Ehlen J Christopher, Paul Ketema N
Circadian Rhythms and Sleep Disorders Program, Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA.
Am J Physiol Regul Integr Comp Physiol. 2009 May;296(5):R1606-12. doi: 10.1152/ajpregu.90878.2008. Epub 2009 Feb 25.
GABA(A) receptor agonists act in the suprachiasmatic nucleus (SCN) to reset circadian rhythms during the day but inhibit the ability of light to reset rhythms during the night. In the present study, we examined whether these paradoxical differences in the effect of GABA(A) receptor stimulation on the circadian system are mediated by separate GABA(A) receptor subtypes. 4,5,6,7-Tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), a GABA(A) receptor agonist, preferentially activates GABA(A) receptors in extrasynaptic locations. THIP, muscimol (a GABA(A) agonist), or vehicle were microinjected into the SCN region of Syrian hamsters free-running in constant darkness during the mid-subjective day, early subjective night, or late subjective night. The subjective night injections were followed by a light pulse or sham control. Behavioral phase shifts of wheel running rhythms and both Period1 (Per1) and Per2 mRNA levels in the SCN were assessed. Animals that received THIP during the subjective day did not exhibit significant phase alterations. During the early and late subjective night, however, THIP abolished the phase-shifting effects of light and the ability of light to increase Per1 and Per2 mRNA levels. The ability of N-methyl-d-aspartic acid to phase-shift wheel running rhythms was also attenuated by THIP. Together these data demonstrate that THIP does not produce phase shifts during the subjective day, but does inhibit the ability of light to produce phase shifts. Thus, extrasynaptic GABA(A) receptors appear to play a role in regulating light input to the SCN, while a different population of GABA(A) receptors appears to be responsible for daytime effects of GABA.
γ-氨基丁酸A（GABA(A)）受体激动剂在白天作用于视交叉上核（SCN）以重置昼夜节律，但在夜间会抑制光线重置节律的能力。在本研究中，我们研究了GABA(A)受体刺激对昼夜节律系统产生的这些矛盾差异是否由不同的GABA(A)受体亚型介导。4,5,6,7-四氢异恶唑并[5,4-c]吡啶-3-醇（THIP）是一种GABA(A)受体激动剂，优先激活突触外部位的GABA(A)受体。在主观日中午、主观夜早期或主观夜晚期，将THIP、蝇蕈醇（一种GABA(A)激动剂）或赋形剂微量注射到在持续黑暗中自由活动的叙利亚仓鼠的SCN区域。主观夜注射后给予光脉冲或假对照。评估转轮节律的行为相位偏移以及SCN中Period1（Per1）和Per2 mRNA水平。在主观日接受THIP的动物未表现出明显的相位改变。然而，在主观夜早期和晚期，THIP消除了光的相位偏移效应以及光增加Per1和Per2 mRNA水平的能力。THIP还减弱了N-甲基-D-天冬氨酸使转轮节律产生相位偏移的能力。这些数据共同表明，THIP在主观日期间不会产生相位偏移，但会抑制光产生相位偏移的能力。因此，突触外GABA(A)受体似乎在调节进入SCN的光输入中发挥作用，而不同群体的GABA(A)受体似乎负责GABA在白天的作用。
