Drug-induced sensitization is said to occur when a drug regimen leads to larger responses to the same dose or measurable responses to a previously ineffective low dose. Sensitization hypotheses of problematic substance use further propose that these effects facilitate the development of incentive responses to drug-paired cues.1 These effects are well-established in rodents,2–5 but, in some circles, it remains controversial whether they occur in primates (Box 1). What is the evidence?
Controversies
Contrary voices
Some well-respected researchers have expressed doubts that stimulant drug–induced sensitization develops in primates; e.g., “there is minimal evidence of sensitization in humans6,” and “sensitization… does not appear to happen in primates.7” Curiously, the latter statement was made when commenting on a study that was not about sensitization. Rhesus monkeys had self-administered cocaine for 100 days but were tested without drug and in an environment that had been paired with the absence of drug.8
History of the controversy
The debate about sensitization in primates primarily reflects 2 related issues. First, questions remain about the mediating neurobiology following extensive drug use. Second, it has been suggested that the low dopamine responses seen in people with substance use disorders under some testing conditions are the primary driver of addiction-related behaviours.9 In comparison, this writer and others propose that low dopamine states aggravate the clinical picture of addiction, but this does not include the ability to activate drug-seeking.10–13 To the contrary, there is considerable evidence for the converse.10,11,14 Dopamine release in humans is increased by all relapse triggers tested to date, including drug-related cues,15–19 small quantities of the drug,20,21 stress,22,23 and, in people with long histories of opioid use, drug withdrawal.24,25 As sagely noted by David Epstein,26 no one feature is likely to account for all clinically relevant aspects of addiction. Claims that sensitization is not one of the critical elements are likely misguided.
Implications for clinical practice
The incentive sensitization model proposes that repeated, intermittent exposure to strong rewards progressively increases their ability to elicit approach.4,12,13 These processes can become tied to either healthy or unhealthy pursuits.13,27,28 There is little evidence that the effects can be reversed, but, among those with addictions, there is evidence that sensitization-influenced reinforcement processes can be redirected toward healthy ones; e.g., the financial rewards provided in contingency management therapy.13,29
The evidence of drug-induced sensitization in humans has also raised concerns about prescribing stimulant medications to youth with attention deficit/hyperactivity disorder. There is little evidence that standard continuous exposure regimens of low to moderate doses lead to sensitization, but problems might arise in some,30 especially those who have been prescribed amphetamines as opposed to methylphenidate.31 This requires further study.
Sensitization to nonstimulant drugs in primates
Few studies have tested whether “non-stimulant” drugs can produce sensitization in primates precluding confident conclusions. This noted, both alcohol and opioids can have stimulant effects and these effects can become sensitized in rodents.32–34 In humans, there is preliminary evidence that striatal dopamine responses to alcohol35,36 and alcohol-paired cues37 are larger in high-than in low-risk drinkers, and alcohol use problems are associated with larger ethanol-induced stimulant responses38 and striatal dopamine release.39 Opioid sensitization in primates is less studied, and the relation to increased drug use remains less clear.32 There is, however, some evidence that repeat morphine administration can lead to behavioural sensitization40 and, in humans, early-life trauma is associated with increased risk of opioid use disorders and augmented morphine reward.41
Stimulant drug–induced behavioural sensitization in healthy humans
The first 2 attempts to demonstrate stimulant drug–induced behavioural sensitization in humans were unsuccessful.42,43 Both administered low doses of d-amphetamine (5 or 10 mg, orally). In comparison, 80 % of studies (8 of 10) administering at least 20 mg of d-amphetamine found evidence of sensitization.44–51 Among the 6 studies that administered at least 3 doses of 20 mg or more, 100 % found an effect.44–47,49,50 The most consistent changes were to the drug’s behaviourally energizing effects12,13 with augmented responses continuing for at least a year49 (Table 1).
Stimulant drug–induced behavioural sensitization in humans
Stimulant drug–induced behavioural sensitization in nonhuman primates
There is consistent evidence of cocaine and amphetamine-induced behavioural sensitization in nonhuman primates.54–69 As in humans, augmented responses have been seen for psychomotor stimulation, but psychosis-like phenomena can emerge following high-dose regimens. The effects can last for more than 2 years60 (Table 2).
Stimulant drug–induced behavioural sensitization in nonhuman primates
Stimulant drug–induced behavioural sensitization in people with addictions
Clinical observations at least raise the possibility that people with stimulant drug addictions exhibit behavioural sensitization; e.g., markedly elevated incentive (drug-seeking) responses to small doses of the drug and drug-related cues. These observations noted, perhaps the most compelling demonstration that extensive substance use can lead to sensitization in humans investigated alcohol. In this 10-year prospective study, young adult drinkers (n = 163) received an alcohol challenge (0.8 g/kg, orally) at baseline and 5 and 10 years later.38 Among those who developed an alcohol use disorder (AUD; n = 39), the self-reported alcohol-induced “wanting” and “stimulation” responses became progressively larger. The larger the wanting and stimulation responses, the greater the likelihood of developing an AUD and the greater the number of AUD symptoms.
Stimulant drug–induced dopamine sensitization in healthy humans
Based on studies in rodents, 2 neurotransmitters have been implicated in drug-induced sensitization: dopamine2–4,70 and glutamate.70–73 In humans, the transmitter release literature is both smaller and limited to dopamine, but evidence of amphetamine-induced sensitization has been found in all 3 studies that administered at least 3 doses (0.3–0.4 mg/kg, orally).44,22,49 Correlational research suggests that these augmentations could continue to accumulate through to 150 uses or more.20 The drug use histories that yield sensitization can also lead to conditioned dopamine release.16,74
Stimulant drug–induced dopamine sensitization in nonhuman primates
Two studies giving 10–50 stimulant drug exposures found sensitized dopamine responses in nonhuman primates;75,76 4 studies with more extensive regimens did not.64,68,77,78 A number of explanations have been offered for the negative findings, including (1) small sample sizes (n = 4–6), particularly since, in both rodents and humans, only some develop an enlarged response;13,49 (2) the absence of drug-related cues during testing, an important feature since the expression of sensitization can become context-dependent;12,79,80 (3) the use of isoflurane,81 an anesthetic that can alter dopamine cell firing and release; (4) evidence that drug-induced dopamine sensitization is readily expressed following modest substance use75 but not following the ingestion of greater quantities with only brief abstinence periods before testing;77,82 (5) the possibility that, following many drug use sessions and the development of highly trained associations, dopamine cell reactivity comes to be influenced by reward-prediction errors (RPE; i.e., larger responses to unexpected drug delivery);21 and (6) for cocaine, sensitized glutamate release might be more important than dopamine.70
Stimulant drug–induced dopamine sensitization in people with addictions
In people with addictions, there is some evidence of dopamine sensitization. Compared with healthy controls, people who used methamphetamine showed larger amphetamine-induced dopamine responses in extrastriatal regions.83 Within the striatum, 1 study found larger responses to ethanol in people with an AUD39 while another study84 found larger responses to amphetamine in people with a gambling disorder. These studies noted, the most common finding in people with cocaine85–88 and amphetamine use disorders89 has been an absence of sensitized responses and even significantly reduced responses. These blunted responses may be specific to the testing conditions rather than evidence of ubiquitous dopamine deficits.12,79,80,90 Indeed, there is well-replicated evidence that people with stimulant use disorders exhibit robust dopamine responses to drug-related cues.15,17–19,91 Moreover, those with a cocaine use disorder can also exhibit larger stimulant drug–induced striatal dopamine responses than healthy volunteers when drug administration is unexpected.21 Together, these findings indicate that, in this population, there remains only modest evidence of dopamine sensitization per se, but the potential for large dopamine responses is retained, differing only in when it is expressed.
Conclusion
This brief analysis yields 3 main conclusions. First, despite occasional claims to the contrary, there is overwhelming evidence of stimulant drug–induced behavioural sensitization in both human and nonhuman primates (18 of 19 studies administering at least 3 doses of at least 0.25 mg/kg of amphetamine or high-dose cocaine). Second, there is compelling evidence of dopamine sensitization in primates (5 of 5 studies administering 3–50 drug doses). Third, behavioural sensitization following extended high-dose drug use occurs, but more work is needed to understand the mediating neurobiology and when the augmented responses are expressed. Answering these questions will require thoughtful study designs. For laboratory research, this includes (1) testing awake subjects in the same environment where the drug was previously given, (2) administering the drug intermittently92,93 with abstinence periods long enough to promote the incubation of both conditioned and sensitized responses, (3) testing how the influence of drug-paired cues (conditioning) and expectations (RPE) might change with progressively greater substance use, and (4) testing samples large enough to capture individual differences in susceptibility. Among those who are susceptible to drug use problems, features 1 and 2 resemble the early substance-use patterns that typically lead to a problem. This might not be a coincidence.
Acknowledgements
The author thanks Isabelle Boileau, Andrea King, and Paul Vezina for feedback on an earlier version of this manuscript.
Footnotes
The views expressed in this editorial are those of the author(s) and do not necessarily reflect the position of the Canadian Medical Association or its subsidiaries, the journal’s editorial board or the Canadian College of Neuropsychopharmacology.
Competing interests: None declared.
This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is noncommercial (i.e., research or educational use), and no modifications or adaptations are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/
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