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. Author manuscript; available in PMC: 2021 Dec 1.
Published in final edited form as: Pharmacol Biochem Behav. 2020 Oct 3;199:173043. doi: 10.1016/j.pbb.2020.173043

Evidence for positive allosteric modulation of cognitive-enhancing effects of nicotine by low-dose galantamine in rats

Britta Hahn 1,✉, Carolyn H Reneski 1, Malcom Lane 2, Greg I Elmer 1, Edna FR Pereira 2
PMCID: PMC7725896  NIHMSID: NIHMS1636620  PMID: 33022302

Abstract

Cognitive-enhancing effects of nicotinic acetylcholine receptor (nAChR) agonists may be of therapeutic potential in disease states characterized by nAChR hypofunction; however, effects tend to be of small magnitude and unlikely clinical significance. The co-administration of a nAChR positive allosteric modulator (PAM) may enable larger effects by potentiating nAChR responses to an agonist. The acetylcholinesterase (AChE) inhibitor galantamine is a nAChR PAM at a low dose range. A recent clinical study testing effects of a single small dose of galantamine found evidence for synergistic effects with nicotine on one of several cognitive measures. In that study, residual AChE inhibition may have obscured interactions on other measures. The present study aimed at examining small galantamine doses devoid of AChE inhibitory activity in a rodent model of attention. The effects of galantamine (0.03–0.25 mg/kg s.c.) were tested in the presence and absence of nicotine (0.1 mg/kg s.c.) in rats performing the 5-Choice Serial Reaction Time Task, employing a within-subject factorial design. There were no effects on response accuracy of either nicotine or galantamine alone. However, the combination of nicotine and 0.06 mg/kg of galantamine significantly enhanced accuracy. AChE activity assays confirmed that, at this dose, galantamine was devoid of AChE inhibitory activity in the brain. The results suggest that cognitive-enhancing effects of nicotine may be potentiated or uncovered by an extremely small dose of galantamine, well below its typical therapeutic range in humans. Furthermore, these findings provide a general proof-of-principle for a nAChR agonist and PAM combination strategy for cognitive enhancement.

Keywords: galantamine, nicotine, attention, positive allosteric modulation, synergistic

1. Introduction

It has long been hypothesized that cognitive deficits in disease states involving nicotinic acetylcholine receptor (nAChR) hypofunction, such as Mild Cognitive Impairment, Alzheimer’s disease (AD), and schizophrenia (Adams and Stevens, 2007; Hong et al., 2011; Kendziorra et al., 2011; Perry et al., 2000; Petrovsky et al., 2010), may benefit from treatments that enhance nAChR activity (Levin and Rezvani, 2002; Singh et al., 2004). It is well established that the prototypical nAChR agonist nicotine can induce acute cognitive benefits, particularly on processes of attention (Hahn, 2015; Heishman et al., 2010; Newhouse et al., 2011), although the magnitude of these effects is unlikely to be of clinical significance. Drug development efforts invested into novel nAChR agonists with greater subtype selectivity have resulted in multiple failed trials due to limited efficacy or side effects (Haydar and Dunlop, 2010; Hurst et al., 2013). In general, effects on cognition tended to be in the expected direction but were of small magnitude (Haydar and Dunlop, 2010; Radek et al., 2010; Wallace et al., 2011).

The co-administration of a nAChR positive allosteric modulator (PAM) with a nAChR agonist may be a way to raise this effect size ceiling. PAMs do not activate the nAChR on their own but bind to an allosteric site and facilitate the receptor’s response to an agonist (Williams et al., 2011). Some (although not all, Gronlien et al., 2007) PAMs appear to achieve this by reversing desensitization of a fraction of nAChRs produced by low to intermediate agonist concentrations (Williams et al., 2011). Thus, combined PAM and low-dose agonist treatment may enhance nAChR activity and associated behavioral effects to a greater degree than an agonist administered alone, and may enable the use of small agonist doses, reducing side effects.

To date, the only nAChR PAM approved for human use is galantamine, prescribed widely for the treatment of AD. Galantamine is primarily known as a acetylcholinesterase (AChE) inhibitor, but it is also a nAChR PAM at concentrations found in human brain after clinical doses (Coyle et al., 2007; Villarroya et al., 2007). It reportedly potentiates α4β2, α3*, α6β4, and α7 nAChR responses induced by acetylcholine, nicotine, or epibatidine (Dajas-Bailador et al., 2003; Samochocki et al., 2003; Santos et al., 2002). Importantly, the concentration range for galantamine′s PAM action appears to be below that for AChE inhibition (Coyle et al., 2007), suggesting that a bias toward its PAM action can be achieved by the use of small doses.

Until recently, the ability of a PAM to enhance cognitive effects of a nAChR agonist had never been tested in a systematic manner in clinical or preclinical studies. Dual administration studies in people with schizophrenia (Choueiry et al., 2019; Deutsch et al., 2013) did not differentiate between effects of either drug alone and their combination. Employing computerized cognitive paradigms, Hahn et al. (2020) tested the effects of nicotine (7 mg/24 h, transdermally), galantamine (4 mg, p.o.), and their combination in healthy human non-smokers in a 2 × 2 factorial within-subject design. While both nicotine and galantamine improved certain aspects of performance independently of each other, only their combination robustly improved reaction time of a change detection task, with no effect of either drug alone. The nature of this interaction is conceptually explainable by galantamine′s PAM action facilitating nicotine effects, but not by AChE inhibition because a greater concentration of acetylcholine in the synaptic cleft would compete with nicotine for the same binding site, thus reducing, not enhancing, effects of nicotine. Overall, these findings suggested that allosteric potentiation of nAChR agonist-induced cognitive benefits is possible in principle.

While the dose of galantamine tested by Hahn et al. (2020) was small in the context of treating symptoms of AD, it still caused a small, albeit significant degree of AChE inhibitory activity as measured in whole blood (16.8%; for comparison, approximately 60% AChE inhibition is achieved by clinical doses in AD; Giacobini (1998)). Some of the performance-enhancing effects of galantamine alone reported by Hahn et al. (2020) were correlated with the level of residual AChE inhibition, but the synergistic effect described above was not, with a trend even suggesting that lower AChE inhibition by galantamine may be associated with larger performance benefit in the presence of nicotine. An even smaller dose of galantamine may have achieved better separation of AChE inhibition from nAChR positive allosteric modulation and uncovered broader potentiation of nicotine’s effects. This possibility is supported by the fact that the paradigm in which synergistic effects with nicotine were seen had always been administered last, when galantamine blood levels were likely to be past their peak (Zhao et al., 2002).

In the present study, we examined the effects of very small systemic doses of galantamine in a rodent model of attention to test whether galantamine can potentiate performance-enhancing effects of nicotine at a dose range demonstrated not to inhibit AChE in rats (Geerts et al., 2005). Neurophysiological effects of galantamine observed at this dose range were reportedly blocked by a nicotinic but not a muscarinic acetylcholine receptor antagonist and were not mimicked by the AChE inhibitor donepezil, suggesting they reflected galantamine’s nAChR PAM effect (Schilstrom et al., 2007). To verify that galantamine is devoid of AChE inhibitory activity in the rat strain and under the experimental conditions employed here, we measured brain AChE activity after systemic injection of galantamine. Our specific prediction, as in the prior human study, was that galantamine alone would have no performance-enhancing effects whereas it would potentiate the effects of nicotine. Such demonstration would indicate that cognitive-enhancing effects of nicotine, or other nAChR agonists, may be potentiated most effectively by doses of galantamine below the dose range for detectable AChE inhibition, providing the rationale for tests in human subjects.

2. Materials and Methods

2.1. Subjects

For the 5-CSRTT experiments, twenty male Wistar rats weighing on average 150 g at arrival were acquired at 6 weeks of age from Charles River Laboratories. The animals were housed individually in a temperature- and humidity-controlled room, fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). The animals were maintained on a 12-h light-dark cycle with lights on at 7 a.m. Rats had free access to water and received a food-restricted diet, starting at 8 weeks of age, to maintain them at 85% of their age-appropriate free-feeding body weights.

For the radiometric AChE assay, 15 male Wistar rats weighing on average 574 g at arrival were acquired from Charles River Laboratories at 6 months of age, to match the age of the rats used for the 5-CSRTT experiments at the time of testing. The assays were performed after one week of acclimatization.

The treatment of all animals followed the ‘Principles of Laboratory Animal Care’ (NIH publication No. 86–23, 1996) and was approved by the Institutional Animal Care and Use Committee of the University of Maryland School of Medicine.

2.2. Apparatus

Eight operant conditioning chambers measuring 26 cm3 (Med Associates, Inc., Fairfax, VT) were housed in sound-insulated enclosures. The curved rear wall of each chamber contained five 2.5 cm2 holes, 2 cm above the grid floor. At the entrance of each hole, a photocell monitored interruptions of a beam of infrared light, and at the rear there was a white light-emitting diode. A food tray was located in the opposite wall, equidistant from each aperture. Illumination was provided by a house light situated in the top portion of the front panel. The apparatus and data collection were controlled by Med-PC software.

2.3. Behavioral Procedure

Rats started 5-CSRTT training at 8 weeks of age. The training procedure was described in detail by Mirza and Stolerman (1998). In the final form of the task, light stimuli of 1 s duration were presented randomly in one of the five holes after an intertrial interval (ITI) of variable duration (3–9 s, average 6 s). A nose-poke into the hole while it was illuminated or within 5 s after the light had terminated (limited hold) was registered as a correct response and resulted in the delivery of a 45-mg food pellet into the trough, followed by a 2-s reward retrieval period. A response into any other hole was recorded as an incorrect response and resulted in a time-out of 5 s duration, during which the house light was extinguished. The house light coming back on signalled the onset of the next trial. A failure to respond before the end of the limited hold was registered as an omission error. A new trial began with the initiation of an ITI either after a reward retrieval period or after time-outs or limited holds in cases of incorrect responses or omission errors. Responses during ITIs had no programmed consequences. All training and test sessions lasted 30 min. The time of day at which training and test sessions were performed was held constant for individual rats. Overall, the training took approximately 4 months. Testing started when stable performance of <30% omissions and >60% correct responses was achieved. The following behavioral measures were analyzed:

Percentage of correct responses (accuracy): 100 × [correct responses / (correct + incorrect responses)]. Response accuracy is a measure of response choice based exclusively on responses that have been emitted and not taking into account omission error trials. This measure is not influenced by the overall rate or speed of responding and is interpreted as the main index of stimulus detection and attention.

Percentage of omission errors: 100 x (omission errors / stimuli presented). Errors of omission are influenced by stimulus detection, but also by the general rate of responding.

Latency of correct responses: the mean time between stimulus onset and a nose-poke in the correct hole.

Anticipatory responses: total number of responses in ITIs. Unpunished anticipatory responses, as in the present version of the task, would reflect general rate-increasing or - decreasing drug effects.

Because anticipatory responses in the ITI preceding a trial have detrimental effects on response accuracy (Hahn et al., 2018; Hahn et al., 2002), trials with any anticipatory responses in the preceding ITI were excluded from the calculation of this measure. The number of trials from which accuracy was calculated ranged from 41 to 131 per session, averaging 77 ±21 (SD). Given nicotine’s propensity to increase anticipatory responses, we tested whether this restriction resulted in the inclusion of a lower proportion of long ITI trials in the calculation of response accuracy in nicotine pretreated sessions. Thus, after excluding trials with responses in the preceding ITI, we quantified the number of trials with a correct or incorrect response at the shortest (3–5 s) and longest three ITI durations (7–9 s) in the nicotine and placebo conditions (summed across levels of galantamine). There were fewer included correct and incorrect response trials when nicotine was given, consistent with a nicotine-induced increase in anticipatory responses. This was supported by a main effect of nicotine in 2-factor ANOVA [F(1,19)=17.9, p<0.001 for correct responses; F(1,19)=18.8, p<0.001 for incorrect responses]. However, this effect did not differ significantly between the shorter and longer ITI durations [ITI length × nicotine condition interaction: F(1,19)=1.78, p=0.20 for correct responses; F(1,19)=1.82, p=0.19 for incorrect].

2.4. Experimental Design

Test sessions were conducted twice a week with training sessions on the other weekdays. Test days were always preceded by at least one training day and by at least two drug-free days. Task parameters in test sessions were identical to those in training sessions.

Two experiments, separated by a two-week training period during which no drugs were given, tested the potential interaction of nicotine and galantamine. The only difference between Experiment 1 and Experiment 2 were the doses of galantamine tested. Galantamine or vehicle was always administered 20 min (Geerts et al., 2005), and nicotine or vehicle 10 min before the start of the test sessions. Both drugs were given subcutaneously (s.c.). The experiments adopted a within-subject design, that is, each rat was tested with nicotine and vehicle, combined with each of two doses of galantamine and vehicle, in a 2 × 3 factorial design. The sequence of the six testing conditions was randomized for each individual animal, but testing conditions were counterbalanced between the six test days to the degree possible.

Experiment 1 tested 0.125 and 0.25 mg/kg of galantamine and vehicle combined with nicotine (0.1 mg/kg) and vehicle. These doses of galantamine were chosen based on a previous report indicating no AChE inhibition at this range (Geerts et al., 2005). The dose of nicotine was chosen because it is small in the context of studies of nicotine-induced behavior, but with demonstrated performance-enhancing effects in the 5-CSRTT (Hahn et al., 2003; Hahn et al., 2002, 2011). Experiment 2 tested even smaller doses of galantamine (0.03 and 0.06 mg/kg) and vehicle combined with nicotine (0.1 mg/kg) and vehicle.

2.5. Radiometric acetylcholinesterase assay

For analysis of the effects of galantamine on brain AChE activity, rats were injected s.c. with saline (N = 5), 0.06 mg/kg (N = 5), or 6 mg/kg of galantamine (N = 5). Thirty min after treatment, rats were euthanized. The brains were removed, rinsed in saline (0.9% NaCl), and snap frozen in liquid nitrogen. Brains were pulverized under liquid nitrogen, weighed, and mixed with equal weight/volume of high salt extraction buffer containing protease inhibitor. Samples were then sonicated on ice for 20 s three times. The protein extracts were centrifuged at 3,000 rpm at 4°C for 5 min, after which time the supernatants were aliquoted and frozen at −80°C.

AChE activity was measured using the radiometric assay described earlier (Albuquerque et al., 2006). Briefly, 80 μl of each supernatant pretreated with the butyrylcholinesterase inhibitor tetraisopropyl pyrophosphoramide (iso-OMPA, 0.1 mM final concentration) were incubated at room temperature for 10 min with 20 μl of 0.1 M ACh chloride and [acetyl-3H]ACh iodide (20 μCi/ml, which produced approximately 260,000 cpm when totally hydrolyzed by eel AChE). At the end of the incubation time, the reaction was stopped by the addition of an aqueous solution (300 μl) consisting of chloroacetic acid (0.50 M), sodium chloride (1 M), and sodium hydroxide (0.25 M). After vortexing the mixture, samples were clarified by centrifugation, and the clarified samples (300 μl) were transferred to a scintillation vial containing 4 ml of the fluor cocktail, which consisted of 90% (v/v) toluene, 10% (v/v) 3-metyl-1-butanol, 0.03% (w/v) 1,4-bis(5-phenyl-2-oxazolyl), and 0.05% (w/v) 2,5-diphenyloxazole. The mix was vortexed for 10 s, and the amount of tritiated acetate in the organic phase was measured by liquid scintillation counting for 2 min (Tri-Carb 2900TR, Perkin Elmer). Each sample was assayed in triplicate, and counts were corrected for background by subtraction of counts obtained using reactions devoid of protein extracts and treated in a similar fashion. Mean background-corrected count per mg tissue from saline-treated animals was taken as 100% and used to normalize the background-corrected counts per mg tissue obtained from each animal.

2.6. Drugs

(−)-Nicotine tartrate (MP Biomedical, Solon, OH) was dissolved in isotonic saline, and the pH was adjusted to 7 with NaOH solution. Galantamine hydrobromide (TCI America, Portland, OR) was dissolved in isotonic saline. All doses are expressed as those of the base. Injections were given s.c. into the flank at a volume of 1 ml/kg.

2.7. Data analysis

Each of the above 5-CSRTT performance measures was analyzed separately by 2-factor ANOVA for repeated measures with nicotine (one dose and vehicle) and galantamine (two doses and vehicle) as within-subject factors. A significant interaction was followed by 1-factor ANOVA and paired t-tests. Given the within-subject design, SEMs plotted in the graphs were adjusted to remove between-subject variability (Cousineau, 2007; Morey, 2008). This method essentially subtracts out interindividual variance in the average performance across testing conditions to only reflect variance related to interindividual differences in drug effect, the focus of this study. Effects of α<0.05 (two-tailed) were considered statistically significant.

Effects of galantamine on brain AChE activity were analyzed by 1-factor ANOVA with galantamine dose level as between-subject factor, followed by a post-hoc Tukey test.

3. Results

3.1. Experiment 1 (testing 0.125 and 0.25 mg/kg of galantamine):

As in previous studies, nicotine reduced omission errors (Figure 1B), shortened response latency, and increased anticipatory responding [main effects of nicotine: all Fs(1,19)>17, Ps<0.001]. There was no main effect of nicotine on response accuracy [F(1,19)=2.20, P=0.15; Figure 1A]. Galantamine had no significant main effect on any measure, although there was a trend suggesting it slightly increased omission errors [F(2,38)=2.55, P=0.09]. There was no nicotine × galantamine interaction on any measure [all Fs(2,38)<1, Ps>0.38].

Figure 1:

Figure 1:

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Average 5-Choice Serial Reaction Time Task performance of rats (N=20) after systemic injections of nicotine or vehicle combined with galantamine or vehicle. Error bars reflect SEMs, adjusted to remove between-subject variability in the average performance across dose levels (Cousineau, 2007; Morey, 2008) to yield variability related to interindividual differences in drug effect. *** P<0.001, paired t-test.

3.2. Experiment 2 (testing 0.03 and 0.06 mg/kg of galantamine):

Nicotine again reduced omission errors (Figure 1D), shortened response latency, and increased anticipatory responding [all Fs(1,19)>26, Ps<0.001]. There was no main effect of nicotine on response accuracy [F(1,19)=0.63, P=0.44]. There were no significant main effects of galantamine; however, there was a significant nicotine x galantamine interaction on response accuracy [F(2,38)=3.66, P=0.035; Figure 1C]. One-factor ANOVAs analyzing the effects of galantamine separately in the presence and absence of nicotine confirmed a significant main effect of galantamine when co-administered with nicotine [F(2,38)=6.39, P=0.004], but not in the absence of nicotine [F(2,38)=0.34, P=0.72]. The combination of nicotine and 0.06 mg/kg of galantamine significantly improved accuracy relative to nicotine alone [t(19)=4.55, P<0.001] and relative to double vehicle [t(19)=2.38, P=0.028], although only the former survived multiple comparisons correction.

3.3. Brain AChE activity

There was a significant effect of galantamine on the activity of AChE in the brain [F(2,12)=41.7, p<0.001]. According to the post-hoc Tukey test, AChE activity measured in the brain of rats treated with 6 mg/kg of galantamine was significantly lower than that measured in the brain of rats treated with saline or with 0.06 mg/kg of galantamine (Figure 2). Importantly, AChE activity in rats treated with 0.06 mg/kg of galantamine, the dose at which significant potentiation of nicotine effects was observed in the 5-CSRTT, did not differ from saline-treated animals [p=0.82]. This suggests that AChE inhibition is unlikely to account for the synergistic interaction between nicotine and galantamine in the 5-CSRTT.

Figure 2:

Figure 2:

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Brain AChE inhibition in rats treated with galantamine. Graph and error bars represent mean and SD of results obtained from 5 rats per dose. *** p<0.001, Tukey post-hoc test.

4. Discussion

The aim of the present experiments was to test if potentiation of cognitive-enhancing effects of nicotine could be achieved with doses of galantamine that are devoid of AChE inhibitory activity, and are, therefore, lower than any dose equivalent previously tested in human subjects. Our starting doses of galantamine (0.125 and 0.25 mg/kg s.c.) were chosen because they are well below its Ki for brain AChE inhibition in rats (7.11 mg/kg), with no detectable inhibition of the enzyme reported at doses up to 0.5 mg/kg s.c. (Geerts et al., 2005). Furthermore, 0.1 mg/kg (s.c.) of galantamine was the most effective dose at increasing dopaminergic cell firing, an effect mediated by nAChRs but not muscarinic receptors and probably reflective of nAChR positive allosteric modulation (Schilstrom et al., 2007). The absence of any significant effects of galantamine in Experiment 1 prompted us to test even lower doses (0.03 and 0.06 mg/kg).

The hypothesized synergistic interaction between galantamine and nicotine was found at 0.06 mg/kg of galantamine. Neither nicotine (0.1 mg/kg) nor galantamine alone had any significant effects on the accuracy or responding (the measure most reflective of attentional performance), which was somewhat unexpected in the case of nicotine given previous findings with this and another strain of rats (Hahn et al., 2016; Hahn et al., 2003; Hahn et al., 2002; Hahn and Stolerman, 2005). However, their combination significantly increased accuracy relative to either drug alone and the drug-free baseline. This effect would be consistent with positive allosteric modulation of the nAChR, but it would be difficult to explain as a result of AChE inhibition. AChE inhibition results in higher concentrations of acetylcholine in the synaptic cleft and thus would be expected to reduce, not enhance, effects of a competing exogenous nAChR agonist, as previously observed with nicotine and a larger dose of galantamine (Sofuoglu et al., 2012). However, if the low doses of nicotine and galantamine both individually resulted in a nAChR tone enhancement that was too low to induce measurable behavioral effects, additive or even synergistic effects may be conceivable even if AChE inhibition was galantamine’s mechanism of action. Therefore, it was important to verify that 0.06 mg/kg of galantamine was indeed devoid of AChE inhibitory activity.

Radiometric AChE assays confirmed that 0.06 mg/kg of galantamine did not inhibit AChE activity in a separate group of age-matched rats, while a much larger dose of galantamine (6 mg/kg), which was included as a positive control, produced robust AChE inhibition. Route and timing of galantamine administration were matched between the 5-CSRTT experiments and the AChE assays, with AChE activity measured at a time point that would be equivalent to 10 min into the 30-min 5-CSRTT session. This strengthens our conclusion that the observed potentiation of nicotine effects by galantamine did not reflect AChE inhibition. Positive allosteric modulation of the nAChR is the most likely mechanism of action of galantamine that could account for the synergistic interaction between galantamine and nicotine in the 5-CSRTT.

The above findings aid the interpretation of our previous study in human non-smokers (Hahn et al., 2020), in which an equivalent synergistic interaction was observed between nicotine and galantamine, but only in one out of three behavioral paradigms (the one tested last, when galantamine blood levels were likely to be past their peak). The present finding strengthens our hypothesis that the dose of galantamine employed in the clinical study, at which a low, but significant degree of AChE inhibition was observed, exceeded the optimal dose range, and that even smaller doses of galantamine may be of greater therapeutic benefit when combined with a nAChR agonist. The use of such low doses would be beneficial also from the perspective of minimizing side effects.

The present results are of direct therapeutic relevance, as both nicotine and galantamine are approved for human use, but they also serve as a general proof of principle that a nAChR agonist and PAM combination may constitute an effective therapeutic strategy to improve cognitive functions. Neither nicotine nor galantamine have any known selectivity for subtypes of the nAChR. Greater benefits may indeed be observed with compounds targeting multiple nAChR subtypes given that cognitive benefits are seen with agonists selective for a variety of different subtypes (reviewed by Hahn, 2015). However, several subtype-selective nAChR agonists and PAMs are under development for human use (e.g., Gee et al., 2017; Hurst et al., 2013), and a combination strategy may achieve greater flexibility and fine-tuning when targeting a critical subset of nAChR subtypes. For example, sub-threshold doses of a nAChR agonist selective for one group of nAChR subtypes may be combined with sub-threshold doses of a PAM selective for another group, but overlapping with the first group on the critical subtype(s). Overall, the targeted co-administration of a low dose of a nAChR agonist and a PAM may achieve a narrower effect profile and be more sparing of native circuit dynamics than larger doses of agonist alone.

In summary, the present results suggest that cognitive-enhancing effects of nicotine may be potentiated or uncovered by the co-administration of a very low dose of galantamine, probably reflecting nAChR positive allosteric modulation by galantamine. This finding provides the rationale for further clinical studies exploring doses of galantamine well below its typical therapeutic range in combination with a nAChR agonist, and for equivalent combination studies employing novel nAChR PAMs and agonists.

Highlights.

Nicotine and low-dose galantamine displayed synergistic effects on attention in rats.

The effective dose of galantamine was too small to inhibit acetylcholinesterase.

Results suggest positive allosteric modulation of nicotinic agonist effects on cognition.

Funding:

This work was supported by the National Institutes of Health [grant number R01DA035813 to B. Hahn].

Footnotes

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The sponsor had no role in study design, the collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the article for publication.

Declarations of interest: none.

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