In people with an opioid use disorder, new bouts of drug use are commonly triggered by one of the following four events: ingestion of a small quantity of the drug, exposure to drug-paired cues, stress, or symptoms of withdrawal. The first three have been related to increased dopamine transmission (Stewart, 2008); the fourth has been associated with decreases (Shaham et al., 1996). The contrasting associations have led to disagreements about the contribution of dopamine transmission to addiction-related behaviors. These controversies are addressed in an intriguing paper published in the current special issue of the European Journal of Neuroscience (Ahn et al., 2023). In brief, laboratory rats were exposed to near-daily morphine injections for a month. Extracellular dopamine concentrations decreased in the ventral striatum during both spontaneous and naloxone-triggered withdrawal on Days 10 and 31. In comparison, extracellular dopamine concentrations increased in the dorsal striatum during naloxone-triggered withdrawal on Day 31. This naloxone-triggered increase reproduces effects recently reported in humans with an opioid use disorder; the more unpleasant the withdrawal, the greater the dorsal striatal dopamine response (Shokri-Kojori et al., 2021). Together, these findings suggest a more cohesive explanation for why all four events trigger opioid seeking and inform the following debates.

As a start, withdrawal symptoms aggravate the clinical picture of opioid use disorders. Despite this, there is evidence that withdrawal symptoms are not sufficient for an addiction, neither in humans (O'Brien et al., 2006) nor in laboratory animals (Stewart & Wise, 1992). The unclear role of withdrawal in substance use disorders led some to propose that it is a consequence of heavy drug use rather than a cause (Wise & Koob, 2014); that is, neither necessary nor sufficient. Indeed, George Koob's proposition that withdrawal has a central role in addictions (Koob & Le Moal, 1997) ruffled many a feather, seeming to contradict the extensive evidence that most goal-directed behaviors are promoted by incentive-based, reward approach processes instead of physiological need-based avoidance. The present results facilitate a rapprochement. First, withdrawal symptoms can become paired with opioid availability, enhancing the incentive salience of the drug and promoting conditioned approach (Hutcheson et al., 2001; Shaham et al., 1996). Second, if these conditioned effects are associated with dopamine elevations specifically in the dorsal striatum, the engaged mechanisms might reflect a combination of incentive motivational and habit-like processes (Giuliano et al., 2019; Hutcheson et al., 2001).

The elegance of Ahn and colleague's results noted, some questions remain. First, the dopamine responses following naloxone administration were statistically significant but not large. One wonders, then, whether larger effects might be seen following more pairing sessions, following self-administered morphine instead of passive receipt, or in the sensorimotor (dorsolateral) striatum instead of the dorsomedial (associative striatum) site targeted by Tony Phillips and colleagues (Ahn et al., 2023).

Second, an unexpected finding was that, on Day 31, increased dopamine release was seen during naloxone-triggered withdrawal but not during spontaneous withdrawal. This might reflect differences in what the animals learned. In brief, the drug schedule consisted of experimenter administered morphine injections (15 mg/kg, i.p.) once a day for 5 days followed by 2 days without drug (Ahn et al., 2023). Following the fifth dose, animals waited 72 h until their next dose, likely weakening (extinguishing) associations between spontaneous withdrawal and drug availability. In comparison, rats administered a relatively high dose of naloxone (2 mg/kg, i.p.) on Day 10 might have learned something different. High-dose naloxone induces withdrawal effects that can be more severe than those occurring during abstinence from a short opioid regimen (Young et al., 1979). Since morphine was then administered 3 h after the dose of naloxone, these animals may have learned that severe withdrawal leads to morphine delivery. If so, when rats received their second naloxone challenge on Day 31, the induced state might now act as a conditioned interoceptive cue, one that was able to elicit long-lasting dopamine responses (>3 h) capable of further increasing the salience of both internal and external drug-paired cues and promoting drug-seeking behaviors (Figure 1).

Koob and colleagues initially suggested that the development of severe addictions reflected a switch from reward pursuit processes to aversion avoidance. More recent formulations propose that multiple drug seeking triggers can operate at the same time; for example, drug cues (both interoceptive and exteroceptive) can act against a background of an abstinence syndrome (Koob & Volkow, 2016). This combination of processes might serve to simultaneously signal that it is time to get more drug and heighten the contrast between available options (Leyton, 2021).

As a concluding contribution, Ahn et al. note that their results also have treatment implications. Whereas dopamine receptor antagonists tested to date have shown little clinical efficacy, the present study might provide an explanation. Dopamine antagonists might prevent drug, cue, stress and withdrawal promoted increases in dopamine related approach but also aggravate withdrawal symptoms. Dopamine receptor agonists, in comparison, run the risk of engaging drug-seeking processes. An intermediate might be needed, a medication that can offset the aversive effects of low dopamine-related withdrawal symptoms while also diminishing dopamine surges that would promote drug seeking. Intriguingly, the authors have recently reported evidence that a botanical used in Vietnam to treat opioid withdrawal symptoms acts as a dopamine autoreceptor antagonist leading to increased accumbens dopamine release (Ahn et al., 2020). Whether this compound also has effects that will yield clinical benefits following the easing of withdrawal requires more study.

对于患有阿片类药物使用障碍的人来说，新一轮的药物使用通常是由以下四种事件之一触发的：摄入少量药物、暴露于药物配对线索、压力或戒断症状。前三个与多巴胺传输增加有关（Stewart，  2008）；第四个与减少有关（Shaham 等，  1996）。这种对比鲜明的关联导致了关于多巴胺传递对成瘾相关行为的贡献的分歧。这些争议在当前《欧洲神经科学杂志》特刊上发表的一篇有趣的论文中得到了解决（Ahn 等人，  2023 年）。简而言之，实验室老鼠在一个月内几乎每天都注射吗啡。在第 10 天和第 31 天的自发戒断和纳洛酮触发戒断期间，腹侧纹状体的细胞外多巴胺浓度下降。相比之下，在纳洛酮触发的第 31 天戒断期间，背侧纹状体的细胞外多巴胺浓度增加。这种纳洛酮触发的增加再现了最近的效果据报道，人类患有阿片类药物使用障碍；戒断越不愉快，背侧纹状体多巴胺反应就越大（Shokri-Kojori et al.,  2021）。总之，这些发现对为什么所有四个事件都会引发阿片类药物寻求提供了更有凝聚力的解释，并为以下辩论提供了信息。

首先，戒断症状会加剧阿片类药物使用障碍的临床表现。尽管如此，有证据表明戒断症状不足以导致成瘾，无论是在人类（O'Brien 等人，  2006 年）还是在实验动物中（Stewart 和 Wise，  1992 年）。由于戒断在物质使用障碍中的作用尚不明确，一些人认为这是大量吸毒的结果而不是原因（Wise & Koob，  2014）；也就是说，既不是必要的也不是充分的。事实上，乔治·库布（George Koob）关于戒断在成瘾中起着核心作用的主张（Koob＆Le Moal，  1997）激怒了许多人，这似乎与大量证据相矛盾，即大多数目标导向的行为是通过基于激励的奖励方法过程来促进的，而不是通过奖励方法来促进的。基于生理需要的回避。目前的结果有利于两国和解。首先，戒断症状可以与阿片类药物的可用性相结合，增强药物的激励显着性并促进条件方法（Hutcheson 等，  2001；Shaham 等，  1996）。其次，如果这些条件效应与背侧纹状体中的多巴胺升高有关，那么参与的机制可能反映了激励动机和习惯样过程的组合（Giuliano 等，  2019；Hutcheson 等，  2001）。

尽管 Ahn 和同事的结果很优雅，但仍然存在一些问题。首先，纳洛酮给药后的多巴胺反应具有统计学意义，但并不大。那么，有人想知道，在更多的配对过程中，在自我施用吗啡而不是被动接受之后，或者在感觉运动（背外侧）纹状体而不是托尼·菲利普斯及其同事所针对的背内侧（关联纹状体）部位之后，是否会出现更大的效果。安等人，  2023）。

其次，一个意外的发现是，在第 31 天，在纳洛酮触发的戒断过程中观察到多巴胺释放增加，但在自发戒断过程中则没有。这可能反映了动物所学到的东西的差异。简而言之，药物时间表包括实验者每天一次注射吗啡（15 mg/kg，腹腔注射），持续 5 天，然后 2 天不用药（Ahn 等人，  2023）。第五次给药后，动物等待 72 小时直到下一次给药，这可能削弱（消除）自发戒断和药物可用性之间的关联。相比之下，在第 10 天给予相对较高剂量的纳洛酮（2 毫克/千克，腹腔注射）的老鼠可能学到了不同的东西。高剂量纳洛酮引起的戒断效应可能比短期阿片类药物戒断期间发生的戒断效应更严重（Young 等，  1979）。由于在纳洛酮给药后 3 小时给予吗啡，这些动物可能已经了解到严重戒断会导致吗啡递送。如果是这样，当大鼠在第 31 天接受第二次纳洛酮挑战时，诱导状态现在可能充当条件性内感受线索，能够引发持久的多巴胺反应（> 3 小时），从而能够进一步增加两者的显着性内部和外部药物配对线索并促进寻药行为（图 1）。

库布和同事最初认为，严重成瘾的发展反映了从奖励追求过程到厌恶回避过程的转变。最近的配方提出，多个药物寻找触发因素可以同时起作用；例如，药物线索（内感受和外感受）可以在戒断综合症的背景下发挥作用（Koob＆Volkow，  2016）。这种过程的组合可能会同时发出信号，表明是时候获得更多药物并增强可用选项之间的对比（Leyton，  2021）。

作为结论性贡献，Ahn 等人。请注意，他们的结果也具有治疗意义。尽管迄今为止测试的多巴胺受体拮抗剂几乎没有显示出临床疗效，但本研究可能提供一个解释。多巴胺拮抗剂可能会阻止药物、暗示、压力和戒断促进多巴胺相关途径的增加，但也会加重戒断症状。相比之下，多巴胺受体激动剂存在参与药物寻求过程的风险。可能需要一种中间体，一种药物可以抵消低多巴胺相关戒断症状的厌恶作用，同时还能减少促进药物寻求的多巴胺激增。有趣的是，作者最近报告了证据，表明越南用于治疗阿片类药物戒断症状的植物药可作为多巴胺自身受体拮抗剂，导致伏隔核多巴胺释放增加（Ahn 等人，2020  ）。这种化合物是否也具有在戒断缓解后产生临床益处的作用，需要更多的研究。