Department of Biology, Valdosta State University, Valdosta, Georgia 31602, USA.
Pharmacol Biochem Behav. 2011 Oct;99(4):712-7. doi: 10.1016/j.pbb.2011.06.029. Epub 2011 Jul 6.
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 (5mg/kg). Neither GS39783 (3-30 mg/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 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.
光诱导的仓鼠昼夜节律活动的相位移变受 GABA(B)受体的调制。最近，描述了 GABA(B)受体的正变构调节剂（PAM），但尚不清楚它们是否影响光诱导的昼夜节律同步。因此，我们研究了两种 GABA(B)PAM，GS39783 和 RacBHFF，对光诱导的仓鼠昼夜节律轮跑活动节律的相位提前和延迟的影响。仓鼠在持续黑暗中保持记录轮跑活动。通过腹膜内给药评估药物调节光诱导的昼夜节律活动节律的能力。巴氯芬（3.75-15mg/kg）剂量依赖性地抑制了光诱导的仓鼠轮跑节律的相位提前和延迟，其作用被选择性 GABA(B)拮抗剂 SCH50911（5mg/kg）阻断。GS39783（3-30mg/kg）或 RacBHFF（0.63-10mg/kg）单独注射均不影响相位提前，但 GS39783（3mg/kg）和 RacBHFF（10mg/kg）均增强了巴氯芬（5mg/kg）的抑制作用。在 3mg/kg 以上剂量时，GS39783 和 RacBHFF 单独显著抑制相位延迟，与“激动剂变构”特性的概念一致。GS39783（0.5mg/kg）但不是 RacBHFF（10mg/kg）增强了巴氯芬对相位延迟的抑制作用。这些数据与 GS39783 和 RacBHFF 作为 GABA(B)受体的 PAM 作用一致，抑制光诱导的相位提前，但它们也具有调节光诱导的相位延迟的（推测的）分离的 GABA(B)受体群体的“变构激动剂”作用。GABA(B)受体显然值得进一步研究，作为治疗与中枢神经系统疾病（如抑郁症）相关的昼夜节律功能障碍的药物。
