Positive allosteric modulators at GABAB receptors exert intrinsic actions and enhance the influence of baclofen on light-induced phase shifts of hamster circadian activity rhythms

Abstract Light-induced phase shifts of hamster circadian activity rhythms are modulated by GABA B receptors. Recently, positive allosteric modulators (PAM)s at GABA B receptors were described, but it is not known whether they affect light-induced entrainment of circadian rhythms. Therefore, we studied the effects of two GABA B PAMs, GS39783 and RacBHFF, upon light-induced phase advances and delays of hamster circadian wheel-running activity rhythms. Wheel running activity was recorded for Syrian hamsters maintained in constant darkness. Drugs administered intraperitoneally were evaluated for their ability to modulate a light-induced shift of the circadian activity rhythm. Baclofen (3.75–15 mg/kg) dose-dependently inhibited both light-induced phase advances and delays of hamster wheel running rhythms, and its actions were blocked by the selective GABA B antagonist, SCH50911 (5 mg/kg). Neither GS39783 (3–30 mg/kg) nor RacBHFF (0.63–10 mg/kg) affected phase advances when injected alone, but both GS39783 (3 mg/kg) and RacBHFF (10 mg/kg) augmented the inhibitory effect of baclofen (5 mg/kg). At doses above 3 mg/kg, GS39783 and RacBHFF significantly inhibited phase delays alone, consistent with the notion of “agonist-allosteric” properties. GS39783 (0.5 mg/kg), but not RacBHFF (10 mg/kg), augmented the inhibitory action of baclofen on phase delays. These data are consistent with the possibility that GS39783 and RacBHFF act as PAMs at GABA B receptors inhibiting light-induced phase advances, yet that they also posses “allosteric agonist” actions at the (presumably separate) population of GABA B receptors modulating light-induced phase delays . GABA B receptors clearly warrant further investigation as agents for modulation of circadian dysfunction associated with CNS disorders such as depression.