Olanzapine increases cell mitotic activity and oligodendrocyte-lineage cells in the hypothalamus.
Weight gain is increasingly recognized as an unwanted side effect of atypical antipsychotic drugs. To explore the mechanisms underlying this side effect, we examined the effects of olanzapine, an atypical antipsychotic drug, on cellular proliferation and differentiation in the adult mouse hypothalamus. A 6-week treatment with olanzapine resulted in a significant increase in body weight. The sizes and numbers of olanzapine-treated mouse adipocytes were significantly larger than those of control mice. No significant differences were observed in the levels of blood insulin, cholesterol, triglyceride, leptin, and ghrelin among olanzapine-, haloperidol-treated and control mice with an exception that adiponectin was significantly higher in olanzapine group than control group. Body temperature and the level of uncoupling protein 2 were also comparable between the olanzapine-treated and control groups. We found that the treatment increased BrdU-incorporating cell numbers in the hypothalamus, while the same regimen with haloperidol or control had little effect on cellular proliferation. Double-labeling immunohistochemistry revealed that the majority of the BrdU-positive cells were also Olig2- or APC-positive, indicating that oligodendrocyte-lineage cells were generated in response to olanzapine treatment. Enhancement of hypothalamic cellular proliferation after intracerebroventricular infusion of cytosine arabinoside coincided with elevated food intake and weight gain. These findings suggest a possible link between gliogenesis in the hypothalamus and weight gain following olanzapine treatment.
Yamauchi
Takahira
T
Department of Psychiatry, Nara Medical University Faculty of Medicine, 840 Shijo-cho, Kashihara City, Nara 634-8521, Japan.
Tatsumi
Kouko
K
Makinodan
Manabu
M
Kimoto
Sohei
S
Toritsuka
Michihiro
M
Okuda
Hiroaki
H
Kishimoto
Toshifumi
T
Wanaka
Akio
A
D017667:Adipocytes / Q000187:drug effects / Q000648:ultrastructure; D000818:Animals; D000963:Antimetabolites; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D015415:Biomarkers; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001973:Bromodeoxyuridine; D019070:Cell Lineage; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D007031:Hypothalamus / Q000166:cytology* / Q000187:drug effects*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis / Q000187:drug effects*; D009043:Motor Activity / Q000187:drug effects; D000077152:Olanzapine; D009836:Oligodendroglia / Q000187:drug effects*
D000963:Antimetabolites; D014150:Antipsychotic Agents; D015415:Biomarkers; D001569:Benzodiazepines; D001973:Bromodeoxyuridine; D006220:Haloperidol; D000077152:Olanzapine