A phase-response curve to the benzodiazepine chlordiazepoxide and the effect of geniculo-hypothalamic tract ablation

The geniculo-hypothalamic tract (GHT) provides input to the mammalian circadian pacemaker in the suprachiasmatic nucleus. Several recent reports indicate that GHT ablation blocks phase shifts to the benzodiazepines triazolam and chlordiazepoxide at circadian times (CTs) 6 and 21. In this study we tested if GHT ablation blocks phase shifts to chlordiazepoxide at a wide range of circadian phases. Syrian hamsters were housed under constant dim light, and running-wheel activity rhythms were monitored. Intraperitoneal injections of either chlordiazepoxide (100 mg/kg) or saline were administered at various circadian times, and a phase-response curve was constructed. In intact animals, chlordiazepoxide produced phase-advance shifts at CTs 0, 4, 6, and 8, and phase-delay shifts between CTs 12-14. Although bursts of increased activity were sometimes observed on the day of injection, activity does not appear to mediate chlordiazepoxide-induced phase shifts. Hamsters with > 45% GHT ablation showed no phase shifts > 20 min to chlordiazepoxide. Our results indicate that the geniculo-hypothalamic tract is necessary for the phase-shifting effects of the benzodiazepine chlordiazepoxide throughout the circadian cycle.