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首页> 外文期刊>Pharmacology, Biochemistry and Behavior >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.
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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.

机译：GABA B受体的正构构调节剂发挥内在作用，并增强巴氯芬对仓鼠昼夜活动节律的光诱导相移的影响。

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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.
机译：光诱导的仓鼠生理活动节律的相移受GABA（B）受体调节。最近，描述了在GABA（B）受体上的阳性变构调节剂（PAM），但尚不清楚它们是否影响光诱导的昼夜节律的夹带。因此，我们研究了两种GABA（B）PAM，GS39783和RacBHFF，对光诱导的仓鼠昼夜轮转活动节律的提前和延迟的影响。记录了保持在黑暗中的叙利亚仓鼠的车轮行驶活动。评估腹膜内给药的药物调节光诱导的昼夜节律活动节律转变的能力。 Baclofen（3.75-15 mg / kg）剂量依赖性地抑制光诱导的相进展和仓鼠轮运行节律的延迟，其作用被选择性GABA（B）拮抗剂SCH50911（5mg / kg）阻断。单独注射时，无论是GS39783（3-30 mg / kg）还是RacBHFF（0.63-10mg / kg）都不影响相的发展，但是GS39783（3mg / kg）和RacBHFF（10mg / kg）都增强了巴氯芬（5mg / kg）的抑制作用。公斤）。在高于3mg / kg的剂量下，GS39783和RacBHFF单独显着抑制了相位延迟，这与“激动剂-变构”性质的概念一致。 GS39783（0.5mg / kg）而非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充当GABA（B）受体的PAM抑制光诱导的相进展的可能性是一致的，但是它们也对（可能是分开的）GABA（B）受体群具有“变构激动剂”作用。调制光诱导的相位延迟。 GABA（B）受体显然可作为调节与中枢神经系统疾病（如抑郁症）相关的昼夜节律障碍的药物，值得进一步研究。

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