Neural mechanisms mediating circadian phase resetting by activation of 5-HT(7) receptors in the dorsal raphe: roles of GABAergic and glutamatergic neurotransmission.

5-HT(7) receptors in the dorsal raphe nucleus (DRN) influence circadian rhythms, sleep, and serotonin release. Because interactions between 5-HT(7) receptors and glutamatergic and GABAergic neurons have been demonstrated previously, the current studies tested the hypothesis that GABAergic and/or glutamatergic neurons mediate phase shifts induced by activation of DRN 5-HT(7) receptors. Hamsters were fitted with guide cannulae aimed at the DRN, housed in cages with running wheels, and exposed to 14h light (L):10h dark (D). In Experiment 1, hamsters received DRN pretreatment with muscimol (87.6 pmol) or vehicle before DRN 8-OH-DPAT (6 pmol) microinjections at ZT6. After exposure to constant darkness (10 days), phase shifts were calculated and animals were re-exposed to 14L:10D. The procedure was repeated to give each animal the alternate pretreatment. In Experiment 2, hamsters received DRN pretreatment with NMDA (20 pmol) or vehicle before 8-OH-DPAT at ZT 6. Other experiments tested the effects of single DRN microinjections of muscimol, bicuculline (136 pmol), NMDA, MK-801 (10 pmol) or vehicle. Phase shifts (mean ± S.E.M., h) in muscimol/8-OH-DPAT-microinjected hamsters (1.02 ± 0.30) were not different (P=0.11) from those in vehicle/8-OH-DPAT-microinjected hamsters (1.34 ± 0.30), while those in NMDA/8-OH-DPAT-microinjected hamsters (0.67 ± 0.17) were smaller (P<0.05) than those in vehicle/8-OH-DPAT-microinjected hamsters (0.97 ± 0.10). DRN single microinjections of bicuculline, but not muscimol, NMDA, or MK-801 induced phase advances. Bicuculline also potentiated 8-OH-DPAT-induced phase advances (P<0.05). These finding suggest that the mechanism mediating DRN 5-HT(7) receptor induction of phase advances involves decreased glutamatergic neurotransmission, and furthermore, that inhibition of DRN GABAergic neurotransmission causes a phase advance.