A genetic deletion of the serotonin transporter greatly enhances the reinforcing properties of MDMA in rats

All drugs of abuse increase synaptic dopamine (DA) but also exert effects on other brain systems that might either enhance or limit subsequent rewarding effects and abuse liability, including serotonin (5-HT). Accordingly, variations in drug-produced DA and/or 5-HT might explain between-subject variability in the propensity to self-administer drugs of abuse. MDMA (3,4-methylenedioxymethamphetamine or ‘ecstasy’) is an excellent candidate to test this idea because, unlike many other drugs of abuse, it preferentially increases 5-HT via blockade of the 5-HT transporter (SERT) and reverse transport. Here we show, for the first time, that rats with a genetic deletion of the SERT (SERT−/− rats) are much more sensitive to the reinforcing properties of MDMA.

Although the abuse liability of MDMA is now well established, it is lower than that of most other drugs of abuse, with only 50% of rats developing reliable MDMA self-administration.1 One possible reason for the lower abuse potential is that MDMA preferentially binds to the SERT thereby enhancing extracellular 5-HT levels to a greater extent than DA.2 This pharmacological effect would be expected to limit the rewarding effects of MDMA because manipulations that increase extracellular 5-HT are not positively reinforcing and actually reduce the rewarding properties of other psychostimulant drugs.3, 4 In the present study, we tested the hypothesis that MDMA’s acute effect on the SERT underlies its reduced abuse liability by measuring MDMA self-administration in rats with a genetic deletion of the SERT. Although these animals have a ninefold higher tonic synaptic (extracellular) level of 5-HT, drug effects mediated by the SERT are inhibited.5

Figure 1a shows the cumulative percentage of SERT−/− and SERT+/+ rats that acquired MDMA self-administration. Within 25 days, 100% of the SERT−/− rats acquired self-administration behavior according to well-established criteria1 compared with only 55% of the SERT+/+ animals. A Kaplan–Meier survival analysis indicated a significant leftward and upward shift in the curve of the SERT−/− group compared with the SERT+/+ group.

Figure 1
figure1

SERT−/− rats are more sensitive to the reinforcing properties of MDMA. (a) Cumulative percentage of SERT−/− (N=13) and SERT+/+ (N=11) rats that acquired (MDMA) self-administration as a function of days of testing, 2-h per day of self-administration. A Kaplan–Meier survival analysis showed a significant genotype effect (χ21=9.41, P=0.002). (b) Responding maintained by a fixed ratio of 1, 2 or 5, reinforced by infusions of 0.5 mg/kg MDMA for those animals that had successfully acquired self-administration (SERT−/−, n=13; SERT+/+, n=6). Bars represent mean number of active lever responses (±s.e.m.) during daily 2-h sessions. A significant effect of genotype (F1,17=5.73, P=0.03) and session (F1.32, 22.38=34.54, P<0.01 (Greenhouse-Geisser corrected as sphericity was violated), but no significant interaction was found. (c) Mean breakpoint achieved as a function of MDMA dose for animals that had successfully acquired self-administration (SERT−/−, n=10; SERT+/+, n=6). Bars represent the mean breakpoint (±s.e.m.). There was a significant dose by genotype interaction (F2,22=4.83, P=0.02). *P<0.05: post-hoc comparison between genotypes.

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When only the rats that acquired MDMA self-administration were considered, this enhanced susceptibility of the SERT−/− rats for MDMA was also apparent, with greater responding maintained by various fixed ratio schedules (Figure 1b) and a higher breakpoint in a progressive ratio schedule of responding (Figure 1c).

These data show that SERT−/− rats are more sensitive to the initial, and subsequent, reinforcing properties of MDMA and are consistent with several previous studies that show that animals lacking the SERT due to selective neurotoxic lesions of the 5-HT neurons increase the rewarding properties of drugs of abuse.6, 7 However, one fundamental difference between the present study and studies using neurotoxic lesions is that SERT−/− rats actually have a ninefold higher basal level of extracellular 5-HT. This indicates that it is the inability of drugs of abuse to induce a phasic 5-HT release, rather than a sustained, tonic reduction in 5-HT levels, that enhances the reinforcing properties.7 Of interest, we have shown that 5,7-dihydroxytryptamine lesions that reduced tissue levels of 5-HT, produced a profile of acquisition of MDMA self-administration that was remarkably similar to the results found in the present study,8 suggesting that a reduction in the 5-HT tone in SERT−/− rats, at least in adulthood, is unlikely to reduce the enhanced sensitivity to MDMA.

Overall then, our data show that SERT−/− are more sensitive to the positively reinforcing effects of MDMA. Given the important role of DA D1 and D2 receptors in MDMA self-administration,9 and the suggestion that serotonin deficits precede reliable self-administration,10 it is possible that SERT−/− rats more readily acquire self-administration of both cocaine9 and MDMA because of an increased response to MDMA-produced synaptic DA. These data from rats are diametrically opposite to results collected from SERT−/− mice11 that were less prone to self-administer MDMA. This difference reinforces the idea that the role of 5-HT in the behavioral response to MDMA differs between species. Most importantly, MDMA acts as a selective DA neurotoxin in mice with minimal effects on 5-HT, whereas in humans, non-human primates and rats there is evidence that long-term use of MDMA leads to selective 5-HT depletion and a decrease in SERT expression, increasing the addictive potential of MDMA.12 Thus, the rat model is consistent with effects that are produced in humans who consume MDMA and increase their intake over time.

Recent pharmacogenetic studies in humans have shown that individuals with the short allele of the SERT (leading to a 50% reduction in SERT activity) are more prevalent among MDMA users than among non-drug users.13 In addition, these individuals are more sensitive to some of the CNS effects of MDMA including attention deficit, risky choice making, mood disorders, and sedation.13, 14 Although cognisant of the need for judicious translation from animal data to humans, our data suggest that individuals with a lower SERT activity will also be more sensitive to the reinforcing properties of MDMA.

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Acknowledgements

This study was supported by a grant from the Maurice & Phyllis Paykel Trust. We thank Professor John Miller for his valuable comments on the paper.

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Correspondence to B A Ellenbroek.

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Oakly, A., Brox, B., Schenk, S. et al. A genetic deletion of the serotonin transporter greatly enhances the reinforcing properties of MDMA in rats. Mol Psychiatry 19, 534–535 (2014). https://doi.org/10.1038/mp.2013.75

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