Amphetamine elevates nucleus accumbens dopamine via an action potential-dependent mechanism that is modulated by endocannabinoids
Amphetamine elevates nucleus accumbens dopamine via an action potential-dependent mechanism that is modulated by endocannabinoids
复制标题
DOI：
10.1111/ejn.13248
复制
发表时间：
2016-06-01
影响因子：
3.4
通讯作者：
Garris, Paul A.
中科院分区：
文献类型：
--
作者：
Covey, Dan P.;Bunner, Kendra D.;Garris, Paul A.
滥用药物的强化作用是通过它们提高丘脑核多巴胺的能力来介导的。安非他明（AMPH）历来被认为是增加多巴胺的动作电位独立的，非胞吐类型的释放称为外排，涉及逆转多巴胺转运蛋白功能和驱动的囊泡多巴胺耗竭。越来越多的证据表明AMPH也通过动作电位依赖性机制起作用。事实上，快速扫描循环伏安法表明，AMPH激活多巴胺瞬变，奖励相关的相位信号产生的多巴胺神经元的突发发射和依赖于完整的囊泡多巴胺。内源性大麻素促进了广泛类别的滥用药物对多巴胺瞬变的激活，这一机制尚未建立，但表明了一种共同的机制。在这里，使用快速扫描循环伏安法结合清醒大鼠的药理学操作，我们研究了AMPH诱导的多巴胺升高的动作电位和内源性大麻素依赖性。AMPH增加了瞬变的频率、幅度和持续时间，这是在多巴胺缓慢增加的基础上观察到的。令人惊讶的是，沉默多巴胺神经元放电取消了所有AMPH诱导的多巴胺升高，确定了动作电位依赖性起源。阻断大麻素1型受体可防止AMPH增加瞬时频率，类似于对其他滥用药物的影响，但不能增加瞬时持续时间和抑制多巴胺摄取。因此，AMPH通过大麻素1型受体引发瞬变并促进时间上一致的瞬变的总和来提高丘脑核多巴胺，AMPH使其数量更多，更大和更宽。总的来说，这些研究结果是不一致的AMPH引起动作电位独立的多巴胺流出和囊泡多巴胺耗竭，并支持内源性大麻素促进阶段性多巴胺信号作为一个共同的行动，在药物强化。
The reinforcing effects of abused drugs are mediated by their ability to elevate nucleus accumbens dopamine. Amphetamine (AMPH) was historically thought to increase dopamine by an action potential-independent, non-exocytotic type of release called efflux, involving reversal of dopamine transporter function and driven by vesicular dopamine depletion. Growing evidence suggests that AMPH also acts by an action potential-dependent mechanism. Indeed, fast-scan cyclic voltammetry demonstrates that AMPH activates dopamine transients, reward-related phasic signals generated by burst firing of dopamine neurons and dependent on intact vesicular dopamine. Not established for AMPH but indicating a shared mechanism, endocannabinoids facilitate this activation of dopamine transients by broad classes of abused drugs. Here, using fast-scan cyclic voltammetry coupled to pharmacological manipulations in awake rats, we investigated the action potential and endocannabinoid dependence of AMPH-induced elevations in nucleus accumbens dopamine. AMPH increased the frequency, amplitude and duration of transients, which were observed riding on top of slower dopamine increases. Surprisingly, silencing dopamine neuron firing abolished all AMPH-induced dopamine elevations, identifying an action potential-dependent origin. Blocking cannabinoid type 1 receptors prevented AMPH from increasing transient frequency, similar to reported effects on other abused drugs, but not from increasing transient duration and inhibiting dopamine uptake. Thus, AMPH elevates nucleus accumbens dopamine by eliciting transients via cannabinoid type 1 receptors and promoting the summation of temporally coincident transients, made more numerous, larger and wider by AMPH. Collectively, these findings are inconsistent with AMPH eliciting action potential-independent dopamine efflux and vesicular dopamine depletion, and support endocannabinoids facilitating phasic dopamine signalling as a common action in drug reinforcement.