinic low-affinity binding in the cerebellum and diminished Dizocilpine-induced increased nicotinic low-affinity binding in the hippocampus and hypothalamus. In contrast, chronic nicotine and Dizocilpine had a mutually potentiating effect of increasing nicotinic low-affinity binding in the frontal cortex. NMDA receptor binding was affected only in the hippocampus, where both Dizocilpine and nicotine significantly increased binding. Chronic nicotine effects on receptor regulation are significantly affected by concurrent blockade of NMDA glutamate receptors.
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nicotine Dizocilpine interactions and working and reference memory performance of rats in the radial arm maze
Pharmacology Biochemistry and Behavior, 1998Co-Authors: Edward D. Levin, Chetan Bettegowda, Tiffaini Weaver, Channelle N. ChristopherAbstract:Both nicotinic cholinergic and NMDA glutaminergic systems are important for memory function. Nicotine has been found repeatedly to significantly improve working memory performance in the radial-arm maze. The NMDA antagonist Dizocilpine has been found to impair working memory performance. There is neuropharmacological evidence that these two systems are functionally related. Nicotine is potent at releasing many transmitters including glutamate. The current study was conducted to examine the interaction of nicotinic and NMDA systems with regard to working and reference memory. Rats were trained on a working/reference procedure on a 16-arm radial maze. After acquisition, they were administered nicotine (0, 0.2, and 0.4 mg/kg) and Dizocilpine (0, 100, and 200 μg/kg) alone or in combination in a repeated measures, counterbalanced design. As seen previously, nicotine at a dose of 0.2 mg/kg caused a significant improvement in working but not reference memory performance in the radial-arm maze. The 200 μg/kg dose of Dizocilpine made the rats nonresponsive on the maze so that choice accuracy could not be assessed. The 100 μg/kg dose of Dizocilpine caused significant impairments in both working and reference memory. The 0.4 mg/kg dose of nicotine significantly attenuated the Dizocilpine-induced deficit in both working and reference memory. NMDA blockade impairs working and reference memory and blocks the expression of the working memory improvement caused by 0.2 mg/kg of nicotine. However, a higher dose of 0.4 mg/kg of nicotine is effective at attenuating the Dizocilpine-induced deficit, even though this dose alone is not effective in improving performance. A second study examined the effects of a lower dose range of Dizocilpine. Comensurately smaller memory impairments were seen with lower doses of Dizocilpine down to 12.5 μg/kg, which did not produce any significant effects on memory performance or response latency. Nicotine had a more modest effect in attenuating the smaller deficits caused by these lower doses of Dizocilpine. These studies provide evidence for important interactions between nicotinic and NMDA systems with regard to memory function.
Geoffrey B Varty - One of the best experts on this subject based on the ideXlab platform.
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m100907 a serotonin 5 ht2a receptor antagonist and putative antipsychotic blocks Dizocilpine induced prepulse inhibition deficits in sprague dawley and wistar rats
Neuropsychopharmacology, 1999Co-Authors: Geoffrey B Varty, Vaishali P Bakshi, Mark A GeyerAbstract:In a recent study using Wistar rats, the serotonergic 5-HT2 receptor antagonists ketanserin and risperidone reduced the disruptive effects of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist Dizocilpine on prepulse inhibition (PPI), suggesting that there is an interaction between serotonin and glutamate in the modulation of PPI. In contrast, studies using the noncompetitive NMDA antagonist phencyclidine (PCP) in Sprague–Dawley rats found no effect with 5-HT2 antagonists. To test the hypothesis that strain differences might explain the discrepancy in these findings, risperidone was tested for its ability to reduce the PPI-disruptive effects of Dizocilpine in Wistar and Sprague–Dawley rats. Furthermore, to determine which serotonergic receptor subtype may mediate this effect, the 5-HT2A receptor antagonist M100907 (formerly MDL 100,907) and the 5-HT2C receptor antagonist SDZ SER 082 were tested against Dizocilpine. Recent studies have found that the PPI-disruptive effects of PCP are reduced by the α1 adrenergic receptor antagonist prazosin. Furthermore, the α1 receptor agonist cirazoline disrupts PPI. As risperidone and M100907 have affinity at the α1 receptor, a final study examined whether M100907 would block the effects of cirazoline on PPI. Risperidone partially, but nonsignificantly, reduced the effects of Dizocilpine in Wistar rats, although this effect was smaller than previously reported. Consistent with previous studies, risperidone did not alter the effects of Dizocilpine in Sprague–Dawley rats. Most importantly, M100907 pretreatment fully blocked the effect of Dizocilpine in both strains; whereas SDZ SER 082 had no effect. M100907 had no influence on PPI by itself and did not reduce the effects of cirazoline on PPI. These studies confirm the suggestion that serotonin and glutamate interact in modulating PPI and indicate that the 5-HT2A receptor subtype mediates this interaction. Furthermore, this interaction occurs in at least two rat strains. [Neuropsychopharmacology 20:311–321, 1999]
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M100907, a Serotonin 5-HT_2A Receptor Antagonist and Putative Antipsychotic, Blocks Dizocilpine-Induced Prepulse Inhibition Deficits in Sprague–Dawley and Wistar Rats
Neuropsychopharmacology, 1999Co-Authors: Vaishali P Bakshi, Mark A Geyer, Geoffrey B VartyAbstract:In a recent study using Wistar rats, the serotonergic 5-HT_2 receptor antagonists ketanserin and risperidone reduced the disruptive effects of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist Dizocilpine on prepulse inhibition (PPI), suggesting that there is an interaction between serotonin and glutamate in the modulation of PPI. In contrast, studies using the noncompetitive NMDA antagonist phencyclidine (PCP) in Sprague–Dawley rats found no effect with 5-HT_2 antagonists. To test the hypothesis that strain differences might explain the discrepancy in these findings, risperidone was tested for its ability to reduce the PPI-disruptive effects of Dizocilpine in Wistar and Sprague–Dawley rats. Furthermore, to determine which serotonergic receptor subtype may mediate this effect, the 5-HT_2A receptor antagonist M100907 (formerly MDL 100,907) and the 5-HT_2C receptor antagonist SDZ SER 082 were tested against Dizocilpine. Recent studies have found that the PPI-disruptive effects of PCP are reduced by the α_1 adrenergic receptor antagonist prazosin. Furthermore, the α_1 receptor agonist cirazoline disrupts PPI. As risperidone and M100907 have affinity at the α_1 receptor, a final study examined whether M100907 would block the effects of cirazoline on PPI. Risperidone partially, but nonsignificantly, reduced the effects of Dizocilpine in Wistar rats, although this effect was smaller than previously reported. Consistent with previous studies, risperidone did not alter the effects of Dizocilpine in Sprague–Dawley rats. Most importantly, M100907 pretreatment fully blocked the effect of Dizocilpine in both strains; whereas SDZ SER 082 had no effect. M100907 had no influence on PPI by itself and did not reduce the effects of cirazoline on PPI. These studies confirm the suggestion that serotonin and glutamate interact in modulating PPI and indicate that the 5-HT_2A receptor subtype mediates this interaction. Furthermore, this interaction occurs in at least two rat strains. [N europsychopharmacology 20:311–321, 1999]
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reversal of a Dizocilpine induced disruption of prepulse inhibition of an acoustic startle response by the 5 ht2 receptor antagonist ketanserin
European Journal of Pharmacology, 1995Co-Authors: Geoffrey B Varty, Guy A HigginsAbstract:Abstract Prepulse inhibition can be reliably disrupted by non-competitive NMDA receptor antagonists such as Dizocilpine. In a recent study, we found that the potent D 2 5-HT 2 receptor antagonist, risperidone, but not the selective dopamine D2 receptor antagonist, raclopride, could reverse this disruption. The present study was therefore designed to examine the effect of the 5-HT2 receptor antagonist, ketanserin, against a Dizocilpine-induced disruption of prepulse inhibition, as well as the behavioural stereotypy produced by this drug. Ketanserin (2 mg/kg) reversed the prepulse inhibition disruption produced by Dizocilpine (0.15 mg/kg), as did the non-selective 5-HT 1 5-HT 2 receptor antagonist metergoline (1 mg/kg). Both drugs also attenuated some components of the behavioural stereotypy syndrome produced by Dizocilpine (0.15 mg/kg). The present studies therefore suggest an interaction between 5-HT2 receptors and glutamaterigic systems. This may be important for the antipsychotic profile of drugs having antagonist activity at 5-HT2 receptors.
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σ Receptor ligands (+)-SKF10,047 and SA4503 improve Dizocilpine-induced spatial memory deficits in rats
European journal of pharmacology, 1998Co-Authors: Li Bo Zou, Kiyofumi Yamada, Toshitaka NabeshimaAbstract:This study examined the effects of the sigma receptor ligands (+)-N-allylnormetazocine ((+)-SKF10,047) and 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) on Dizocilpine-induced impairment of working and reference memory in a radial arm maze task in rats. Dizocilpine, a non-competitive NMDA receptor antagonist, significantly impaired both reference and working memory, an effect which was accompanied by ataxia and impairment of food intake. The Dizocilpine-induced impairment of reference memory was dose-dependently attenuated by (+)-SKF10,047 and SA4503. SA4503 also attenuated the Dizocilpine-induced working memory impairment, although (+)-SKF10,047 had no effect. Neither sigma receptor ligand affected the behavioral symptoms such as ataxia and impairment of food intake induced by Dizocilpine. The ameliorating effects of both (+)-SKF10,047 and SA4503 on Dizocilpine-induced spatial memory impairment were completely antagonized by a sigma1 receptor antagonist N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine-mon ohydrochloride. These results suggest that the interaction of sigma1 receptors with NMDA receptors modulates spatial memory in rats.
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σ receptor ligands skf10 047 and sa4503 improve Dizocilpine induced spatial memory deficits in rats
European Journal of Pharmacology, 1998Co-Authors: Li Bo Zou, Kiyofumi Yamada, Toshitaka NabeshimaAbstract:This study examined the effects of the sigma receptor ligands (+)-N-allylnormetazocine ((+)-SKF10,047) and 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) on Dizocilpine-induced impairment of working and reference memory in a radial arm maze task in rats. Dizocilpine, a non-competitive NMDA receptor antagonist, significantly impaired both reference and working memory, an effect which was accompanied by ataxia and impairment of food intake. The Dizocilpine-induced impairment of reference memory was dose-dependently attenuated by (+)-SKF10,047 and SA4503. SA4503 also attenuated the Dizocilpine-induced working memory impairment, although (+)-SKF10,047 had no effect. Neither sigma receptor ligand affected the behavioral symptoms such as ataxia and impairment of food intake induced by Dizocilpine. The ameliorating effects of both (+)-SKF10,047 and SA4503 on Dizocilpine-induced spatial memory impairment were completely antagonized by a sigma1 receptor antagonist N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine-mon ohydrochloride. These results suggest that the interaction of sigma1 receptors with NMDA receptors modulates spatial memory in rats.
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role of nitric oxide and cyclic gmp in the Dizocilpine induced impairment of spontaneous alternation behavior in mice
Neuroscience, 1996Co-Authors: Kiyofumi Yamada, Yukihiro Noda, Takayoshi Mamiya, Masayuki Hiramatsu, Masaaki Murai, T Kameyama, Yumiko Komori, Toshiaki Nikai, Hisayoshi Sugihara, Toshitaka NabeshimaAbstract:Abstract The activation of N -methyl- d -aspartate receptors induces the synthesis of nitric oxide, which activates soluble guanylate cyclase and leads to the formation of cyclic GMP in the brain. The inhibition of nitric oxide production, as well as the blockade of N -methyl- d -aspartate receptors, has been reported to prevent the induction of hippocampal long-term potentiation and learning and memory formation in vivo , although the effects of inhibitors of nitric oxide synthase are still controversial. We investigated the putative role of nitric oxide and cyclic GMP in Dizocilpine-induced memory impairment in mice. The nitric oxide synthase inhibitors, N G -nitro- l -arginine methyl ester and 7-nitro indazole, as well as Dizocilpine, a non-competitive N -methyl- d -aspartate receptor antagonist, dose-dependently impaired spatial working memory in mice, assessed by their spontaneous alternation behavior in a Y-maze. The inhibitory effects of both N G -nitro- l -arginine methyl ester and Dizocilpine on their behavior were completely reversed by 8-bromo-cyclic GMP. Cyclic GMP levels in the cerebellum were reduced by treatment with Dizocilpine. N G -Nitro- l -arginine methyl ester and 7-nitro indazole reduced cyclic GMP levels in the cerebral cortex/hippocampus and cerebellum, and the suppressive effect of N G -nitro- l -arginine methyl ester on cyclic GMP levels in the cerebral cortex/hippocampus was reversed by co-treatment with l -arginine. Cyclic AMP levels in the brain were not affected by treatment with either Dizocilpine, N G -nitro- l -arginine methyl ester, or 7-nitro indazole. Neither N G -nitro- l -arginine methyl ester nor l -arginine had any effect on monoamine and acetylcholine metabolism in the brain. These results suggest that the reduction in nitric oxide/cyclic GMP production in the brain may be responsible for Dizocilpine-induced impairment of spontaneous alternation behavior in a Y-maze.