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Residual social, memory and oxytocin-related changes in rats following repeated exposure to γ-hydroxybutyrate (GHB), 3,4-methylenedioxymethamphetamine (MDMA) or their combination

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Abstract

Rationale

There has been little investigation of the possible lasting adverse effects of γ-hydroxybutyrate (GHB).

Objectives

This study aims to study whether GHB produces residual adverse effects on memory and social behaviour in rats and lasting changes in brain monoamines and oxytocin-related gene expression.

Methods

Rats received daily intraperitoneal injections of GHB (500 mg/kg), methylenedioxymethamphetamine (MDMA; 5 mg/kg) or their combination (GHB/MDMA) over ten consecutive days. Locomotor activity and body weight were assessed during the dosing period and withdrawal-related anxiety was assessed 24 h after drug cessation. After a washout of 4 weeks, rats were tested on the emergence, social interaction, and object recognition tasks over a 2-week period. Monoamine levels in cortex and striatum, and hypothalamic oxytocin and oxytocin receptor mRNA, were then assessed.

Results

MDMA and GHB/MDMA caused modest sensitization of locomotor activity over time, while sedative effects of GHB diminished with repeated exposure. GHB-treated rats showed reduced social interaction 24 h after the final dose, indicating GHB withdrawal-induced anxiety. All drug-treated groups displayed residual deficits in social interaction and object recognition. No changes in monoamine levels were detected 8 weeks post-drug. However, MDMA pre-exposure increased hypothalamic oxytocin mRNA while GHB pre-exposure upregulated oxytocin receptor mRNA. GHB/MDMA pre-exposure caused intermediate changes in both of these measures.

Conclusions

GHB treatment caused residual impairments in memory and social behaviour and increases in anxiety, paralleling the lasting adverse effects of MDMA. Both drugs caused lasting neuroadaptations in brain oxytocin systems and this may be related to the long-term social interaction deficiencies caused by both drugs.

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References

  • Able JA, Gudelsky GA, Vorhees CV, Williams MT (2006) 3, 4-Methylenedioxymethamphetamine in adult rats produces deficits in path integration and spatial reference memory. Biol Psychiatry 59:1219–1226

    Article  CAS  PubMed  Google Scholar 

  • Andriamampandry C, Taleb O, Viry S, Muller C, Humbert JP, Gobaille S, Aunis D, Maitre M (2003) Cloning and characterization of a rat brain receptor that binds the endogenous neuromodulator gamma-hydroxybutyrate (GHB). FASEB J 17:1691–1693

    CAS  PubMed  Google Scholar 

  • Bania TC, Ashar T, Press G, Carey PM (2003) Gamma-hydroxybutyric acid tolerance and withdrawal in a rat model. Acad Emerg Med 10:697–704

    Article  PubMed  Google Scholar 

  • Baumann MH, Wang X, Rothman RB (2007) 3, 4-Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of past and present findings. Psychopharmacology (Berl) 189:407–424

    Article  CAS  Google Scholar 

  • Carter LP, Richards BD, Mintzer MZ, Griffiths RR (2006) Relative abuse liability of GHB in humans: a comparison of psychomotor, subjective, and cognitive effects of supratherapeutic doses of triazolam, pentobarbital, and GHB. Neuropsychopharmacology 31:2537–2551

    Article  CAS  PubMed  Google Scholar 

  • Clemens KJ, Cornish JL, Hunt GE, McGregor IS (2007) Repeated weekly exposure to MDMA, methamphetamine or their combination: long-term behavioural and neurochemical effects in rats. Drug Alcohol Depend 86:183–190

    Article  CAS  PubMed  Google Scholar 

  • 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 28:1895–1910

    Article  PubMed  Google Scholar 

  • 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 30:1056–1063

    Article  CAS  PubMed  Google Scholar 

  • Cruz HG, Ivanova T, Lunn ML, Stoffel M, Slesinger PA, Luscher C (2004) Bi-directional effects of GABA(B) receptor agonists on the mesolimbic dopamine system. Nat Neurosci 7:153–159

    Article  CAS  PubMed  Google Scholar 

  • Dumont GJ, Sweep FC, van der Steen R, Hermsen R, Donders AR, Touw DJ, van Gerven JM, Buitelaar JK, Verkes RJ (2009) Increased oxytocin concentrations and prosocial feelings in humans after ecstasy (3, 4-methylenedioxymethamphetamine) administration. Soc Neurosci 4:359–366

    Article  CAS  PubMed  Google Scholar 

  • Ennaceur A, Delacour J (1988) A new one-trial test for neurobiological studies of memory in rats. 1: behavioral data. Behav Brain Res 31:47–59

    Article  CAS  PubMed  Google Scholar 

  • File SE, Mabbutt PS, Andrews N (1991) Diazepam withdrawal responses measured in the social interaction test of anxiety and their reversal by baclofen. Psychopharmacology (Berl) 104:62–66

    Article  CAS  Google Scholar 

  • Fone KC, Beckett SR, Topham IA, Swettenham J, Ball M, Maddocks L (2002) Long-term changes in social interaction and reward following repeated MDMA administration to adolescent rats without accompanying serotonergic neurotoxicity. Psychopharmacology (Berl) 159:437–444

    Article  CAS  Google Scholar 

  • Forsling ML, Fallon JK, Shah D, Tilbrook GS, Cowan DA, Kicman AT, Hutt AJ (2002) The effect of 3, 4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) and its metabolites on neurohypophysial hormone release from the isolated rat hypothalamus. Br J Pharmacol 135:649–656

    Article  CAS  PubMed  Google Scholar 

  • Frenzilli G, Ferrucci M, Giorgi FS, Blandini F, Nigro M, Ruggieri S, Murri L, Paparelli A, Fornai F (2007) DNA fragmentation and oxidative stress in the hippocampal formation: a bridge between 3, 4-methylenedioxymethamphetamine (ecstasy) intake and long-lasting behavioral alterations. Behav Pharmacol 18:471–481

    Article  CAS  PubMed  Google Scholar 

  • Fuller DE, Hornfeldt CS, Kelloway JS, Stahl PJ, Anderson TF (2004) The Xyrem risk management program. Drug Saf 27:293–306

    Article  CAS  PubMed  Google Scholar 

  • Geldenhuys FG, Sonnendecker EW, De Klrk MC (1968) Experience with sodium-gamma-4-hydroxybutyric acid (gamma-OH) in obstetrics. J Obstet Gynaecol Br Commonw 75:405–413

    CAS  PubMed  Google Scholar 

  • Gouzoulis-Mayfrank E, Thimm B, Rezk M, Hensen G, Daumann J (2003) Memory impairment suggests hippocampal dysfunction in abstinent ecstasy users. Prog Neuropsychopharmacol Biol Psychiatry 27:819–827

    Article  CAS  PubMed  Google Scholar 

  • Green A, Marsden C, Fone K (2008) MDMA as a clinical tool: a note of caution. A response to Sessa and Nutt. J Psychopharmacol 22:929–931

    Article  PubMed  Google Scholar 

  • Harkin A, Connor TJ, Mulrooney J, Kelly JP, Leonard BE (2001) Prior exposure to methylenedioxyamphetamine (MDA) induces serotonergic loss and changes in spontaneous exploratory and amphetamine-induced behaviors in rats. Life Sci 68:1367–1382

    Article  CAS  PubMed  Google Scholar 

  • Husain AM, Ristanovic RK, Bogan RK (2009) Weight loss in narcolepsy patients treated with sodium oxybate. Sleep Med 10:661–663

    Article  PubMed  Google Scholar 

  • Itzhak Y, Ali SF (2002) Repeated administration of gamma-hydroxybutyric acid (GHB) to mice: assessment of the sedative and rewarding effects of GHB. Ann NY Acad Sci 965:451–460

    Article  CAS  PubMed  Google Scholar 

  • Jean A, Conductier G, Manrique C, Bouras C, Berta P, Hen R, Charnay Y, Bockaert J, Compan V (2007) Anorexia induced by activation of serotonin 5-HT4 receptors is mediated by increases in CART in the nucleus accumbens. Proc Natl Acad Sci USA 104:16335–16340

    Article  CAS  PubMed  Google Scholar 

  • Kaupmann K, Cryan JF, Wellendorph P, Mombereau C, Sansig G, Klebs K, Schmutz M, Froestl W, van der Putten H, Mosbacher J, Brauner-Osborne H, Waldmeier P, Bettler B (2003) Specific gamma-hydroxybutyrate-binding sites but loss of pharmacological effects of gamma-hydroxybutyrate in GABA(B)(1)-deficient mice. Eur J Neurosci 18:2722–2730

    Article  PubMed  Google Scholar 

  • Knapp DJ, Overstreet DH, Breese GR (2007) Baclofen blocks expression and sensitization of anxiety-like behavior in an animal model of repeated stress and ethanol withdrawal. Alcohol Clin Exp Res 31:582–595

    Article  CAS  PubMed  Google Scholar 

  • Kovacs GL, Sarnyai Z, Szabo G (1998) Oxytocin and addiction: a review. Psychoneuroendocrinology 23:945–962

    Article  CAS  PubMed  Google Scholar 

  • Kueh D, Iwamoto K, Poling A, Baker LE (2008) Effects of gamma-hydroxybutyrate (GHB) and its metabolic precursors on delayed-matching-to-position performance in rats. Pharmacol Biochem Behav 89:179–187

    Article  CAS  PubMed  Google Scholar 

  • Lee SJ, Levounis P (2008) Gamma hydroxybutyrate: an ethnographic study of recreational use and abuse. J Psychoactive Drugs 40:245–253

    PubMed  Google Scholar 

  • Lee PR, Brady DL, Shapiro RA, Dorsa DM, Koenig JI (2005) Social interaction deficits caused by chronic phencyclidine administration are reversed by oxytocin. Neuropsychopharmacology 30:1883–1894

    Article  CAS  PubMed  Google Scholar 

  • LeTourneau JL, Hagg DS, Smith SM (2008) Baclofen and gamma-hydroxybutyrate withdrawal. Neurocrit Care 8:430–433

    Article  PubMed  Google Scholar 

  • Lipschitz DL, Crowley WR, Armstrong WE, Bealer SL (2005) Neurochemical bases of plasticity in the magnocellular oxytocin system during gestation. Exp Neurol 196:210–223

    Article  CAS  PubMed  Google Scholar 

  • Ludwig V, Mihov Y, Schwarting RK (2008) Behavioral and neurochemical consequences of multiple MDMA administrations in the rat: role of individual differences in anxiety-related behavior. Behav Brain Res 189:52–64

    Article  CAS  PubMed  Google Scholar 

  • McElroy SL, Guerdjikova AI, Winstanley EL, O’Melia AM, Mori N, Keck PE, Jr., Hudson JI (2010) Sodium oxybate in the treatment of binge eating disorder: an open-label, prospective study. Int J Eat Disord (in press)

  • McGregor IS, Clemens KJ, Van der Plasse G, Li KM, Hunt GE, Chen F, Lawrence AJ (2003a) 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  CAS  PubMed  Google Scholar 

  • McGregor IS, Gurtman CG, Morley KC, Clemens KJ, Blokland A, Li KM, Cornish JL, Hunt GE (2003b) Increased anxiety and “depressive” symptoms months after MDMA (“ecstasy”) in rats: drug-induced hyperthermia does not predict long-term outcomes. Psychopharmacology (Berl) 168:465–474

    Article  CAS  Google Scholar 

  • McGregor IS, Callaghan PD, Hunt GE (2008) From ultrasocial to antisocial: a role for oxytocin in the acute reinforcing effects and long-term adverse consequences of drug use? Br J Pharmacol 154:358–368

    Article  CAS  PubMed  Google Scholar 

  • McMurray MS, Williams SK, Jarrett TM, Cox ET, Fay EE, Overstreet DH, Walker CH, Johns JM (2008) Gestational ethanol and nicotine exposure: effects on maternal behavior, oxytocin, and offspring ethanol intake in the rat. Neurotoxicol Teratol 30:475–486

    Article  CAS  PubMed  Google Scholar 

  • Morley KC, Gallate JE, Hunt GE, Mallet PE, McGregor IS (2001) Increased anxiety and impaired memory in rats 3 months after administration of 3, 4-methylenedioxymethamphetamine (“ecstasy”). Eur J Pharmacol 433:91–99

    Article  CAS  PubMed  Google Scholar 

  • Navarro JF, Pedraza C, Gonzalez F (2007) Acute and subchronic effects of gamma-hydroxybutyrate on isolation-induced aggression in male mice. Meth Find Exp Clin Pharmacol 29:379–382

    Article  CAS  Google Scholar 

  • Navarro JF, Davila G, Pedraza C, Arias JL (2008) Anxiogenic-like effects of gamma-hydroxybutyric acid (GHB) in mice tested in the light-dark box. Psicothema 20:460–464

    PubMed  Google Scholar 

  • Neumann ID (2008) Brain oxytocin: a key regulator of emotional and social behaviours in both females and males. J Neuroendocrinol 20:858–865

    Article  CAS  PubMed  Google Scholar 

  • Nutt D (2009) Equasy—an overlooked addiction with implications for the current debate on drug harms. J Psychopharmacol 23:3–5

    Article  CAS  PubMed  Google Scholar 

  • O’Shea E, Granados R, Esteban B, Colado MI, Green AR (1998) The relationship between the degree of neurodegeneration of rat brain 5-HT nerve terminals and the dose and frequency of administration of MDMA (‘ecstasy’). Neuropharmacology 37:919–926

    Article  PubMed  Google Scholar 

  • O’Shea E, Orio L, Escobedo I, Sanchez V, Camarero J, Green AR, Colado MI (2006) MDMA-induced neurotoxicity: long-term effects on 5-HT biosynthesis and the influence of ambient temperature. Br J Pharmacol 148:778–785

    Article  PubMed  Google Scholar 

  • Pedraza C, Garcia FB, Navarro JF (2009) Neurotoxic effects induced by gammahydroxybutyric acid (GHB) in male rats. Int J Neuropsychopharmacol 12:1165–1177

    CAS  Google Scholar 

  • Pfaffl MW, Horgan GW, Dempfle L (2002) Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res 30:e36

    Article  PubMed  Google Scholar 

  • Piper BJ, Fraiman JB, Owens CB, Ali SF, Meyer JS (2008) Dissociation of the neurochemical and behavioral toxicology of MDMA (‘Ecstasy’) by citalopram. Neuropsychopharmacology 33:1192–1205

    Article  CAS  PubMed  Google Scholar 

  • Queva C, Bremner-Danielsen M, Edlund A, Ekstrand AJ, Elg S, Erickson S, Johansson T, Lehmann A, Mattsson JP (2003) Effects of GABA agonists on body temperature regulation in GABA(B(1))−/− mice. Br J Pharmacol 140:315–322

    Article  CAS  PubMed  Google Scholar 

  • Quinn HR, Matsumoto I, Callaghan PD, Long LE, Arnold JC, Gunasekaran N, Thompson MR, Dawson B, Mallet PE, Kashem MA, Matsuda-Matsumoto H, Iwazaki T, McGregor IS (2008) Adolescent rats find repeated delta(9)-THC less aversive than adult rats but display greater residual cognitive deficits and changes in hippocampal protein expression following exposure. Neuropsychopharmacology 33:1113–1126

    Article  PubMed  Google Scholar 

  • Robinson TE, Berridge KC (2003) Addiction. Annu Rev Psychol 54:25–53

    Article  PubMed  Google Scholar 

  • Rogers G, Elston J, Garside R, Roome C, Taylor R, Younger P, Zawada A, Somerville M (2009) The harmful health effects of recreational ecstasy: a systematic review of observational evidence. Health Technol Assess 13(iii–iv, ix–xii):1–315

    Google Scholar 

  • Sarnyai Z, Biro E, Babarczy E, Vecsernyes M, Laczi F, Szabo G, Krivan M, Kovacs GL, Telegdy G (1992) Oxytocin modulates behavioural adaptation to repeated treatment with cocaine in rats. Neuropharmacology 31:593–598

    Article  CAS  PubMed  Google Scholar 

  • Sgaravatti AM, Sgarbi MB, Testa CG, Durigon K, Pederzolli CD, Prestes CC, Wyse AT, Wannmacher CM, Wajner M, Dutra-Filho CS (2007) Gamma-hydroxybutyric acid induces oxidative stress in cerebral cortex of young rats. Neurochem Int 50:564–570

    Article  CAS  PubMed  Google Scholar 

  • Sgaravatti AM, Magnusson AS, Oliveira AS, Mescka CP, Zanin F, Sgarbi MB, Pederzolli CD, Wyse AT, Wannmacher CM, Wajner M, Dutra-Filho CS (2009) Effects of 1, 4-butanediol administration on oxidative stress in rat brain: study of the neurotoxicity of gamma-hydroxybutyric acid in vivo. Metab Brain Dis 24:271–282

    Article  CAS  PubMed  Google Scholar 

  • Silva SM, Madeira MD, Ruela C, Paula-Barbosa MM (2002) Prolonged alcohol intake leads to irreversible loss of vasopressin and oxytocin neurons in the paraventricular nucleus of the hypothalamus. Brain Res 925:76–88

    Article  CAS  PubMed  Google Scholar 

  • Sircar R, Basak A, Sircar D (2008) Gamma-hydroxybutyric acid-induced cognitive deficits in the female adolescent rat. Ann NY Acad Sci 1139:386–389

    Article  CAS  PubMed  Google Scholar 

  • Sivukhina EV, Dolzhikov AA, Morozov Iu E, Jirikowski GF, Grinevich V (2006) Effects of chronic alcoholic disease on magnocellular and parvocellular hypothalamic neurons in men. Horm Metab Res 38:382–390

    Article  CAS  PubMed  Google Scholar 

  • Stone DM, Merchant KM, Hanson GR, Gibb JW (1987) Immediate and long-term effects of 3, 4-methylenedioxymethamphetamine on serotonin pathways in brain of rat. Neuropharmacology 26:1677–1683

    Article  CAS  PubMed  Google Scholar 

  • Sumnall HR, Woolfall K, Edwards S, Cole JC, Beynon CM (2008) Use, function, and subjective experiences of gamma-hydroxybutyrate (GHB). Drug Alcohol Depend 92:286–290

    Article  CAS  PubMed  Google Scholar 

  • Theodosis DT, Schachner M, Neumann ID (2004) Oxytocin neuron activation in NCAM-deficient mice: anatomical and functional consequences. Eur J Neurosci 20:3270–3280

    Article  CAS  PubMed  Google Scholar 

  • Thompson MR, Callaghan PD, Hunt GE, Cornish JL, McGregor IS (2007) A role for oxytocin and 5-HT(1A) receptors in the prosocial effects of 3, 4 methylenedioxymethamphetamine (“ecstasy”). Neuroscience 146:509–514

    Article  CAS  PubMed  Google Scholar 

  • Thompson MR, Hunt GE, McGregor IS (2009) Neural correlates of MDMA (“Ecstasy”)-induced social interaction in rats. Soc Neurosci 4:60–72

    Article  CAS  PubMed  Google Scholar 

  • Uys JD, Niesink RJ (2005) Pharmacological aspects of the combined use of 3, 4-methylenedioxymethamphetamine (MDMA, ecstasy) and gamma-hydroxybutyric acid (GHB): a review of the literature. Drug Alcohol Rev 24:359–368

    Article  PubMed  Google Scholar 

  • van Nieuwenhuijzen PS, McGregor IS (2009) Sedative and hypothermic effects of gamma-hydroxybutyrate (GHB) in rats alone and in combination with other drugs: assessment using biotelemetry. Drug Alcohol Depend 103:137–147

    Article  PubMed  Google Scholar 

  • van Nieuwenhuijzen PS, Li K, Hunt GE, McGregor IS (2009a) Weekly gamma-hydroxybutyrate (GHB) exposure sensitizes locomotor hyperactivity to low dose 3, 4-methylenedioxymethamphetamine (MDMA) in rats. Neuropsychobiology 60:195–203

    Article  PubMed  Google Scholar 

  • van Nieuwenhuijzen PS, McGregor IS, Hunt GE (2009b) The distribution of gamma-hydroxybutyrate-induced Fos expression in rat brain: comparison with baclofen. Neuroscience 158:441–455

    Article  PubMed  Google Scholar 

  • van Nieuwenhuijzen PS, Kashem MA, Matsumoto I, Hunt GE, McGregor IS (2010) A long hangover from party drugs: residual proteomic changes in the hippocampus of rats 8 weeks after gamma-hydroxybutyrate (GHB), 3, 4-methylenedioxymethamphetamine (MDMA) or their combination. Neurochem Int 56:871–877

    Article  PubMed  Google Scholar 

  • Weerts EM, Goodwin AK, Griffiths RR, Brown PR, Froestl W, Jakobs C, Gibson KM (2005) Spontaneous and precipitated withdrawal after chronic intragastric administration of gamma-hydroxybutyrate (GHB) in baboons. Psychopharmacology (Berl) 179:678–687

    Article  CAS  Google Scholar 

  • Wolff K, Tsapakis EM, Winstock AR, Hartley D, Holt D, Forsling ML, Aitchison KJ (2006) Vasopressin and oxytocin secretion in response to the consumption of ecstasy in a clubbing population. J Psychopharmacol 20:400–410

    Article  CAS  PubMed  Google Scholar 

  • You ZD, Li JH, Song CY, Wang CH, Lu CL (2000) Chronic morphine treatment inhibits oxytocin synthesis in rats. NeuroReport 11:3113–3116

    Article  CAS  PubMed  Google Scholar 

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Acknowledgement

Research supported by a National Health and Medical Research Council grant to ISM and GEH.

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Authors and Affiliations

  1. School of Psychology, University of Sydney, Sydney, NSW, 2006, Australia

    Petra S. van Nieuwenhuijzen, Leonora E. Long & Iain S. McGregor

  2. Discipline of Psychological Medicine, Concord Hospital, University of Sydney, Sydney, NSW, 2139, Australia

    Glenn E. Hunt

  3. School of Medical Science (Pharmacology), University of Sydney, Sydney, NSW, 2006, Australia

    Jonathon C. Arnold

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  1. Petra S. van Nieuwenhuijzen
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  2. Leonora E. Long
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  3. Glenn E. Hunt
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Correspondence to Petra S. van Nieuwenhuijzen.

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van Nieuwenhuijzen, P.S., Long, L.E., Hunt, G.E. et al. Residual social, memory and oxytocin-related changes in rats following repeated exposure to γ-hydroxybutyrate (GHB), 3,4-methylenedioxymethamphetamine (MDMA) or their combination. Psychopharmacology 212, 663–674 (2010). https://doi.org/10.1007/s00213-010-1986-5

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