Synergistic effect of combined treatment with risperidone and galantamine on phencyclidine-induced impairment of latent visuospatial learning and memory: Role of nAChR activation-dependent increase of dopamine D1 receptor-mediated neurotransmission

Dayong Wang, Yukihiro Noda, Yuan Zhou, Atsumi Nitta, Hiroshi Furukawa, Toshitaka Nabeshima

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Abstract

The clinically achievable efficacy of the atypical antipsychotics on cognitive symptoms of schizophrenia is practically limited by their dose-dependent side effects. Thus, there is the need for adjuvant treatments or strategies for the cognitive impairments. Further, human autopsy and genetic data in schizophrenia have indicated the existence of the abnormality of nicotinic acetylcholine receptors (nAChR). In the present study, we aimed to investigate the synergistic effect and mechanisms of a combined treatment with an atypical antipsychotic risperidone and galantamine, which is a nAChR-allosteric modulator and a modest cholinesterase inhibitor, on the impairment of latent visuospatial learning and memory in mice resembling the cognitive impairment of schizophrenia. Repeated treatment with phencyclidine (PCP, 10 mg/kg, 14 days)-induced cognitive impairment in mice in a one trial water-finding test was used as a model of the cognitive impairment of schizophrenia. In vivo microdialysis was used to investigate the extracellular concentration of dopamine in the medial prefrontal cortex (mPFC). Combined treatment with galantamine and risperidone, at low, ineffective doses (both at 0.05 mg/kg) showed a synergistic effect to reverse cognitive impairment and increase extracellular concentration of dopamine in the mPFC. The synergistic behavioral effect was abolished by a dopamine-D1 receptor antagonist, SCH 23390, and a nAChR antagonist, mecamylamine, but not a muscarinic AChR (mAChR) antagonist, scopolamine. Mecamylamine also blocked the synergistic effect on dopamine release in the mPFC of PCP-treated mice. The study indicates that galantamine and risperidone may have synergistic effect on the cognitive impairments in schizophrenia patients by synergistically promoting the nAChR activation-dependent increase of dopamine D1 receptor-mediated neurotransmission.

Original languageEnglish
Pages (from-to)379-389
Number of pages11
JournalNeuropharmacology
Volume53
Issue number3
DOIs
Publication statusPublished - 01-09-2007
Externally publishedYes

Fingerprint

Galantamine
Phencyclidine
Dopamine D1 Receptors
Risperidone
Nicotinic Receptors
Synaptic Transmission
Learning
Schizophrenia
Prefrontal Cortex
Mecamylamine
Dopamine
Antipsychotic Agents
Neurobehavioral Manifestations
Muscarinic Antagonists
Scopolamine Hydrobromide
Dopamine Antagonists
Cholinesterase Inhibitors
Microdialysis
Medical Genetics
Cholinergic Antagonists

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

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title = "Synergistic effect of combined treatment with risperidone and galantamine on phencyclidine-induced impairment of latent visuospatial learning and memory: Role of nAChR activation-dependent increase of dopamine D1 receptor-mediated neurotransmission",
abstract = "The clinically achievable efficacy of the atypical antipsychotics on cognitive symptoms of schizophrenia is practically limited by their dose-dependent side effects. Thus, there is the need for adjuvant treatments or strategies for the cognitive impairments. Further, human autopsy and genetic data in schizophrenia have indicated the existence of the abnormality of nicotinic acetylcholine receptors (nAChR). In the present study, we aimed to investigate the synergistic effect and mechanisms of a combined treatment with an atypical antipsychotic risperidone and galantamine, which is a nAChR-allosteric modulator and a modest cholinesterase inhibitor, on the impairment of latent visuospatial learning and memory in mice resembling the cognitive impairment of schizophrenia. Repeated treatment with phencyclidine (PCP, 10 mg/kg, 14 days)-induced cognitive impairment in mice in a one trial water-finding test was used as a model of the cognitive impairment of schizophrenia. In vivo microdialysis was used to investigate the extracellular concentration of dopamine in the medial prefrontal cortex (mPFC). Combined treatment with galantamine and risperidone, at low, ineffective doses (both at 0.05 mg/kg) showed a synergistic effect to reverse cognitive impairment and increase extracellular concentration of dopamine in the mPFC. The synergistic behavioral effect was abolished by a dopamine-D1 receptor antagonist, SCH 23390, and a nAChR antagonist, mecamylamine, but not a muscarinic AChR (mAChR) antagonist, scopolamine. Mecamylamine also blocked the synergistic effect on dopamine release in the mPFC of PCP-treated mice. The study indicates that galantamine and risperidone may have synergistic effect on the cognitive impairments in schizophrenia patients by synergistically promoting the nAChR activation-dependent increase of dopamine D1 receptor-mediated neurotransmission.",
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