Skip to main content
SpringerLink
Log in

MDMA induces Per1, Per2 and c-fos gene expression in rat suprachiasmatic nuclei

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

±3,4-Methylenedioxymethamphetamine (MDMA, ‘ecstasy’) is a psychoactive drug that has marked effects on the serotonergic system. Serotonergic agonists are known to interact with the circadian pacemaker located in the suprachiasmatic nuclei (SCN).

Objectives

Given changes reported in the behavioral activity rhythm following MDMA treatment, the effects of MDMA on core clock gene (Per1, Per2) and c-fos expression were evaluated.

Methods

Male Long–Evans rats (n = 72) were injected once with MDMA (5 mg/kg i.p.) or saline either at the middle of their ‘rest’ phase (Zeitgeber Time: ZT6) or the middle of their ‘active’ phase (Zeitgeber Time: ZT16) and killed at 30, 60, or 120 min posttreatment for gene expression analysis in the SCN using PCR. Behavioral rhythms of a separate group of rats (n = 20) were measured following treatment at ZT16 while they were held in constant darkness for 10 days posttreatment.

Results

At ZT6, c-fos mRNA was significantly induced 120 min post-MDMA treatment but there were no significant changes in Per1 or Per2 mRNA expression. At ZT16, there were significant inductions of c-fos mRNA (30 and 60 min) and Per1 and Per2 mRNA (both 60 min) post-MDMA treatment. However, no differences in behavioral activity patterns were noted following MDMA treatment at ZT16.

Conclusions

These data provide evidence that MDMA has time of day dependent actions on SCN functioning, as evident from its induction of core clock genes that are important for generating and maintaining circadian rhythmicity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Agostino PV, Plano SA, Golombek DA (2007) Sildenafil accelerates re-entrainment of circadian rhythms after advancing light schedules. Proc Natl Acad Sci USA 104:9834–9839

    Article  PubMed  CAS  Google Scholar 

  • Albrecht U (2002) Functional genomics of sleep and circadian rhythms: invited review: regulation of mammalian circadian clock genes. J Appl Physiol 92:1348–1355

    PubMed  CAS  Google Scholar 

  • Allen RP, McCann UD, Ricaurte GA (1993) Persistent effects of (+−)3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) on human sleep. Sleep 16:560–564

    PubMed  CAS  Google Scholar 

  • Balogh B, Molnar E, Jakus R, Quate L, Olverman HJ, Kelly PAT et al (2004) Effects of a single dose of 3,4-methylenedioxymethamphetamine on circadian patterns, motor activity and sleep in drug-naive rats and rats previously exposed to MDMA. Psychopharmacology 173:296–309

    Article  PubMed  CAS  Google Scholar 

  • Biello SM, Dafters RI (2001) MDMA and fenfluramine alter the response of the circadian clock to a serotonergic agonist in vitro. Brain Res 920:202–209

    Article  PubMed  CAS  Google Scholar 

  • Carhart-Harris RL, Nutt DJ, Munafo M, Wilson SJ (2009) Current and former ecstasy users report different sleep to matched controls: a web-based questionnaire study. J Psychopharmacol 23:249–257

    Article  PubMed  CAS  Google Scholar 

  • Challet E (2007) Minireview: entrainment of the suprachiasmatic clockwork in diurnal and nocturnal mammals. Endocrinology 148:5648–5655

    Article  PubMed  CAS  Google Scholar 

  • Colbron S, Jones M, Biello SM (2002) MDMA alters the response of the circadian clock to a photic and non-photic stimulus. Brain Res 956:45–52

    Article  PubMed  CAS  Google Scholar 

  • Cuesta M, Clesse D, Pévet P, Challet E (2009) New light on the serotonergic paradox in the rat circadian system. J Neurochem 110:231–243

    Article  PubMed  CAS  Google Scholar 

  • Cutrera RA, Saboureau M, Pévet P (1996) Phase-shifting effect of 8-OH-DPAT, a 5-HT1A/5-HT7 receptor agonist, on locomotor activity in golden hamster in constant darkness. Neurosci Lett 210:1–4

    Article  PubMed  CAS  Google Scholar 

  • Dardente H, Cermakian N (2007) Molecular circadian rhythms in central and peripheral clocks in mammals. Chronobiol Int 24:195–213

    Google Scholar 

  • Dijk DJ, Czeisler CA (1995) Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans. J Neurosci 15:3526–3538

    PubMed  CAS  Google Scholar 

  • Dudley TE, Dinardo LA, Glass JD (1999) In vivo assessment of the midbrain Raphe nuclear regulation of serotonin release in the hamster suprachiasmatic nucleus. J Neurophysiol 81:1469–1477

    PubMed  CAS  Google Scholar 

  • Edgar DM, Miller JD, Prosser RA, Dean RR, Dement WC (1993) Serotonin and the mammalian circadian system: II. Phase-shifting rat behavioral rhythms with serotonergic agonists. J Biol Rhythms 8:17–37

    Article  PubMed  CAS  Google Scholar 

  • Gardani M, Blance RN, Biello SM (2005) MDMA alters the response of the mammalian circadian clock in hamsters: effects on re-entrainment and triazolam-induced phase shifts. Brain Res 1046:105–115

    Article  PubMed  CAS  Google Scholar 

  • Graff C, Challet E, Pévet P, Wollnik F (2007) 5-HT3 receptor-mediated photic-like responses of the circadian clock in the rat. Neuropharmacology 52:662–671

    Article  PubMed  CAS  Google Scholar 

  • Horikawa K, Shibata S (2004) Phase-resetting response to (+) 8-OH-DPAT, a serotonin (1A/7) receptor agonist, in the mouse in vivo. Neurosci Lett 368:130–134

    Article  PubMed  CAS  Google Scholar 

  • Huxster J (2006) The sub-acute effects of recreational ecstasy (MDMA) use: a controlled study in humans. J Psychopharmacol 20:281–290

    Article  PubMed  Google Scholar 

  • Johansson C, Willeit M, Smedh C, Ekholm J, Paunio T, Kieseppa T et al (2003) Circadian clock-related polymorphisms in seasonal affective disorder and their relevance to diurnal preference. Neuropsychopharmacology 28:734–739

    Article  PubMed  CAS  Google Scholar 

  • Jones KA, Callen F, Blagrove MT, Parrott AC (2008) Sleep, energy and self rated cognition across 7 nights following recreational Ecstasy/MDMA use. Sleep Hypn 10:16–28

    Google Scholar 

  • Kennaway DJ (2004) Resetting the suprachiasmatic nucleus clock. Front Biosci 9:56–62

    Article  PubMed  CAS  Google Scholar 

  • Kennaway DJ (2010) Review: clock genes at the heart of depression. J Psychopharmacol 24:5–14

    Article  PubMed  CAS  Google Scholar 

  • Kennaway DJ, Moyer RW (1998) Serotonin 5-HT2c agonists mimic the effect of light pulses on circadian rhythms. Brain Res 806:257–270

    Article  PubMed  CAS  Google Scholar 

  • Kennaway DJ, Rowe SA, Ferguson SA (1996) Serotonin agonists mimic the phase shifting effects of light on the melatonin rhythm in rats. Brain Res 737:301–307

    Article  PubMed  CAS  Google Scholar 

  • Kohler M, Kalkowski A, Wollnik F (1999) Serotonin agonist quipazine induces photic-like phase shifts of the circadian activity rhythm and c-Fos expression in the rat suprachiasmatic nucleus. J Biol Rhythms 14:131–140

    Article  PubMed  CAS  Google Scholar 

  • Liechti ME, Vollenweider FX (2000) The serotonin uptake inhibitor citalopram reduces acute cardiovascular and vegetative effects of 3,4-methylenedioxymethamphetamine (‘Ecstasy’) in healthy volunteers. J Psychopharmacol 14:269–274

    Article  PubMed  CAS  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2-[delta][delta]CT method. Methods 25:402–408

    Article  PubMed  CAS  Google Scholar 

  • McCann U, Ricaurte G (2007) Effects of (+−)3,4-methylenedioxymetamphetamine (MDMA) on sleep and circadian rhythms. Sci World J 7:231–238

    Article  Google Scholar 

  • McCann UD, Eligulashvili V, Ricaurte GA (2000) (+−)3,4-Methylenedioxymethamphetamine (‘Ecstasy’)-induced serotonin neurotoxicity: clinical studies. Neuropsychobiology 42:11–16

    Article  PubMed  CAS  Google Scholar 

  • McGregor IS, Clemens KJ, Van der Plasse G, Li KM, Hunt GE, Chen F et al (2003) Increased anxiety 3 months after brief exposure to MDMA (‘Ecstasy’) in rats: association with altered 5-HT transporter and receptor density. Neuropsychopharmacology 28:1472–1484

    Article  PubMed  CAS  Google Scholar 

  • Mistlberger RE (1991) Effects of daily schedules of forced activity on free-running rhythms in the rat. J Biol Rhythms 6:71–80

    Article  PubMed  CAS  Google Scholar 

  • Mistlberger RE, Antle MC, Glass JD, Miller JD (2000) Behavioral and serotonergic regulation of circadian rhythms. Biol Rhythm Res 31:240–283

    Article  CAS  Google Scholar 

  • Moore RY (2003) Circadian timing. In: Squire LR, Bloom FE, McConnell SK, Roberts JL, Spitzer NC, Zigmond MJ (eds) Fundamental neuroscience. Elsevier, California

    Google Scholar 

  • Moore RY, Eichler VB (1972) Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat. Brain Res 42:201–206

    Article  PubMed  CAS  Google Scholar 

  • Montgomery C, Fisk JE, Wareing M, Murphy P (2007) Self reported sleep quality and cognitive performance in ecstasy users. Hum Psychopharmacol 22:537–548

    Article  PubMed  Google Scholar 

  • Mrosovsky N (1996) Locomotor activity and non-photic influences on circadian clocks. Biol Rev 71:343–372

    Article  PubMed  CAS  Google Scholar 

  • Nichols DE (1986) Differences between the mechanism of action of MDMA, MBDB, and the classic hallucinogens—identification of a new therapeutic class—entactogens. J Psychoactive Drugs 18:305–313

    Article  PubMed  CAS  Google Scholar 

  • Oberlender R, Nichols DE (1990) (+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine as a discriminative stimulus in studies of 3,4-methylenedioxy-methamphetamine-like behavioral activity. J Pharmacol Exp Ther 255:1098–1106

    PubMed  CAS  Google Scholar 

  • Ogeil RP, Rajaratnam SMW, Redman JR, Broadbear JH (2010) Acute MDMA administration alters the distribution and circadian rhythm of wheel running activity in the rat. Brain Res 1359:128–136

    Article  PubMed  CAS  Google Scholar 

  • Ogeil RP, Rajaratnam SMW, Broadbear JH (2011) Ecstasy and sleep disturbance: progress towards elucidating a role for the circadian system. Sleep Biol Rhythms. Accepted 1st July, 2011. doi:10.1111/j.1479-8425.2011.00510.x

  • Parks KA, Kennedy CL (2004) Club drugs: reasons for and consequences of use. J Psychoactive Drugs 36:295–302

    Article  PubMed  Google Scholar 

  • Randall S, Johanson CE, Tancer M, Roehrs T (2009) Effects of acute 3, 4-methylenedioxymethamphetamine on sleep and daytime sleepiness in MDMA users: a preliminary study. Sleep 32:1513–1519

    PubMed  Google Scholar 

  • Reppert SM, Weaver DR (2001) Molecular analysis of mammalian circadian rhythms. Annu Rev Physiol 63:647–676

    Article  PubMed  CAS  Google Scholar 

  • Reppert SM, Weaver DR (2002) Coordination of circadian timing in mammals. Nature 418:935–941

    Article  PubMed  CAS  Google Scholar 

  • Schuhler S, Saboureau M, Pitrosky B, Pévet P (1998) In Syrian hamsters, 5-HT fibres within the suprachiasmatic nuclei are necessary for the expression of 8-OH-DPAT induced phase-advance of locomotor activity rhythm. Neurosci Lett 256:33–36

    Article  PubMed  CAS  Google Scholar 

  • Stephan FK, Zucker I (1972) Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions. Proc Natl Acad Sci USA 69:1583–1586

    Article  PubMed  CAS  Google Scholar 

  • Stephan FK, Berkley KJ, Moss RL (1981) Efferent connections of the rat suprachiasmatic nucleus. Neuroscience 6:2625–2641

    Article  PubMed  CAS  Google Scholar 

  • Varcoe TJ, Kennaway DJ (2008) Activation of 5-HT2C receptors acutely induces Per1 gene expression in the rat SCN in vitro. Brain Res 1209:19–28

    Article  PubMed  CAS  Google Scholar 

  • Varcoe TJ, Kennaway DJ, Voultsios A (2003) Activation of 5-HT2C receptors acutely induces per gene expression in the rat suprachiasmatic nucleus at night. Mol Brain Res 119:192–200

    Article  PubMed  CAS  Google Scholar 

  • Verheyden SL, Hadfield J, Calin T, Curran HV (2002) Sub-acute effects of MDMA (+−3,4-methylenedioxymethamphetamine, “ecstasy”) on mood: evidence of gender differences. Psychopharmacology 161:23–31

    Article  PubMed  CAS  Google Scholar 

  • Wallace TL, Gudelsky GA, Vorhees CV (2001) Alterations in diurnal and nocturnal locomotor activity in rats treated with a monoamine-depleting regimen of methamphetamine or 3,4-methylenedioxymethamphetamine. Psychopharmacology 153:321–326

    Article  PubMed  CAS  Google Scholar 

  • Weaver D (1998) The suprachiasmatic nucleus: a 25-year retrospective. J Biol Rhythms 13:100–112

    Article  PubMed  CAS  Google Scholar 

  • Wirz-Justice A (2003) Chronobiology and mood disorders. Dialogues Clin Neurosci 5:315–325

    PubMed  Google Scholar 

  • Wirz-Justice A (2006) Biological rhythm disturbances in mood disorders. Int Clin Psychopharmacol 21:S11–S15

    Article  PubMed  Google Scholar 

  • Xie T, Tong L, McLane MW, Hatzidimitriou G, Yuan J, McCann U et al (2006) Loss of serotonin transporter protein after MDMA and other ring-substituted amphetamines. Neuropsychopharmacology 31:2639–2651

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr. Tamara Varcoe, A/Prof. Jennifer Redman, Prof. Grahame Coleman, Dr. Zane Andrews, Dr. Sarah Spencer, Ms. Cheryl Roberts, Ms Hania Czerwinska and Ms. Terry Lane for their guidance and support. Rowan Ogeil was the recipient of an Australian Postgraduate award and a Faculty of Medicine, Nursing and Health Sciences Postgraduate Excellence Award from Monash University.

Author disclosure

This research was conducted without specific funding from the public, commercial or not-for-profit sectors. All authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

  1. School of Psychology and Psychiatry, Monash University, Clayton, Victoria, 3800, Australia

    Rowan P. Ogeil, Shantha M. W. Rajaratnam & Jillian H. Broadbear

  2. Robinson Institute, Research Centre for Reproductive Health, Discipline of Obstetrics and Gynaecology, University of Adelaide, Adelaide, South Australia, 5005, Australia

    David J. Kennaway & Mark D. Salkeld

Authors
  1. Rowan P. Ogeil
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David J. Kennaway
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark D. Salkeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shantha M. W. Rajaratnam
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jillian H. Broadbear
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rowan P. Ogeil.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ogeil, R.P., Kennaway, D.J., Salkeld, M.D. et al. MDMA induces Per1, Per2 and c-fos gene expression in rat suprachiasmatic nuclei. Psychopharmacology 220, 835–843 (2012). https://doi.org/10.1007/s00213-011-2541-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-011-2541-8

Keywords

Search

Navigation