Effects of the Hypnotic Drug Zolpidem on Cell Proliferation and Survival in the Dentate Gyrus of Young and Old Rats

Sleep loss/disruption has been shown to suppress adult hippocampal neurogenesis. Whether the administration of hypnotic drugs, by promoting sleep, especially in older subjects, who typically exhibit poor sleep, has a beneficial effect on neurogenesis parameters is unknown. We examined the effects of zolpidem, a widely prescribed nonbenzodiazepine hypnotic, on cell proliferation and survival in the dentate gyrus of young ( approximately 2 1/2 months) and old ( approximately 13 months) male Sprague-Dawley rats. Zolpidem (5, 10 or 20 mg/kg, i.p.) or vehicle was administered twice daily, at the beginning and middle of the sleep period, for either 2 days (acute study) or 21 days (chronic study). Proliferation and cell survival were measured by staining for Ki67 or 5-bromo-2'-deoxyurdine (BrdU), respectively. Acute administration of zolpidem produced a suppression of cell proliferation, which attained statistical significance only in the aged animals. The magnitude of the suppressive effect was larger in the hilus than in the subgranular zone (SGZ). In contrast, chronic administration of zolpidem produced little or no effect on proliferation in either age group, despite marked differences in basal proliferation levels between the two age groups. Similarly, there was little change in cell survival following chronic zolpidem administration in young versus old animals. A slight reduction of cell survival in the granular cell layer (GCL)/SGZ was observed in young animals and a slight augmentation in aged animals. To the extent that zolpidem improves sleep, these data suggest little or no benefit of hypnotic drug treatment on neurogenesis parameters in young or old rats.