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.
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.
Wang
Dayong
D
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.
Noda
Yukihiro
Y
Zhou
Yuan
Y
Nitta
Atsumi
A
Furukawa
Hiroshi
H
Nabeshima
Toshitaka
T
D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005702:Galantamine / Q000627:therapeutic use*; D007859:Learning Disabilities / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy*; D051379:Mice; D008813:Mice, Inbred ICR; D017551:Microdialysis; D018697:Nootropic Agents / Q000627:therapeutic use*; D010622:Phencyclidine / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D017447:Receptors, Dopamine D1 / Q000502:physiology; D011978:Receptors, Nicotinic / Q000502:physiology; D018967:Risperidone / Q000627:therapeutic use*; D013028:Space Perception / Q000187:drug effects
D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D018697:Nootropic Agents; D017447:Receptors, Dopamine D1; D011978:Receptors, Nicotinic; D005702:Galantamine; D010622:Phencyclidine; D018967:Risperidone