Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden.
Beroendekliniken, Sahlgrenska University Hospital, Sweden.
Addict Biol. 2019 May;24(3):355-363. doi: 10.1111/adb.12598. Epub 2018 Jan 2.
The endocannabinoid (eCB) system modulates several phenomena related to addictive behaviors, and drug-induced changes in eCB signaling have been postulated to be important mediators of physiological and pathological reward-related synaptic plasticity. Here, we studied eCB-mediated long-term depression (eCB-LTD) in the dorsolateral striatum, a brain region critical for acquisition of habitual and automatic behavior. We report that nicotine differentially affects ex vivo eCB signaling depending on previous exposure in vivo. In the nicotine-naïve brain, nicotine facilitates eCB-signaling and LTD, whereas tolerance develops to this facilitating effect after subchronic exposure in vivo. In the end, a progressive impairment of eCB-induced LTD is established after protracted withdrawal from nicotine. Endocannabinoid-LTD is reinstated 6 months after the last drug injection, but a brief period of nicotine re-exposure is sufficient to yet again impair eCB-signaling. LTD induced by the cannabinoid 1 receptor agonist WIN55,212-2 is not affected, suggesting that nicotine modulates eCB production or release. Nicotine-induced facilitation of eCB-LTD is occluded by the dopamine D2 receptor agonist quinpirole, and by the muscarinic acetylcholine receptor antagonist scopolamine. In addition, the same compounds restore eCB-LTD during protracted withdrawal. Nicotine may thus modulate eCB-signaling by affecting dopaminergic and cholinergic neurotransmission in a long-lasting manner. Overall, the data presented here suggest that nicotine facilitates eCB-LTD in the initial phase, which putatively could promote neurophysiological and behavioral adaptations to the drug. Protracted withdrawal, however, impairs eCB-LTD, which may influence or affect the ability to maintain cessation.
内源性大麻素（eCB）系统调节与成瘾行为相关的多种现象，并且药物诱导的 eCB 信号变化被推测是生理和病理性奖赏相关突触可塑性的重要介质。在这里，我们研究了背外侧纹状体中的 eCB 介导的长时程抑制（eCB-LTD），这是大脑中与习惯和自动行为获得有关的关键区域。我们报告说，尼古丁根据体内先前的暴露，以不同的方式影响体外 eCB 信号。在尼古丁未接触的大脑中，尼古丁促进 eCB 信号和 LTD，而在体内亚慢性暴露后，会对这种促进作用产生耐受性。最终，在从尼古丁中长时间戒断后，会建立 eCB 诱导的 LTD 的进行性损害。内源性大麻素 LTD 在最后一次药物注射后 6 个月恢复，但短暂的尼古丁再暴露足以再次损害 eCB 信号。大麻素 1 型受体激动剂 WIN55,212-2 诱导的 LTD 不受影响，表明尼古丁调节 eCB 的产生或释放。尼古丁诱导的 eCB-LTD 易化被多巴胺 D2 受体激动剂喹吡罗和毒蕈碱乙酰胆碱受体拮抗剂东莨菪碱阻断。此外，相同的化合物在长时间戒断期间恢复 eCB-LTD。因此，尼古丁可能通过以持久的方式影响多巴胺能和胆碱能神经传递来调节 eCB 信号。总体而言，本文提供的数据表明，尼古丁在初始阶段促进 eCB-LTD，这可能促进对药物的神经生理和行为适应。然而，长时间戒断会损害 eCB-LTD，这可能会影响或影响维持戒断的能力。
