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

研究成果: Article

28 引用 (Scopus)

抜粋

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.

元の言語English
ページ(範囲)379-389
ページ数11
ジャーナルNeuropharmacology
53
発行部数3
DOI
出版物ステータスPublished - 01-09-2007
外部発表Yes

    フィンガープリント

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cellular and Molecular Neuroscience

これを引用