, Volume 235, Issue 7, pp 1907–1914 | Cite as

A genetic reduction in the serotonin transporter differentially influences MDMA and heroin induced behaviours

  • Bridget W. Brox
  • Bart A. Ellenbroek
Original Investigation



Despite ongoing study and research to better understand drug addiction, it continues to be a heavy burden. Only a small percentage of individuals who take drugs of abuse go on to develop addiction. However, there is growing evidence to suggest that a reduction in the serotonin transporter may play an important role for those that transition to compulsive drug taking. Studies have demonstrated that reduced serotonin transporter function potentiates self-administration of psychostimulant drugs (“ecstasy,” MDMA; cocaine); however, additional research revealed no differences between genotypes when the opioid heroin was self-administered. These results suggest that a reduction in the serotonin transporter may confer susceptibility to the development of addiction to some classes of drugs but not others. Importantly, the mechanism underlying facilitated psychostimulant self-administration is currently unknown.


Therefore, to continue investigating the relationship between compromised serotonergic function and different classes of drugs, a series of experiments was conducted investigating locomotor activity (LMA) and conditioned taste aversion (CTA) in the serotonin transporter knockout (SERT KO) rat model.


MDMA-induced hyperactivity was reduced, while MDMA-induced CTA was enhanced, in SERT KO rats. However, there were no genotype differences in heroin-induced behaviours.


These results reinforce the idea that a reduction in the serotonin transporter drives differential effects between disparate classes of drugs of abuse.


Serotonin MDMA Heroin SERT 



The authors would like to extend thanks to Mr. Richard Moore, Mr. Peter Van Compernolle and Mr. Michael Roberts for providing day-to-day husbandry, support and care of the animals used in these experiments. We would also like to thank Dr. Uta Waterhouse for providing assistance with the injections in the conditioned taste aversion experiments.

Author contributions

Bridget W. Brox contributed to this work by planning experiments, collecting data, data analysis and writing the first draft of this manuscript.

Bart A. Ellenbroek contributed to this work by advising in planning experiments, data analysis and supported the final revision of this manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Albaugh DL, Rinker JA, Baumann MH, Sink JR, Riley AL (2011) Rats preexposed to MDMA display attenuated responses to its aversive effects in the absence of persistent monoamine depletions. Psychopharmacology 216:441–449CrossRefPubMedGoogle Scholar
  2. Amalric M, Koob GF (1985) Low doses of methylnaloxonium in the nucleus accumbens antagonize hyperactivity induced by heroin in the rat. Pharmacol Biochem Behav 23:411–415CrossRefPubMedGoogle Scholar
  3. Anden NE, Butcher SG, Corrodi H, Fuxe K, Ungerstedt U (1970) Receptor activity and turnover of dopamine and noradrenaline after NEUROLEPTICS. Eur J Pharmacol 11:303–314CrossRefPubMedGoogle Scholar
  4. Badiani A, Belin D, Epstein D, Calu D, Shaham Y (2011) Opiate versus psychostimulant addiction: the differences do matter. Nat Rev Neurosci 12:685–700CrossRefPubMedPubMedCentralGoogle Scholar
  5. Ball KT, Budreau D, Rebec GV (2003) Acute effects of 3,4-methylenedioxymethamphetamine on striatal single-unit activity and behavior in freely moving rats: differential involvement of dopamine D-1 and D-2 receptors. Brain Res 994:203–215CrossRefPubMedGoogle Scholar
  6. Barghon R, Protais P, Colboc O, Costentin J (1981) Hypokinesia in mice and catalepsy in rats elicited by morphine associated with antidopaminergic agents, including atypical neuroleptics. Neurosci Lett 27:69–73CrossRefPubMedGoogle Scholar
  7. Bengel D, Murphy DL, Andrews AM, Wichems CH, Feltner D, Heils A, Mossner R, Westphal H, Lesch KP (1998) Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4-methylenedioxymethamphetamine (“ecstasy”) in serotonin transporter-deficient mice. Mol Pharmacol 53:649–655CrossRefPubMedGoogle Scholar
  8. Beninger RJ (1983) The role of dopamine in locomotor activity and learning. Brain Res Rev 6:173–196CrossRefGoogle Scholar
  9. Bradbury S, Gittings D, Schenk S (2012) Repeated exposure to MDMA and amphetamine: sensitization, cross-sensitization, and response to dopamine D-1- and D-2-like agonists. Psychopharmacology 223:389–399CrossRefPubMedGoogle Scholar
  10. Brennan KA, Carati C, Lea RA, Fitzmaurice PS, Schenk S (2009) Effect of D1-like and D2-like receptor antagonists on methamphetamine and 3,4-methylenedioxymethamphetamine self-administration in rats. Behav Pharmacol 20:688–694CrossRefPubMedGoogle Scholar
  11. Brox BW, Day DJ, Ellenbroek BA (2017, Under review) Haplo-insufficiency or knockout of the serotonin transporter does not affect heroin self-administration but decreases BDNF in the frontal cortex. OBM NeurobioologyGoogle Scholar
  12. Callaway CW, Rempel N, Peng RY, Geyer MA (1992) Serotonin 5-HT(1)-like receptors mediate hyperactivity in rats induced by 3,4-METHYLENEDIOXYMETHAMPHETAMINE. Neuropsychopharmacology 7:113–127PubMedGoogle Scholar
  13. Callaway CW, Wing LL, Geyer MA (1990) Serotonin release contributes to the LOCOMOTOR stimulant effects of 3,4-METHYLENEDIOXYMETHAMPHETAMINE in rats. J Pharmacol Exp Ther 254:456–464PubMedGoogle Scholar
  14. Cappell H, Leblanc AE (1977) Parametric investigations of effects of prior exposure to amphetamine and morphine on conditioned gustatory aversion. Psychopharmacology 51:265–271CrossRefPubMedGoogle Scholar
  15. Carlsson A, Lindqvist M, Magnusson T, Waldeck B (1958) Presence of 3-hydroxytyramine in brain. Science 127:471–471CrossRefPubMedGoogle Scholar
  16. Carroll ME, Lac ST, Asencio M, Kragh R (1990a) Fluoxetine reduces intravenous cocaine selfadministration in rats. Pharmacol Biochem Behav 35:237–244Google Scholar
  17. Carroll ME, Lac ST, Asencio M, Kragh R (1990b) Intravenous cocaine self-administration in rats is reduced by dietary L-tryptophan. Psychopharmacology 100:293–300Google Scholar
  18. Colussi-Mas J, Schenk S (2008) Acute and sensitized response to 3,4-methylenedioxymethamphetamine in rats: different behavioral profiles reflected in different patterns of Fos expression. Eur J Neurosci 28:1895–1910CrossRefPubMedGoogle Scholar
  19. Conductier G, Crosson C, Hen R, Bockaert J, Compan V (2005) 3,4-N-methlenedioxymethamphetamine-induced hypophagia is maintained in 5-HT1B receptor knockout mice, but suppressed by the 5-HT2C receptor antagonist RS102221. Neuropsychopharmacology 30:1056–1063CrossRefPubMedGoogle Scholar
  20. Cunningham KA, Anastasio NC (2014) Serotonin at the nexus of impulsivity and cue reactivity in cocaine addiction. Neuropharmacology 76 Pt B:460–78Google Scholar
  21. Daniela E, Brennan K, Gittings D, Hely L, Schenk S (2004) Effect of SCH 23390 on (+/−)-3,4-methylenedioxymethamphetamine hyperactivity and self-administration in rats. Pharmacol Biochem Behav 77:745–750CrossRefPubMedGoogle Scholar
  22. de la Torre R, Yubero-Lahoz S, Pardo-Lozano R, Farre M (2012) MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant? Front Genet 3:235PubMedPubMedCentralGoogle Scholar
  23. Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A 85:5274–5278CrossRefPubMedPubMedCentralGoogle Scholar
  24. Estler CJ (1973) Effect of and adrenergic blocking agents and para-chlorophenylalanine on morphine- and caffeine-stimulated locomotor activity of mice. Psychopharmacologia 28:261–268CrossRefPubMedGoogle Scholar
  25. Fenu S, Cadoni C, Di Chiara G (2010) Conditioned saccharin avoidance and sensitization to drugs of abuse. Behav Brain Res 214:248–253CrossRefPubMedGoogle Scholar
  26. Filip M, Spampinato U, McCreary AC, Przegalinski E (2012) Pharmacological and genetic interventions in serotonin (5-HT)(2C) receptors to alter drug abuse and dependence processes. Brain Res 1476:132–53Google Scholar
  27. Fray PJ, Sahakian BJ, Robbins TW, Koob GF, Iversen SD (1980) An observational method for quantifying the behavioral-effects of dopamine agonists—contrasting effects of d-amphetamine and apomorphine. Psychopharmacology 69:253–259CrossRefPubMedGoogle Scholar
  28. Galaj E, Ananthan S, Saliba M, Ranaldi R (2014) The effects of the novel DA D3 receptor antagonist SR 21502 on cocaine reward, cocaine seeking and cocaine-induced locomotor activity in rats. Psychopharmacology 231:501–510CrossRefPubMedGoogle Scholar
  29. Goudie AJ (1979) Aversive stimulus properties of drugs. Neuropharmacology 18:971–979CrossRefPubMedGoogle Scholar
  30. Grigson PS (1997) Conditioned taste aversions and drugs of abuse: a reinterpretation. Behav Neurosci 111:129–136CrossRefPubMedGoogle Scholar
  31. Grigson PS, Lyuboslavsky PN, Tanase D, Wheeler RA (1999) Water-deprivation prevents morphine-, but not LiCl-induced, suppression of sucrose intake. Physiol Behav 67:277–286CrossRefPubMedGoogle Scholar
  32. Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F, Goldman D, Egan MF, Weinberger DR (2002) Serotonin transporter genetic variation and the response of the human amygdala. Science 297:400–403CrossRefPubMedGoogle Scholar
  33. Heinz A, Braus DF, Smolka MN, Wrase J, Puls I, Hermann D, Klein S, Grusser SM, Flor H, Schumann G, Mann K, Buchel C (2005) Amygdala-prefrontal coupling depends on a genetic variation of the serotonin transporter. Nat Neurosci 8:20–21CrossRefPubMedGoogle Scholar
  34. Higgins GA, Sellers EM, Fletcher PJ (2013) From obesity to substance abuse: therapeutic opportunities for 5-HT2C receptor agonists. Trends Pharmacol Sci 34:560–70Google Scholar
  35. Homberg J, Boer S, Raasø H, Olivier JA, Verheul M, Ronken E, Cools A, Ellenbroek B, Schoffelmeer AM, Vanderschuren LMJ, Vries T, Cuppen E (2008) Adaptations in pre- and postsynaptic 5-HT1A receptor function and cocaine supersensitivity in serotonin transporter knockout rats. Psychopharmacology 200:367–380CrossRefPubMedGoogle Scholar
  36. Hunt T, Amit Z (1987) Conditioned taste-aversion induced by self-administered drugs—paradox revisited. Neurosci Biobehav Rev 11:107–130CrossRefPubMedGoogle Scholar
  37. Ikemoto S, Bonci A (2014) Neurocircuitry of drug reward. Neuropharmacology 76:329–341Google Scholar
  38. Isaacson RL, Yongue B, McClearn D (1978) Dopamine agonists—their effect on locomotion and exploration. Behav Biol 23:163–179CrossRefPubMedGoogle Scholar
  39. Ise Y, Katayama S, Hirano M, Aoki T, Narita M, Suzuki T (2001) Effects of fluvoxamine on morphine-induced inhibition of gastrointestinal transit, antinociception and hyperlocomotion in mice. Neurosci Lett 299:29–32CrossRefPubMedGoogle Scholar
  40. Jones K, Brennan KA, Colussi-Mas J, Schenk S (2010) Tolerance to 3,4-methylenedioxymethamphetamine is associated with impaired serotonin release. Addict Biol 15:289–298CrossRefPubMedGoogle Scholar
  41. Kalivas PW, Duffy P (1987) Sensitization to repeated morphine injection in the rat—possible involvement of A10 dopamine neurons. J Pharmacol Exp Ther 241:204–212PubMedGoogle Scholar
  42. Koob GF, Lloyd GK, Mason BJ (2009) Development of pharmacotherapies for drug addiction: a Rosetta Stone approach. Nat Rev Drug Discov 8:500–515CrossRefPubMedPubMedCentralGoogle Scholar
  43. Lizarraga LE, Phan AV, Cholanians AB, Herndon JM, Lau SS, Monks TJ (2014) Serotonin reuptake transporter deficiency modulates the acute thermoregulatory and locomotor activity response to 3,4-(±)-methylenedioxymethamphetamine, and attenuates depletions in serotonin levels in SERT-KO rats. Toxicol Sci 139:421–431CrossRefPubMedPubMedCentralGoogle Scholar
  44. Lyon M, Robbins T (1975) THE action of central nervous system stimulant drugs a general theory concerning amphetamine effectsGoogle Scholar
  45. McHugh SB, Barkus C, Lima J, Glover LR, Sharp T, Bannerman DM (2015) SERT and uncertainty: serotonin transporter expression influences information processing biases for ambiguous aversive cues in mice. Genes Brain Behavior 14:330–336CrossRefGoogle Scholar
  46. Oakly AC, Brox BW, Schenk S, Ellenbroek BA (2014) A genetic deletion of the serotonin transporter greatly enhances the reinforcing properties of MDMA in rats. Mol Psychiatry 19:534–535CrossRefPubMedGoogle Scholar
  47. Oka T, Hosoya E (1976) Effect of humoral modulators of morphine-induced increase in locomotor activity of mice. Jpn J Pharmacol 26:615–619CrossRefPubMedGoogle Scholar
  48. Olivier JDA, Van Der Hart MGC, Van Swelm RPL, Dederen PJ, Homberg JR, Cremers T, Deen PMT, Cuppen E, Cools AR, Ellenbroek BA (2008) A study in male and female 5-HT transporter knockout rats: an animal model for anxiety and depression disorders. Neuroscience 152:573–584CrossRefPubMedGoogle Scholar
  49. Pardo-Lozano R, Farre M, Yubero-Lahoz S, O’Mathuna B, Torrens M, Mustata C, Perez-Mana C, Langohr K, Cuyas E, Carbo M, de la Torre R (2012) Clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”): the influence of gender and genetics (CYP2D6, COMT, 5-HTT). PLoS One 7:e47599CrossRefPubMedPubMedCentralGoogle Scholar
  50. Parker LA (1995) Rewarding drugs produce taste avoidance, but not taste-aversion. Neurosci Biobehav Rev 19:143–151CrossRefPubMedGoogle Scholar
  51. Parsons LH, Weiss F, Koob GF (1996) Serotonin1b receptor stimulation enhances dopaminemediated reinforcement. Psychopharmacology (Berl) 128:150–60Google Scholar
  52. Pijnenburg AJJ, van Rossum JM (1973) Stimulation of locomotor activity following injection of dopamine into the nucleus accumbens. J Pharm Pharmacol 25:1003–1005CrossRefPubMedGoogle Scholar
  53. Porras G, Di Matteo V, De Deurwaerdere P, Esposito E, Spampinato U (2002a) Central serotonin4 receptors selectively regulate the impulse-dependent exocytosis of dopamine in the rat striatum: in vivo studies with morphine, amphetamine and cocaine. Neuropharmacology 43:1099–1109CrossRefPubMedGoogle Scholar
  54. Porras G, Di Matteo V, Fracasso C, Lucas G, De Deurwaerdere P, Caccia S, Esposito E, Spampinato U (2002b) 5-HT2A and 5-HT2C/2B receptor subtypes modulate dopamine release induced in vivo by amphetamine and morphine in both the rat nucleus accumbens and striatum. Neuropsychopharmacology 26:311–324CrossRefPubMedGoogle Scholar
  55. Ranaldi R, Egan J, Kest K, Fein M, Delamater AR (2009) Repeated heroin in rats produces locomotor sensitization and enhances appetitive Pavlovian and instrumental learning involving food reward. Pharmacol Biochem Behav 91:351–357CrossRefPubMedGoogle Scholar
  56. Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Rev 18:247–291CrossRefPubMedGoogle Scholar
  57. Robinson TE, Berridge KC (2001) Incentive-sensitization and addiction. Addiction 96:103–114CrossRefPubMedGoogle Scholar
  58. Rothman RB, Baumann MH (2003) Monoamine transporters and psychostimulant drugs. Eur J Pharmacol 479:23–40Google Scholar
  59. Sills TL, Fletcher PJ (1997) Fluoxetine attenuates morphine-induced locomotion and blocks morphine-sensitization. Eur J Pharmacol 337:161–164CrossRefPubMedGoogle Scholar
  60. Trigo JM, Renoir T, Lanfumey L, Hamon M, Lesch KP, Robledo P, Maldonado R (2007) 3,4-Methylenedioxymethamphetamine self-administration is abolished in serotonin transporter knockout mice. Biol Psychiatry 62:669–679CrossRefPubMedGoogle Scholar
  61. Tulunay FC, Ayhan IH, Sparber SB (1982) The effects of morphine and Delta-9-Tetrahydrocannabinol on motor-activity in rats. Psychopharmacology 78:358–360CrossRefPubMedGoogle Scholar
  62. Ungerstedt U (1979) Central dopamine mechanisms and behaviour. Academic PressGoogle Scholar
  63. Vaccarino FJ, Corrigall WA (1987) Effects of opiate antagonist treatment into either the periaqueductal grey or nucleus accumbens on heroin-induced locomotor activation. Brain Res Bull 19:545–549CrossRefPubMedGoogle Scholar
  64. Vanderschuren L, Kalivas PW (2000) Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies. Psychopharmacology 151:99–120CrossRefPubMedGoogle Scholar
  65. Vasko MR, Domino EF (1974) Biphasic effects of morphine on locomotor activity and brain acetylcholine utilization in non-tolerant and tolerant rats. Pharmacologist 16:204–204Google Scholar
  66. Verendeev A, Riley AL (2012) Conditioned taste aversion and drugs of abuse: history and interpretation. Neurosci Biobehav Rev 36:2193–2205CrossRefPubMedGoogle Scholar
  67. Volkow ND, Fowler JS, Wang GJ, Baler R, Telang F (2009) Imaging dopamine’s role in drug abuse and addiction. Neuropharmacology 56(Suppl 1):3–8CrossRefPubMedGoogle Scholar
  68. Volkow ND, Wang GJ, Fowler JS, Tomasi D (2012) Addiction circuitry in the human brain. Annu Rev Pharmacol Toxicol 52:321–336CrossRefPubMedGoogle Scholar
  69. Walsh RN, Cummins RA (1976) The open-field test: a critical review. Psychol Bull 83:482–504CrossRefPubMedGoogle Scholar
  70. Wu X, Pang G, Zhang YM, Li G, Xu S, Dong L, Stackman RW, Jr., Zhang G (2015) Activation of serotonin 5-HT(2C) receptor suppresses behavioral sensitization and naloxone-precipitated withdrawal symptoms in heroin-treated mice. Neurosci Lett 607:23–28Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.School of Psychology, Behavioural Neurogenetics GroupVictoria University of WellingtonWellingtonNew Zealand

Personalised recommendations