The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Herbert Y Meltzer - One of the best experts on this subject based on the ideXlab platform.

  • muscarinic receptor signaling contributes to atypical antipsychotic drug reversal of the phencyclidine induced deficit in novel object recognition in rats
    Journal of Psychopharmacology, 2017
    Co-Authors: Masanori Miyauchi, Nichole M Neugebauer, Tatsuya Sato, Hossein Ardehali, Herbert Y Meltzer
    Abstract:

    Enhancement of cholinergic function via muscarinic acetylcholine receptor M1 agonism improves cognition in some schizophrenia patients. Most atypical antipsychotic drugs, including clozapine and its active metabolite, N-Desmethylclozapine, and lurasidone, enhance the release of acetylcholine in key brain regions involved in cognition (e.g. hippocampus). We determined the effect of muscarinic acetylcholine receptor M1 stimulation on novel object recognition and its contribution to the ability of atypical antipsychotic drugs to reverse the novel object recognition deficit in rats withdrawn from subchronic phencyclidine, a rodent model of cognitive impairment in schizophrenia. In control rats, the non-specific muscarinic acetylcholine receptor antagonist, scopolamine, and the M1 selective antagonist, VU0255035, induced a novel object recognition deficit, which was reversed by the M1 agonist, AC260584. Scopolamine fully blocked the effect of clozapine and N-Desmethylclozapine, but not lurasidone, to restore novel object recognition in subchronic phencyclidine-treated rats. VU0255035 also blocked these effects of clozapine and N-Desmethylclozapine, but not lurasidone; however, the blockade was not as complete as that achieved with scopolamine. Furthermore, subchronic phencyclidine increased hippocampal M1 mRNA expression. These data suggest that M1 agonism is required for clozapine and N-Desmethylclozapine to ameliorate the phencyclidine-induced deficit in novel object recognition, additional evidence that M1 agonism is a potential target for treating cognitive impairment in schizophrenia.

  • discriminative stimulus properties of n Desmethylclozapine the major active metabolite of the atypical antipsychotic clozapine in c57bl 6 mice
    Behavioural Pharmacology, 2012
    Co-Authors: Jason M Wiebelhaus, Herbert Y Meltzer, Sarah A Vunck, Joseph H Porter
    Abstract:

    N-Desmethylclozapine (NDMC) is the major active metabolite of the atypical antipsychotic drug clozapine and may contribute to the therapeutic efficacy of clozapine. Although they share many pharmacological features, it is noteworthy that NDMC is a partial dopamine D2 and cholinergic muscarinic M1/M4 agonist, whereas clozapine is a weak dopamine D2 receptor inverse agonist/antagonist and a nonselective muscarinic antagonist. To better understand the in-vivo pharmacological mechanisms of these drugs, male C57BL/6NHsd-wild-type mice were trained to discriminate 10.0 mg/kg NDMC from vehicle in a two-lever drug discrimination procedure for food reward. It was found that the parent drug clozapine fully substituted for NDMC, whereas the typical antipsychotic drug haloperidol (dopamine D2 antagonist) and the atypical antipsychotic drug aripiprazole (D2 partial agonist) did not substitute for NDMC. These results demonstrated that clozapine and its major metabolite NDMC share in-vivo behavioral properties (i.e. discriminative stimulus properties) that are likely due to shared pharmacological mechanisms that differ from other antipsychotic drugs. The discriminative stimulus properties of NDMC probably reflect a compound cue similar to that of its parent drug clozapine due to its diverse binding profile.

  • the metabolites n Desmethylclozapine and n desmethylolanzapine produce cross tolerance to the discriminative stimulus of the atypical antipsychotic clozapine in c57bl 6 mice
    Behavioural Pharmacology, 2011
    Co-Authors: Jason M Wiebelhaus, Herbert Y Meltzer, Kevin A Webster, Joseph H Porter
    Abstract:

    It has been previously shown that cross-tolerance to the discriminative stimulus properties of clozapine can be demonstrated with the drug discrimination paradigm. This study examined the ability of N-Desmethylclozapine and N-desmethylolanzapine (metabolites of the atypical antipsychotic drugs cloza

  • attenuation of phencyclidine induced object recognition deficits by the combination of atypical antipsychotic drugs and pimavanserin acp 103 a 5 hydroxytryptamine2a receptor inverse agonist
    Journal of Pharmacology and Experimental Therapeutics, 2010
    Co-Authors: S Snigdha, Masakuni Horiguchi, Joanna C. Neill, Zhu Li, Mohammed Shahid, Herbert Y Meltzer
    Abstract:

    Subchronic administration of the N -methyl-d-aspartate receptor antagonist, phencyclidine (PCP), in rodents has been shown to produce impairment in novel object recognition (NOR), a model of visual learning and memory. We tested the hypothesis that the selective 5-HT2A inverse agonists, pimavanserin and ( R )-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl]-4-piperidinemethanol (M100907), would potentiate subeffective doses of atypical antipsychotic drugs (APDs) to reverse the NOR deficits. Female rats received vehicle or PCP (2 mg/kg b.i.d.) for 7 days, followed by a 7-day washout. Pimavanserin (3 mg/kg) or M100907 (1 mg/kg) alone, or four atypicial APDs, risperidone (0.05–0.1 mg/kg), melperone (1–3 mg/kg), olanzapine (1–2 mg/kg), or N -Desmethylclozapine (1–2 mg/kg), and the typical APD, haloperidol (0.05–0.1 mg/kg), were administered alone, or in combination with pimavanserin or M100907, before NOR testing. The exploration times of objects during 3-min acquisition and retention trials, separated by a 1-min interval, were compared by analysis of variance. Vehicle-, but not PCP-treated, animals, explored the novel object significantly more than the familiar in the retention trial ( p < 0.05–0.01). Pretreatment with the higher doses of the atypical APDs, but not pimavanserin, M100907, or haloperidol alone, reversed the effects of PCP. The effect of risperidone was blocked by haloperidol pretreatment. Coadministration of pimavanserin or M100907, with ineffective doses of the atypical APDs, but not haloperidol, also reversed the PCP-induced deficit in NOR. These results support the importance of 5-hydroxytryptamine2A receptor blockade relative to D2 receptor blockade in the ability of atypicals to ameliorate the effect of subchronic PCP, a putative measure of cognitive dysfunction in schizophrenia.

  • effect of muscarinic receptor agonists xanomeline and sabcomeline on acetylcholine and dopamine efflux in the rat brain comparison with effects of 4 3 4 butylpiperidin 1 yl propyl 7 fluoro 4h benzo 1 4 oxazin 3 one ac260584 and n Desmethylclozapine
    European Journal of Pharmacology, 2008
    Co-Authors: Shikha Snigdha, Alex S Roseman, Jin Dai, Herbert Y Meltzer
    Abstract:

    Abstract We have demonstrated that the main metabolite of clozapine, N -Desmethylclozapine, has a significant role in the ability of clozapine to improve some aspects of cognition in schizophrenia. Furthermore, there is also evidence to suggest that it is the muscarinic M 1 receptor agonist effect of N -Desmethylclozapine that underlies its cognitive effects. In the present study we examined the efficacy of two muscarinic receptor agonists xanomeline and sabcomeline to increase the efflux of acetylcholine and dopamine in rat medial prefrontal cortex and nucleus accumbens. Microdialysis in awake, freely moving rats was used to demonstrate that xanomeline at 10, but not 1 or 3 mg/kg (s.c.), significantly increased acetylcholine efflux in both the medial prefrontal cortex and nucleus accumbens. Sabcomeline, at 1 but not 0.1 or 0.5 mg/kg (s.c.), significantly increased acetylcholine efflux in the medial prefrontal cortex but not the nucleus accumbens. Both xanomeline and sabcomeline dose-dependently increased dopamine efflux in the medial prefrontal cortex but only high dose of xanomeline (10 mg/kg, s.c.) and sabcomeline (1 mg/kg, s.c.) increased that in the nucleus accumbens. The acetylcholine and dopamine efflux induced by xamomeline (10 mg/kg, s.c.) and sabcomeline (1 mg/kg, s.c.) were significantly blocked by the preferential muscarinic M 1 receptor antagonist telenzepine (3 mg/kg, s.c.), but significantly potentiated by the atypical antipsychotic drug risperidone (0.1 mg/kg, s.c.), which does not have much affinity for muscarinic receptor(s). According to the analysis of net-AUC (area under the curve) values of acetylcholine and dopamine levels, the rank order of ability of these drugs to increase acetylcholine or dopamine levels is sabcomeline > xanomeline ≈ AC260584 >  N -Desmethylclozapine. The present study suggests that the binding potency of muscarinic M 1 receptors is greatly related to their ability to increase cortical acetylcholine and dopamine efflux, and that this may have some relevance for treatment of the cognitive deficit of schizophrenia.

Shikha Snigdha - One of the best experts on this subject based on the ideXlab platform.

  • effect of muscarinic receptor agonists xanomeline and sabcomeline on acetylcholine and dopamine efflux in the rat brain comparison with effects of 4 3 4 butylpiperidin 1 yl propyl 7 fluoro 4h benzo 1 4 oxazin 3 one ac260584 and n Desmethylclozapine
    European Journal of Pharmacology, 2008
    Co-Authors: Shikha Snigdha, Alex S Roseman, Jin Dai, Herbert Y Meltzer
    Abstract:

    Abstract We have demonstrated that the main metabolite of clozapine, N -Desmethylclozapine, has a significant role in the ability of clozapine to improve some aspects of cognition in schizophrenia. Furthermore, there is also evidence to suggest that it is the muscarinic M 1 receptor agonist effect of N -Desmethylclozapine that underlies its cognitive effects. In the present study we examined the efficacy of two muscarinic receptor agonists xanomeline and sabcomeline to increase the efflux of acetylcholine and dopamine in rat medial prefrontal cortex and nucleus accumbens. Microdialysis in awake, freely moving rats was used to demonstrate that xanomeline at 10, but not 1 or 3 mg/kg (s.c.), significantly increased acetylcholine efflux in both the medial prefrontal cortex and nucleus accumbens. Sabcomeline, at 1 but not 0.1 or 0.5 mg/kg (s.c.), significantly increased acetylcholine efflux in the medial prefrontal cortex but not the nucleus accumbens. Both xanomeline and sabcomeline dose-dependently increased dopamine efflux in the medial prefrontal cortex but only high dose of xanomeline (10 mg/kg, s.c.) and sabcomeline (1 mg/kg, s.c.) increased that in the nucleus accumbens. The acetylcholine and dopamine efflux induced by xamomeline (10 mg/kg, s.c.) and sabcomeline (1 mg/kg, s.c.) were significantly blocked by the preferential muscarinic M 1 receptor antagonist telenzepine (3 mg/kg, s.c.), but significantly potentiated by the atypical antipsychotic drug risperidone (0.1 mg/kg, s.c.), which does not have much affinity for muscarinic receptor(s). According to the analysis of net-AUC (area under the curve) values of acetylcholine and dopamine levels, the rank order of ability of these drugs to increase acetylcholine or dopamine levels is sabcomeline > xanomeline ≈ AC260584 >  N -Desmethylclozapine. The present study suggests that the binding potency of muscarinic M 1 receptors is greatly related to their ability to increase cortical acetylcholine and dopamine efflux, and that this may have some relevance for treatment of the cognitive deficit of schizophrenia.

  • effect of muscarinic receptor agonists xanomeline and sabcomeline on acetylcholine and dopamine efflux in the rat brain comparison with effects of 4 3 4 butylpiperidin 1 yl propyl 7 fluoro 4h benzo 1 4 oxazin 3 one ac260584 and n Desmethylclozapine
    European Journal of Pharmacology, 2008
    Co-Authors: Shikha Snigdha, Alex S Roseman, Jin Dai, Herbert Y Meltzer
    Abstract:

    We have demonstrated that the main metabolite of clozapine, N-Desmethylclozapine, has a significant role in the ability of clozapine to improve some aspects of cognition in schizophrenia. Furthermore, there is also evidence to suggest that it is the muscarinic M(1) receptor agonist effect of N-Desmethylclozapine that underlies its cognitive effects. In the present study we examined the efficacy of two muscarinic receptor agonists xanomeline and sabcomeline to increase the efflux of acetylcholine and dopamine in rat medial prefrontal cortex and nucleus accumbens. Microdialysis in awake, freely moving rats was used to demonstrate that xanomeline at 10, but not 1 or 3 mg/kg (s.c.), significantly increased acetylcholine efflux in both the medial prefrontal cortex and nucleus accumbens. Sabcomeline, at 1 but not 0.1 or 0.5 mg/kg (s.c.), significantly increased acetylcholine efflux in the medial prefrontal cortex but not the nucleus accumbens. Both xanomeline and sabcomeline dose-dependently increased dopamine efflux in the medial prefrontal cortex but only high dose of xanomeline (10 mg/kg, s.c.) and sabcomeline (1 mg/kg, s.c.) increased that in the nucleus accumbens. The acetylcholine and dopamine efflux induced by xamomeline (10 mg/kg, s.c.) and sabcomeline (1 mg/kg, s.c.) were significantly blocked by the preferential muscarinic M(1) receptor antagonist telenzepine (3 mg/kg, s.c.), but significantly potentiated by the atypical antipsychotic drug risperidone (0.1 mg/kg, s.c.), which does not have much affinity for muscarinic receptor(s). According to the analysis of net-AUC (area under the curve) values of acetylcholine and dopamine levels, the rank order of ability of these drugs to increase acetylcholine or dopamine levels is sabcomeline>xanomeline approximately AC260584>N-Desmethylclozapine. The present study suggests that the binding potency of muscarinic M(1) receptors is greatly related to their ability to increase cortical acetylcholine and dopamine efflux, and that this may have some relevance for treatment of the cognitive deficit of schizophrenia.

Jin Dai - One of the best experts on this subject based on the ideXlab platform.

  • effect of muscarinic receptor agonists xanomeline and sabcomeline on acetylcholine and dopamine efflux in the rat brain comparison with effects of 4 3 4 butylpiperidin 1 yl propyl 7 fluoro 4h benzo 1 4 oxazin 3 one ac260584 and n Desmethylclozapine
    European Journal of Pharmacology, 2008
    Co-Authors: Shikha Snigdha, Alex S Roseman, Jin Dai, Herbert Y Meltzer
    Abstract:

    Abstract We have demonstrated that the main metabolite of clozapine, N -Desmethylclozapine, has a significant role in the ability of clozapine to improve some aspects of cognition in schizophrenia. Furthermore, there is also evidence to suggest that it is the muscarinic M 1 receptor agonist effect of N -Desmethylclozapine that underlies its cognitive effects. In the present study we examined the efficacy of two muscarinic receptor agonists xanomeline and sabcomeline to increase the efflux of acetylcholine and dopamine in rat medial prefrontal cortex and nucleus accumbens. Microdialysis in awake, freely moving rats was used to demonstrate that xanomeline at 10, but not 1 or 3 mg/kg (s.c.), significantly increased acetylcholine efflux in both the medial prefrontal cortex and nucleus accumbens. Sabcomeline, at 1 but not 0.1 or 0.5 mg/kg (s.c.), significantly increased acetylcholine efflux in the medial prefrontal cortex but not the nucleus accumbens. Both xanomeline and sabcomeline dose-dependently increased dopamine efflux in the medial prefrontal cortex but only high dose of xanomeline (10 mg/kg, s.c.) and sabcomeline (1 mg/kg, s.c.) increased that in the nucleus accumbens. The acetylcholine and dopamine efflux induced by xamomeline (10 mg/kg, s.c.) and sabcomeline (1 mg/kg, s.c.) were significantly blocked by the preferential muscarinic M 1 receptor antagonist telenzepine (3 mg/kg, s.c.), but significantly potentiated by the atypical antipsychotic drug risperidone (0.1 mg/kg, s.c.), which does not have much affinity for muscarinic receptor(s). According to the analysis of net-AUC (area under the curve) values of acetylcholine and dopamine levels, the rank order of ability of these drugs to increase acetylcholine or dopamine levels is sabcomeline > xanomeline ≈ AC260584 >  N -Desmethylclozapine. The present study suggests that the binding potency of muscarinic M 1 receptors is greatly related to their ability to increase cortical acetylcholine and dopamine efflux, and that this may have some relevance for treatment of the cognitive deficit of schizophrenia.

  • effect of muscarinic receptor agonists xanomeline and sabcomeline on acetylcholine and dopamine efflux in the rat brain comparison with effects of 4 3 4 butylpiperidin 1 yl propyl 7 fluoro 4h benzo 1 4 oxazin 3 one ac260584 and n Desmethylclozapine
    European Journal of Pharmacology, 2008
    Co-Authors: Shikha Snigdha, Alex S Roseman, Jin Dai, Herbert Y Meltzer
    Abstract:

    We have demonstrated that the main metabolite of clozapine, N-Desmethylclozapine, has a significant role in the ability of clozapine to improve some aspects of cognition in schizophrenia. Furthermore, there is also evidence to suggest that it is the muscarinic M(1) receptor agonist effect of N-Desmethylclozapine that underlies its cognitive effects. In the present study we examined the efficacy of two muscarinic receptor agonists xanomeline and sabcomeline to increase the efflux of acetylcholine and dopamine in rat medial prefrontal cortex and nucleus accumbens. Microdialysis in awake, freely moving rats was used to demonstrate that xanomeline at 10, but not 1 or 3 mg/kg (s.c.), significantly increased acetylcholine efflux in both the medial prefrontal cortex and nucleus accumbens. Sabcomeline, at 1 but not 0.1 or 0.5 mg/kg (s.c.), significantly increased acetylcholine efflux in the medial prefrontal cortex but not the nucleus accumbens. Both xanomeline and sabcomeline dose-dependently increased dopamine efflux in the medial prefrontal cortex but only high dose of xanomeline (10 mg/kg, s.c.) and sabcomeline (1 mg/kg, s.c.) increased that in the nucleus accumbens. The acetylcholine and dopamine efflux induced by xamomeline (10 mg/kg, s.c.) and sabcomeline (1 mg/kg, s.c.) were significantly blocked by the preferential muscarinic M(1) receptor antagonist telenzepine (3 mg/kg, s.c.), but significantly potentiated by the atypical antipsychotic drug risperidone (0.1 mg/kg, s.c.), which does not have much affinity for muscarinic receptor(s). According to the analysis of net-AUC (area under the curve) values of acetylcholine and dopamine levels, the rank order of ability of these drugs to increase acetylcholine or dopamine levels is sabcomeline>xanomeline approximately AC260584>N-Desmethylclozapine. The present study suggests that the binding potency of muscarinic M(1) receptors is greatly related to their ability to increase cortical acetylcholine and dopamine efflux, and that this may have some relevance for treatment of the cognitive deficit of schizophrenia.

  • n Desmethylclozapine a major metabolite of clozapine increases cortical acetylcholine and dopamine release in vivo via stimulation of m1 muscarinic receptors
    Neuropsychopharmacology, 2005
    Co-Authors: Mei Huang, Jin Dai, Junji Ichikawa, Herbert Y Meltzer
    Abstract:

    The active moiety of clozapine, the prototypical antipsychotic drug, consists of clozapine and its major metabolite, N-Desmethylclozapine (NDMC). Previous studies have suggested that NDMC may be more important than the patent compound itself for the improvement in cognition in patients with schizophrenia treated with clozapine. While the pharmacology of clozapine and NDMC are similar in most respects, NDMC has been shown to be an M1 muscarinic receptor partial agonist whereas clozapine is an M1 antagonist in vitro and in vivo. We hypothesized that NDMC may improve cognition by increasing dopamine (DA) and acetylcholine (ACh) release in medial prefrontal cortex (mPFC) via direct stimulation of M1 receptors, whereas both NDMC and clozapine itself would do so by other mechanisms as well, and that clozapine would inhibit the M1 agonist effect of NDMC. In the present study, using microdialysis in awake, freely moving rats, we found that NDMC at doses of 10 and 20, but not 5 mg/kg, significantly increased DA and ACh release in the mPFC and HIP, but not in the nucleus accumbens (NAC). The M1-preferring antagonist, telenzepine (3 mg/kg), completely blocked NDMC (10 mg/kg)-induced increases in cortical DA and ACh release. Clozapine (1.25 mg/kg), which by itself had no effect on DA or ACh release in the cortex, blocked NDMC (10 mg/kg)-induced ACh, but not DA, release in the mPFC. The 5-HT1A receptor antagonist, WAY100635 (0.2 mg/kg) blocked NDMC (20 mg/kg)-induced cortical DA but not ACh release. These findings suggest that: (1) NDMC is an M1 agonist while clozapine is an M1 antagonist in vivo; (2) M1 agonism of NDMC can contribute to the release of cortical ACh and DA release; (3) NDMC, because of its M1 agonism, may more effectively treat the cognitive impairments observed in schizophrenia than clozapine itself; and (4) M1 receptor agonism may be a valuable target for the development of drugs that can improve cognitive deficit in schizophrenia, and perhaps other neuropsychiatric disorders as well.

Alex S Roseman - One of the best experts on this subject based on the ideXlab platform.

  • effect of muscarinic receptor agonists xanomeline and sabcomeline on acetylcholine and dopamine efflux in the rat brain comparison with effects of 4 3 4 butylpiperidin 1 yl propyl 7 fluoro 4h benzo 1 4 oxazin 3 one ac260584 and n Desmethylclozapine
    European Journal of Pharmacology, 2008
    Co-Authors: Shikha Snigdha, Alex S Roseman, Jin Dai, Herbert Y Meltzer
    Abstract:

    Abstract We have demonstrated that the main metabolite of clozapine, N -Desmethylclozapine, has a significant role in the ability of clozapine to improve some aspects of cognition in schizophrenia. Furthermore, there is also evidence to suggest that it is the muscarinic M 1 receptor agonist effect of N -Desmethylclozapine that underlies its cognitive effects. In the present study we examined the efficacy of two muscarinic receptor agonists xanomeline and sabcomeline to increase the efflux of acetylcholine and dopamine in rat medial prefrontal cortex and nucleus accumbens. Microdialysis in awake, freely moving rats was used to demonstrate that xanomeline at 10, but not 1 or 3 mg/kg (s.c.), significantly increased acetylcholine efflux in both the medial prefrontal cortex and nucleus accumbens. Sabcomeline, at 1 but not 0.1 or 0.5 mg/kg (s.c.), significantly increased acetylcholine efflux in the medial prefrontal cortex but not the nucleus accumbens. Both xanomeline and sabcomeline dose-dependently increased dopamine efflux in the medial prefrontal cortex but only high dose of xanomeline (10 mg/kg, s.c.) and sabcomeline (1 mg/kg, s.c.) increased that in the nucleus accumbens. The acetylcholine and dopamine efflux induced by xamomeline (10 mg/kg, s.c.) and sabcomeline (1 mg/kg, s.c.) were significantly blocked by the preferential muscarinic M 1 receptor antagonist telenzepine (3 mg/kg, s.c.), but significantly potentiated by the atypical antipsychotic drug risperidone (0.1 mg/kg, s.c.), which does not have much affinity for muscarinic receptor(s). According to the analysis of net-AUC (area under the curve) values of acetylcholine and dopamine levels, the rank order of ability of these drugs to increase acetylcholine or dopamine levels is sabcomeline > xanomeline ≈ AC260584 >  N -Desmethylclozapine. The present study suggests that the binding potency of muscarinic M 1 receptors is greatly related to their ability to increase cortical acetylcholine and dopamine efflux, and that this may have some relevance for treatment of the cognitive deficit of schizophrenia.

  • effect of muscarinic receptor agonists xanomeline and sabcomeline on acetylcholine and dopamine efflux in the rat brain comparison with effects of 4 3 4 butylpiperidin 1 yl propyl 7 fluoro 4h benzo 1 4 oxazin 3 one ac260584 and n Desmethylclozapine
    European Journal of Pharmacology, 2008
    Co-Authors: Shikha Snigdha, Alex S Roseman, Jin Dai, Herbert Y Meltzer
    Abstract:

    We have demonstrated that the main metabolite of clozapine, N-Desmethylclozapine, has a significant role in the ability of clozapine to improve some aspects of cognition in schizophrenia. Furthermore, there is also evidence to suggest that it is the muscarinic M(1) receptor agonist effect of N-Desmethylclozapine that underlies its cognitive effects. In the present study we examined the efficacy of two muscarinic receptor agonists xanomeline and sabcomeline to increase the efflux of acetylcholine and dopamine in rat medial prefrontal cortex and nucleus accumbens. Microdialysis in awake, freely moving rats was used to demonstrate that xanomeline at 10, but not 1 or 3 mg/kg (s.c.), significantly increased acetylcholine efflux in both the medial prefrontal cortex and nucleus accumbens. Sabcomeline, at 1 but not 0.1 or 0.5 mg/kg (s.c.), significantly increased acetylcholine efflux in the medial prefrontal cortex but not the nucleus accumbens. Both xanomeline and sabcomeline dose-dependently increased dopamine efflux in the medial prefrontal cortex but only high dose of xanomeline (10 mg/kg, s.c.) and sabcomeline (1 mg/kg, s.c.) increased that in the nucleus accumbens. The acetylcholine and dopamine efflux induced by xamomeline (10 mg/kg, s.c.) and sabcomeline (1 mg/kg, s.c.) were significantly blocked by the preferential muscarinic M(1) receptor antagonist telenzepine (3 mg/kg, s.c.), but significantly potentiated by the atypical antipsychotic drug risperidone (0.1 mg/kg, s.c.), which does not have much affinity for muscarinic receptor(s). According to the analysis of net-AUC (area under the curve) values of acetylcholine and dopamine levels, the rank order of ability of these drugs to increase acetylcholine or dopamine levels is sabcomeline>xanomeline approximately AC260584>N-Desmethylclozapine. The present study suggests that the binding potency of muscarinic M(1) receptors is greatly related to their ability to increase cortical acetylcholine and dopamine efflux, and that this may have some relevance for treatment of the cognitive deficit of schizophrenia.

Zhu Li - One of the best experts on this subject based on the ideXlab platform.

  • attenuation of phencyclidine induced object recognition deficits by the combination of atypical antipsychotic drugs and pimavanserin acp 103 a 5 hydroxytryptamine2a receptor inverse agonist
    Journal of Pharmacology and Experimental Therapeutics, 2010
    Co-Authors: S Snigdha, Masakuni Horiguchi, Joanna C. Neill, Zhu Li, Mohammed Shahid, Herbert Y Meltzer
    Abstract:

    Subchronic administration of the N -methyl-d-aspartate receptor antagonist, phencyclidine (PCP), in rodents has been shown to produce impairment in novel object recognition (NOR), a model of visual learning and memory. We tested the hypothesis that the selective 5-HT2A inverse agonists, pimavanserin and ( R )-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl]-4-piperidinemethanol (M100907), would potentiate subeffective doses of atypical antipsychotic drugs (APDs) to reverse the NOR deficits. Female rats received vehicle or PCP (2 mg/kg b.i.d.) for 7 days, followed by a 7-day washout. Pimavanserin (3 mg/kg) or M100907 (1 mg/kg) alone, or four atypicial APDs, risperidone (0.05–0.1 mg/kg), melperone (1–3 mg/kg), olanzapine (1–2 mg/kg), or N -Desmethylclozapine (1–2 mg/kg), and the typical APD, haloperidol (0.05–0.1 mg/kg), were administered alone, or in combination with pimavanserin or M100907, before NOR testing. The exploration times of objects during 3-min acquisition and retention trials, separated by a 1-min interval, were compared by analysis of variance. Vehicle-, but not PCP-treated, animals, explored the novel object significantly more than the familiar in the retention trial ( p < 0.05–0.01). Pretreatment with the higher doses of the atypical APDs, but not pimavanserin, M100907, or haloperidol alone, reversed the effects of PCP. The effect of risperidone was blocked by haloperidol pretreatment. Coadministration of pimavanserin or M100907, with ineffective doses of the atypical APDs, but not haloperidol, also reversed the PCP-induced deficit in NOR. These results support the importance of 5-hydroxytryptamine2A receptor blockade relative to D2 receptor blockade in the ability of atypicals to ameliorate the effect of subchronic PCP, a putative measure of cognitive dysfunction in schizophrenia.

  • AC260584 (4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one), a selective muscarinic M1 receptor agonist, increases acetylcholine and dopamine release in rat medial prefrontal cortex and hippocampus.
    European journal of pharmacology, 2007
    Co-Authors: Zhu Li, Adam J Prus, Douglas W Bonhaus, Herbert Y Meltzer
    Abstract:

    Both muscarinic and nicotinic receptors are implicated in cognition. We have previously suggested that stimulation of the muscarinic M1 receptor has a beneficial effect on cognition, based upon evidence that the muscarinic M1 receptor agonist of N-Desmethylclozapine, the major metabolite of clozapine, may contribute to the ability of clozapine to improve some domains of cognition in schizophrenia. Present study examined the effectiveness of a new muscarinic M1 receptor agonist, 4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one (AC260584), to increase the release of acetylcholine and dopamine in the rat medial prefrontal cortex and hippocampus. Using microdialysis in awake, freely moving rats, AC260584, 3 and 10, but not 1 mg/kg (s.c.), significantly increased dopamine release in the medial prefrontal cortex and hippocampus. However, only the high dose of AC260584, 10 mg/kg (s.c.), significantly increased acetylcholine release in these regions. Moreover, the increases in acetylcholine release produced by AC260584, 10 mg/kg, were attenuated by the muscarinic M1 receptor antagonist telenzepine (3 mg/kg, s.c.) but not by the 5-HT1A receptor antagonist N-[2-(4-2-methoxyphenyl)-1-piperazinyl]-N-(2-pyridyl) cyclohexanecarboxamide (WAY100635, 0.2 mg/kg, s.c.). However, the increase in dopamine release produced by 10 mg/kg AC260584 was blocked by both telenzepine and WAY100635. In addition, pretreatment with the atypical antipsychotic drug risperidone (0.1 mg/kg, s.c.) potentiated AC260584 (1.0 mg/kg, s.c.)-induced acetylcholine and dopamine release in the medial prefrontal cortex. These findings suggest that the muscarinic M1 receptor agonist property of AC260584 contributes to its enhancement of cortical acetylcholine and dopamine efflux. Therefore, AC260584, as well as other muscarinic M1 receptor agonists, may be a valuable target for the development of drugs which can improve the cognitive deficits in schizophrenia and perhaps other neuropsychiatric disorders, as well.