Cannabinoids excite circadian clock neurons.
Cannabinoids excite circadian clock neurons.
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DOI：
10.1523/jneurosci.5838-09.2010
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发表时间：
2010-07-28
期刊：
影响因子：
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通讯作者：
van den Pol AN
中科院分区：
文献类型：
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作者：
Acuna-Goycolea C;Obrietan K;van den Pol AN
大麻素是大麻和印度大麻等滥用药物的主要活性剂，往往会产生扭曲的时间感。在这里，我们研究大麻素对大脑的生物钟，视交叉上核（SCN）的影响，使用膜片钳和细胞贴附电生理记录，RT-PCR，免疫细胞化学和行为分析。SCN表达大麻素受体CB 1 R的强表达，如用RT-PCR检测的。SCN神经元，包括使用GABA作为递质的神经元和SCN内的轴突，表达CB 1 R免疫反应性。从行为上看，大麻素并没有改变小鼠大脑中内源性自由运行的昼夜节律，但确实减弱了昼夜节律钟诱导光授时计的能力。在没有光的情况下，CB 1 R拮抗剂AM 251的输注引起适度的相移，表明内源性大麻素对时钟定时的调节。有趣的是，大麻素对视网膜下丘脑投射的谷氨酸释放没有影响，表明大麻素对视网膜下丘脑束的直接作用不太可能解释相移的抑制。在SCN内，大麻素是兴奋性的突触前CB 1 R衰减轴突GABA释放的基础上的机制。这些数据提高了大麻素使用者所描述的时间解离可能部分来自生物钟功能的改变和/或环境时间线索的夹带。
Cannabinoids, the primary active agent in drugs of abuse such as marijuana and hashish, tend to generate a distorted sense of time. Here we study the effect of cannabinoids on the brain’s circadian clock, the suprachiasmatic nucleus (SCN), using patch clamp and cell-attached electrophysiological recordings, RT-PCR, immunocytochemistry, and behavioral analysis. The SCN expressed strong expression of the cannabinoid receptor CB1R, as detected with RT-PCR. SCN neurons, including those using GABA as a transmitter, and axons within the SCN, expressed CB1R immunoreactivity. Behaviorally, cannabinoids did not alter the endogenous free-running circadian rhythm in the mouse brain, but did attenuate the ability of the circadian clock to entrain to light zeitgebers. In the absence of light, infusion of the CB1R antagonist AM251 caused a modest phase shift, suggesting endocannabinoid modulation of clock timing. Interestingly, cannabinoids had no effect on glutamate release from the retinohypothalamic projection, suggesting a direct action of cannabinoids on the retinohypothalamic tract was unlikely to explain the inhibition of the phase shift. Within the SCN, cannabinoids were excitatory by a mechanism based on presynaptic CB1R attenuation of axonal GABA release. These data raise the possibility that the time dissociation described by cannabinoid users may result in part from altered circadian clock function and/or entrainment to environmental time cues.