Learning from opioid withdrawal: Effects on striatal dopamine (Commentary on Ahn et al., 2023)

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. Marco Leyton: Wrote the first draft with input from MN. Maja Nikolic: Visualization; writing—review and editing. We thank Dr. Marin Halut for assistance creating the figure. The authors have nothing to disclose. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/ejn.16235. The data that support the findings of this study are available from the corresponding author upon reasonable request.

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