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 GABAB receptors. Recently, positive allosteric modulators (PAM)s at GABAB receptors were described, but it is not known whether they affect light-induced entrainment of circadian rhythms. Therefore, we studied the effects of two GABAB 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 (3.75–15mg/kg) dose-dependently inhibited both light-induced phase advances and delays of hamster wheel running rhythms, and its actions were blocked by the selective GABAB antagonist, SCH50911 (5mg/kg). Neither GS39783 (3–30mg/kg) nor RacBHFF (0.63–10mg/kg) affected phase advances when injected alone, but both GS39783 (3mg/kg) and RacBHFF (10mg/kg) augmented the inhibitory effect of baclofen (5mg/kg). At doses above 3mg/kg, GS39783 and RacBHFF significantly inhibited phase delays alone, consistent with the notion of “agonist-allosteric” properties. GS39783 (0.5mg/kg), but not RacBHFF (10mg/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 GABAB receptors inhibiting light-induced phase advances, yet that they also posses “allosteric agonist” actions at the (presumably separate) population of GABAB receptors modulating light-induced phase delays. GABAB receptors clearly warrant further investigation as agents for modulation of circadian dysfunction associated with CNS disorders such as depression.