Enhanced Functional Activity of the Cannabinoid Type-1 Receptor Mediates Adolescent Behavior
Enhanced Functional Activity of the Cannabinoid Type-1 Receptor Mediates Adolescent Behavior
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DOI：
10.1523/jneurosci.1937-15.2015
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发表时间：
2015-10-14
影响因子：
5.3
通讯作者：
Spanagel, Rainer
中科院分区：
文献类型：
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作者：
Schneider, Miriam;Kasanetz, Fernando;Spanagel, Rainer
青春期的特点是剧烈的行为适应，是出现各种精神疾病的特别脆弱时期。越来越多的证据表明，这些疾病的病理生理学可能源于青少年大脑正常神经发育变化的异常。因此，了解青少年行为的分子基础对于理解精神病理学的起源至关重要，但引发青少年行为的分子机制尚不清楚。在这里，我们假设大麻素1型受体（CB1R）可能在调节青少年行为中起关键作用，因为已表明增强的内源性大麻素（eCB）信号传导在青春期短暂发生。为了研究CB1R信号的增强，我们在编码CB1R的大鼠Cnr1基因中引入了一个错义突变（F238L）。根据我们的假设，携带F238L突变（Cnr1(F238L)）的大鼠应该在成年后保持青春期的行为特征。该突变受体的功能通过硅模拟得到证实，并在一系列生化和电生理实验中得到功能性验证。与野生鼠相比，突变鼠在成年期表现出类似青少年的表型，具有典型的高风险/新奇追求，同伴互动增加，冲动性增强，对药物和非药物奖励的奖励敏感性增强。在Cnr1（F238L）突变大鼠中，CB1R活性的部分抑制使行为正常化，并导致野生型表型。我们的结论是，CB1R的活动状态和功能对调节青少年行为至关重要。这些发现暗示了eCB系统作为青少年发病精神健康障碍神经病理学的重要研究目标。
Adolescence is characterized by drastic behavioral adaptations and comprises a particularly vulnerable period for the emergence of various psychiatric disorders. Growing evidence reveals that the pathophysiology of these disorders might derive from aberrations of normal neurodevelopmental changes in the adolescent brain. Understanding the molecular underpinnings of adolescent behavior is therefore critical for understanding the origin of psychopathology, but the molecular mechanisms that trigger adolescent behavior are unknown. Here, we hypothesize that the cannabinoid type-1 receptor (CB1R) may play a critical role in mediating adolescent behavior because enhanced endocannabinoid (eCB) signaling has been suggested to occur transiently during adolescence. To study enhanced CB1R signaling, we introduced a missense mutation (F238L) into the rat Cnr1 gene that encodes for the CB1R. According to our hypothesis, rats with the F238L mutation (Cnr1(F238L)) should sustain features of adolescent behavior into adulthood. Gain of function of the mutated receptor was demonstrated by in silico modeling and was verified functionally in a series of biochemical and electrophysiological experiments. Mutant rats exhibit an adolescent-like phenotype during adulthood compared with wild-type littermates, with typical high risk/novelty seeking, increased peer interaction, enhanced impulsivity, and augmented reward sensitivity for drug and nondrug reward. Partial inhibition of CB1R activity in Cnr1(F238L) mutant rats normalized behavior and led to a wild-type phenotype. We conclude that the activity state and functionality of the CB1R is critical for mediating adolescent behavior. These findings implicate the eCB system as an important research target for the neuropathology of adolescent-onset mental health disorders.