TY - JOUR
T1 - The influence of N-desmethylclozapine and clozapine on recognition memory and BDNF expression in hippocampus
AU - Ertuĝrul, Aygün
AU - Özdemir, Hatice
AU - Vural, Atay
AU - Dalkara, Turgay
AU - Meltzer, Herbert Y.
AU - Saka, Esen
N1 - Funding Information:
This study was supported by Turkish Psychiatric Association and Hacettepe University . NDMC was a gift from ACADIA (San Diego, USA), clozapine was a gift from Adeka companies (Samsun, Turkey). We thank Koray Basar, Yasemin Ozdemir, M. Kazim Yazici, and Bulent Elibol for their support at various steps of the study.
PY - 2011/2/1
Y1 - 2011/2/1
N2 - Clozapine, which is the most effective treatment option for treatment-refractory schizophrenia, has been reported to have both positive and negative effects on specific cognitive symptoms in patients with schizophrenia and in animal models of cognition. Clozapine has a major metabolite, N-desmethylclozapine (NDMC), which has been suggested to be more effective than clozapine itself to improve cognition. Enhancement of brain derived neurotrophic factor (BDNF) expression in the hippocampus has been proposed to contribute to the cognitive-enhancing effects of antipsychotic drugs. The aims of this study were to investigate the change in short and long term memory as assessed by the novel object recognition (NOR) test and BDNF expression in hippocampus produced by an acute hypoglutamatergic model of memory impairment in schizophrenia induced by administration of the NMDA receptor non-competitive antagonist, MK-801 and the ability of clozapine and NDMC to prevent the deleterious effects of MK-801. Both short (1. h) and long-term (24. h) memory were impaired in MK-801 (0.1. mg/kg) - and clozapine (5. mg/kg)-, but not NDMC (5. mg/kg)-treated rats. Neither NDMC (5. mg/kg) nor clozapine (5. mg/kg) reversed the effect of MK-801. Western blotting studies showed that BDNF levels in hippocampus were not different in rats administered MK-801 alone, clozapine or NDMC alone. These results show that in this model clozapine affects memory negatively, while NDMC does not. The absence of impairment of NOR with NDMC is consistent with previous evidence that it has a more benign effect on cognition than does the parent compound, and may support the efforts to study its effects on other cognitive functions. These findings do not provide any support for the role of BDNF in the MK-801-induced impairment in NOR or for differences between clozapine and NDMC.
AB - Clozapine, which is the most effective treatment option for treatment-refractory schizophrenia, has been reported to have both positive and negative effects on specific cognitive symptoms in patients with schizophrenia and in animal models of cognition. Clozapine has a major metabolite, N-desmethylclozapine (NDMC), which has been suggested to be more effective than clozapine itself to improve cognition. Enhancement of brain derived neurotrophic factor (BDNF) expression in the hippocampus has been proposed to contribute to the cognitive-enhancing effects of antipsychotic drugs. The aims of this study were to investigate the change in short and long term memory as assessed by the novel object recognition (NOR) test and BDNF expression in hippocampus produced by an acute hypoglutamatergic model of memory impairment in schizophrenia induced by administration of the NMDA receptor non-competitive antagonist, MK-801 and the ability of clozapine and NDMC to prevent the deleterious effects of MK-801. Both short (1. h) and long-term (24. h) memory were impaired in MK-801 (0.1. mg/kg) - and clozapine (5. mg/kg)-, but not NDMC (5. mg/kg)-treated rats. Neither NDMC (5. mg/kg) nor clozapine (5. mg/kg) reversed the effect of MK-801. Western blotting studies showed that BDNF levels in hippocampus were not different in rats administered MK-801 alone, clozapine or NDMC alone. These results show that in this model clozapine affects memory negatively, while NDMC does not. The absence of impairment of NOR with NDMC is consistent with previous evidence that it has a more benign effect on cognition than does the parent compound, and may support the efforts to study its effects on other cognitive functions. These findings do not provide any support for the role of BDNF in the MK-801-induced impairment in NOR or for differences between clozapine and NDMC.
KW - Brain derived neurotrophic factor (BDNF)
KW - Clozapine
KW - Memory
KW - N-desmethylclozapine (NDMC)
KW - Schizophrenia
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U2 - 10.1016/j.brainresbull.2010.11.014
DO - 10.1016/j.brainresbull.2010.11.014
M3 - Article
C2 - 21134422
AN - SCOPUS:79451473008
SN - 0361-9230
VL - 84
SP - 144
EP - 150
JO - Journal of Electrophysiological Techniques
JF - Journal of Electrophysiological Techniques
IS - 2
ER -