Chronic Δ9-tetrahydrocannabinol during adolescence provokes sex-dependent changes in the emotional profile in adult rats:: Behavioral and biochemical correlates
Chronic Δ9-tetrahydrocannabinol during adolescence provokes sex-dependent changes in the emotional profile in adult rats:: Behavioral and biochemical correlates
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DOI：
10.1038/sj.npp.1301664
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发表时间：
2008-10-01
影响因子：
7.6
通讯作者：
Parolaro, Daniela
中科院分区：
文献类型：
--
作者：
Rubino, Tiziana;Vigano', Daniela;Parolaro, Daniela
关于青少年大麻素消费的长期神经生物学后果的报道很少，而且往往相互矛盾。内源性大麻素系统在大脑发育的不同阶段起着重要作用，因为大麻素影响不同神经递质的释放和作用并促进神经发生。这项研究测试了大麻素对青春期内源性大麻素系统发育的长期干扰是否会导致成年大鼠持续的行为改变。用递增剂量的Delta（9）-四氢大麻酚（THC）处理青春期雌性和雄性大鼠11天（出生后（PND）35-45天），并且不受干扰直到成年（PND 75），此时进行行为和生物化学测定。四氢大麻酚暴露可显著降低雌性大鼠杏仁核（Amyg）、腹侧被盖区（VTA）和中脑核（NAc）的CB 1受体水平和CB 1/G蛋白偶联，而雄性大鼠仅在杏仁核和海马结构有显著改变。雌性和雄性大鼠的焦虑反应（高架十字迷宫和旷场测试）均未显示出任何变化，但雌性大鼠表现出明显的“行为绝望”（强迫游泳测试），这是由快感缺乏（蔗糖偏好）引起的。相比之下，雄性大鼠没有表现出行为绝望，但确实存在快感缺乏。这种不同的行为图片支持抑郁症的生化参数，即CREB改变。只有雌性大鼠在海马结构和前额叶皮质中CREB活性较低，而在NAc中则通过强啡肽表达的增加而具有高活性。这些结果表明，在青春期大量吸食大麻可能会引起雌性大鼠情绪回路的微妙变化，最终导致抑郁样行为，而雄性大鼠对奖励刺激的敏感性改变。
Few and often contradictory reports exist on the long-term neurobiological consequences of cannabinoid consumption in adolescents. The endocannabinoid system plays an important role during the different stages of brain development as cannabinoids influence the release and action of different neurotransmitters and promote neurogenesis. This study tested whether long-lasting interference by cannabinoids with the developing endogenous cannabinoid system during adolescence caused persistent behavioral alterations in adult rats. Adolescent female and male rats were treated with increasing doses of Delta(9)-tetrahydrocannabinol (THC) for 11 days (postnatal day (PND) 35-45) and left undisturbed until adulthood (PND 75) when behavioral and biochemical assays were carried out. CB1 receptor level and CB1/G-protein coupling were significantly reduced by THC exposure in the amygdala (Amyg), ventral tegmental area (VTA) and nucleus accumbens (NAc) of female rats, whereas male rats had significant alterations only in the amygdala and hippocampal formation. Neither female nor male rats showed any changes in anxiety responses (elevated plus maze and open-field tests) but female rats presented significant 'behavioral despair' (forced swim test) paralleled by anhedonia (sucrose preference). In contrast, male rats showed no behavioral despair but did present anhedonia. This different behavioral picture was supported by biochemical parameters of depression, namely CREB alteration. Only female rats had low CREB activity in the hippocampal formation and prefrontal cortex and high activity in the NAc paralleled by increases in dynorphin expression. These results suggest that heavy cannabis consumption in adolescence may induce subtle alterations in the emotional circuit in female rats, ending in depressive-like behavior, whereas male rats show altered sensitivity to rewarding stimuli.