title: Influence of nicotine on doxorubicin and cyclophosphamide combination treatment-induced spatial cognitive impairment and anxiety-like behavior in rats.
abstract: In the present study, we examined the effects of nicotine on cognitive impairment, anxiety-like behavior, and hippocampal cell proliferation in rats treated with a combination of doxorubicin and cyclophosphamide. Combined treatment with doxorubicin and cyclophosphamide produced cognitive impairment and anxiety-like behavior in rats. Nicotine treatment reversed the inhibition of novel location recognition induced by the combination treatment. This effect of nicotine was blocked by methyllycaconitine, a selective α7 nicotinic acetylcholine receptor (nAChR) antagonist, and dihydro-β-erythroidine, a selective α4β2 nAChR antagonist. In addition, nicotine normalized the amount of spontaneous alternation seen during the Y-maze task, which had been reduced by the combination treatment. This effect of nicotine was inhibited by dihydro-β-erythroidine. In comparison, nicotine did not affect the anxiety-like behavior induced by the combination treatment. Furthermore, the combination treatment reduced the number of proliferating cells in the subgranular zone of the hippocampal dentate gyrus, and this was also prevented by nicotine. Finally, the combination of doxorubicin and cyclophosphamide significantly reduced hippocampal α7 nAChR mRNA expression. These results suggest that nicotine inhibits doxorubicin and cyclophosphamide-induced cognitive impairment via α7 nAChR and α4β2 nAChR, and also enhances hippocampal neurogenesis.
authors.affiliation: Department of Clinical Pharmacy; Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho; Kita-ku, Okayama, 700-8558, Japan. kitamu-y@cc.okayama-u.ac.jp.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kitamura
authors.affiliation: Department of Clinical Pharmacy; Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho; Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Erika
authors.initials: E
authors.lastname: Kanemoto
authors.affiliation: Department of Clinical Pharmacy; Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho; Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Misaki
authors.initials: M
authors.lastname: Sugimoto
authors.affiliation: Department of Clinical Pharmacy; Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho; Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Machida
authors.affiliation: Department of Clinical Pharmacy; Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho; Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Clinical Pharmacy; Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho; Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Nanami
authors.initials: N
authors.lastname: Naito
authors.affiliation: Department of Clinical Pharmacy; Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho; Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kanzaki
authors.affiliation: Department of Medical Neurobiology; Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho; Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Miyazaki
authors.affiliation: Department of Medical Neurobiology; Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho; Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Asanuma
authors.affiliation: Department of Clinical Pharmacy; Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho; Kita-ku, Okayama, 700-8558, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sendo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001007:Anxiety / Q000139:chemically induced / Q000188:drug therapy*; D001522:Behavior, Animal / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D060825:Cognitive Dysfunction / Q000139:chemically induced / Q000188:drug therapy*; D003520:Cyclophosphamide / Q000009:adverse effects*; D003975:Diazepam / Q000494:pharmacology; D004317:Doxorubicin / Q000009:adverse effects*; D004347:Drug Interactions; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D008297:Male; D009538:Nicotine / Q000494:pharmacology / Q000627:therapeutic use*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000235:genetics; D065852:Spatial Memory / Q000187:drug effects; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D018733:Nicotinic Antagonists; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2; D009538:Nicotine; D004317:Doxorubicin; D003520:Cyclophosphamide; D003975:Diazepam
keywords: Anxiety; Cognitive impairment; Cyclophosphamide; Doxorubicin; Neurogenesis; Nicotine