TY - JOUR
T1 - Synergistic effect of combined treatment with risperidone and galantamine on phencyclidine-induced impairment of latent visuospatial learning and memory
T2 - Role of nAChR activation-dependent increase of dopamine D1 receptor-mediated neurotransmission
AU - Wang, Dayong
AU - Noda, Yukihiro
AU - Zhou, Yuan
AU - Nitta, Atsumi
AU - Furukawa, Hiroshi
AU - Nabeshima, Toshitaka
N1 - Funding Information:
We appreciate Janssen Pharmaceutical K.K. (Tokyo 101-0065, Japan) for providing purified galantamine and risperidone. This work was supported, in part, by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (14370031) (15922139) (16922036) (17390018), by a Grant-in-aid from the Ministry of Education, Culture, Sports, Science and Technology to promote multidisciplinary research projects, by a Grant-in-aid for Scientific Research on Priority Areas on “Elucidation of glia-neuron network-mediated information processing systems” from the Ministry of Education, Culture, Sports, Science and Technology (16047214), by Funds from Integrated Molecular Medicine for Neuronal and Neoplastic Disorders (21st Century COE program), by the Japan Brain Foundation, by the Mitsubishi Pharma Research Foundation, by an SRF Grant for Biomedical Research, and by Brain Research Center of the 21st Century Frontier Research Program of the Ministry of Science and Technology, Republic of Korea. There is no conflict of interest to be disclosed for any of the authors.
PY - 2007/9
Y1 - 2007/9
N2 - 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.
AB - 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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U2 - 10.1016/j.neuropharm.2007.05.026
DO - 10.1016/j.neuropharm.2007.05.026
M3 - Article
C2 - 17632185
AN - SCOPUS:34547657189
SN - 0028-3908
VL - 53
SP - 379
EP - 389
JO - Neuropharmacology
JF - Neuropharmacology
IS - 3
ER -