Δ9-Tetrahydrocannabinol does not upregulate an aversive dopamine receptor mechanism in adolescent brain unlike in adults.
Δ9-Tetrahydrocannabinol does not upregulate an aversive dopamine receptor mechanism in adolescent brain unlike in adults.
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DOI：
10.1016/j.crneur.2023.100107
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
George, Susan R
中科院分区：
文献类型：
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作者：
Di Raddo, Marie-Eve;Milenkovic, Marija;Sivasubramanian, Meenalochani;Hasbi, Ahmed;Bergman, Jack;Withey, Sarah;Madras, Bertha K;George, Susan R
使用大麻的年龄越早，患大麻使用障碍和成瘾、焦虑、烦躁不安、精神病等不良后果的风险就越高，这主要是由于其主要精神活性成分Δ9-tetrahydrocannabinol（四氢大麻酚）和多巴胺能功能的改变。由于多巴胺D1-D2受体异聚体激活导致焦虑和快感缺乏，该信号复合体被认为有助于四氢大麻酚诱导的情感症状。为了研究这一点，我们对青春期猴子和青春期或成年大鼠反复施用四氢大麻酚。Drug-naïve青春期大鼠D1-D2异聚体纹状体密度低于成年大鼠。青春期大鼠和青春期猴反复给予四氢大麻酚后，成年大鼠伏隔核和背纹状体D1-D2异构体的表达没有变化，但上调了D1-D2异构体的表达。行为上，四氢大麻酚处理的成年大鼠，而不是青春期大鼠，表现出焦虑和快感缺乏样行为，复合负面情绪得分升高，与纹状体D1-D2密度相关。四氢大麻酚改变了成人纹状体中D1-D2激活的下游标记物，但对青少年纹状体没有影响。四氢大麻酚加大麻二酚对D1-D2的表达没有影响。在成年大鼠中，CB1受体（CB1R）逆激动剂与四氢大麻酚共给药可减弱D1-D2的上调，暗示大麻素参与调节纹状体D1-D2异聚体的表达。四氢大麻酚暴露揭示了一种适应性的年龄特异性、焦虑性和反奖励机制，这种机制在成年纹状体中有效，但在青春期大鼠和猴子纹状体中缺乏，这可能使青春期大鼠和猴子纹状体对四氢大麻酚奖励的敏感性增加，同时限制了其负面影响，从而促进了四氢大麻酚的持续使用，并增加了对大麻长期不良影响的脆弱性。多巴胺D1-D2异源体纹状体表达随青春期成熟而增加。慢性四氢大麻酚可上调成年大鼠和猴子的D1-D2异构体，但对青春期大鼠和猴子无调节作用。D1-D2异聚体下游信号仅在成人NAc中被四氢大麻酚激活。四氢大麻酚诱导的成年大鼠负性情绪与纹状体D1-D2表达相关。四氢大麻酚对D1-D2异构体的上调依赖于cb1r。
Earlier age of cannabis usage poses higher risk of Cannabis Use Disorder and adverse consequences, such as addiction, anxiety, dysphoria, psychosis, largely attributed to its principal psychoactive component, Δ9-tetrahydrocannabinol (THC) and altered dopaminergic function. As dopamine D1-D2 receptor heteromer activation causes anxiety and anhedonia, this signaling complex was postulated to contribute to THC-induced affective symptoms. To investigate this, we administered THC repeatedly to adolescent monkeys and adolescent or adult rats. Drug-naïve adolescent rat had lower striatal densities of D1-D2 heteromer compared to adult rat. Repeated administration of THC to adolescent rat or adolescent monkey did not alter D1-D2 heteromer expression in nucleus accumbens or dorsal striatum but upregulated it in adult rat. Behaviourally, THC-treated adult, but not adolescent rat manifested anxiety and anhedonia-like behaviour, with elevated composite negative emotionality scores that correlated with striatal D1-D2 density. THC modified downstream markers of D1-D2 activation in adult, but not adolescent striatum. THC administered with cannabidiol did not alter D1-D2 expression. In adult rat, co-administration of CB1 receptor (CB1R) inverse agonist with THC attenuated D1-D2 upregulation, implicating cannabinoids in the regulation of striatal D1-D2 heteromer expression. THC exposure revealed an adaptable age-specific, anxiogenic, anti-reward mechanism operant in adult striatum but deficient in adolescent rat and monkey striatum that may confer increased sensitivity to THC reward in adolescence while limiting its negative effects, thus promoting continued use and increasing vulnerability to long-term adverse cannabis effects. Dopamine D1-D2 heteromer striatal expression increases with adolescent maturation. Chronic THC upregulates D1-D2 heteromer in adult but not adolescent rat or monkey. D1-D2 heteromer downstream signaling is activated by THC only in adult NAc. THC-induced negative emotionality in adult rat correlates to striatal D1-D2 expression. D1-D2 heteromer upregulation by THC is CB1R-dependent.