Differential modulations of striatal tyrosine hydroxylase and dopamine metabolism by cannabinoid agonists as evidence for functional selectivity in vivo
Differential modulations of striatal tyrosine hydroxylase and dopamine metabolism by cannabinoid agonists as evidence for functional selectivity in vivo
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DOI：
10.1016/j.neuropharm.2012.02.003
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发表时间：
2012-06-01
影响因子：
4.7
通讯作者：
Hermans, Emmanuel
中科院分区：
文献类型：
--
作者：
Bosier, Barbara;Muccioli, Giulio G.;Hermans, Emmanuel
通常认为大麻素通过间接调节多巴胺的释放来诱导多巴胺传输的瞬时调节。然而，我们之前描述了大麻素介导的体外酪氨酸羟化酶（TH）表达的直接控制。我们在此报告大麻素激动剂对儿茶酚胺合成中这一关键酶的表达以及对成年大鼠多巴胺含量的改变的影响。正如大麻素激动剂所预期的那样，接触 Delta(9)-THC、HU 210 或 CP 55,940 会诱发僵直症和运动功能减退。我们注意到 HU 210 介导的纹状体 TH 表达显着增加，同时纹状体多巴胺含量增加，这支持了对多巴胺能活性可能的长期控制。令人惊讶的是，虽然 Delta(9)-THC 也报告了类似的趋势，但 CP 55,940 完全无法调节 TH 表达或多巴胺含量。尽管如此，通过测定组织中的药物浓度和离体结合实验，验证了 CP 55,940 进入大脑结构的情况。此外，多巴胺代谢物的分析显示纹状体 DOPAC 浓度降低，证实了 CP 55,940 的中心活性。与 CB1 大麻素受体参与这些不同反应一致，SR 141716A 可以阻止 HU 210 和 CP 55,940 介导的作用。因此，目前的数据表明 HU 210 和 CP 55,940 都会导致多巴胺神经传递系统的延迟/持续调节。然而，这些常用的大麻素激动剂具有相似的药效学特性，明显引发了不同的生化反应，突出了体内功能选择性的存在。 (C) 2012 Elsevier Ltd. 保留所有权利。
It is generally assumed that cannabinoids induce transient modulations of dopamine transmission through indirect regulation of its release. However, we previously described a direct cannabinoid-mediated control of tyrosine hydroxylase (TH) expression, in vitro. We herein report on the influence of cannabinoid agonists on the expression of this key enzyme in catecholamine synthesis as well as on the modification of dopamine content in adult rats. As expected for cannabinoid agonists, the exposure to either Delta(9)-THC, HU 210 or CP 55,940 induced both catalepsy and hypolocomotion. Supporting a possible long-lasting control on dopaminergic activity, we noticed a significant HU 210-mediated increase in TH expression in the striatum that was concomitant with an increase in striatal dopamine content. Surprisingly, while a similar trend was reported with Delta(9)-THC, CP 55,940 completely failed to modulate TH expression or dopamine content. Nevertheless, the access of CP 55,940 to brain structures was validated by determinations of drug concentrations in the tissue and by ex vivo binding experiments. Furthermore, confirming the central activity of CP 55,940, the analysis of dopamine metabolites revealed a reduction in striatal DOPAC concentrations. Consistent with the involvement of the CB1 cannabinoid receptor in these different responses, both HU 210- and CP 55,940-mediated effects were prevented by SR 141716A. Therefore, the present data suggest that both HU 210 and CP 55,940 cause a delayed/persistent regulation of the dopamine neurotransmission system. Nevertheless, these commonly used cannabinoid agonists endowed with similar pharmacodynamic properties clearly triggered distinct biochemical responses highlighting the existence of functional selectivity in vivo. (C) 2012 Elsevier Ltd. All rights reserved.