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Treatment with MDMA from P11–20 disrupts spatial learning and path integration learning in adolescent rats but only spatial learning in older rats

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Abstract

Rationale

Previous studies in rats showed that postnatal day (P)11–20 exposure to ±3,4-methylenedioxymethamphetamine (MDMA, ecstasy) causes learning and memory deficits in adulthood. The emergence and permanence of these learning deficits are currently unknown.

Objective

This study was designed to investigate learning and memory deficits in adolescent (P30 or P40) and older (P180 or P360) rats exposed to MDMA from P11–20.

Materials and methods

Within each litter half the animals were exposed to MDMA (20 mg/kg) and half to saline (SAL) twice a day (8 h apart) from P11–20. In experiment (exp) 1, behavioral testing began on either P30 or P40, whereas in exp 2, testing began on either P180 or P360. Offspring were tested in the Cincinnati water maze (CWM), a test of path integration learning (2 trials/day for 5 days), and the Morris water maze (MWM) (three phases, with 5 days of 4 trials/day and a probe trial on the sixth day per phase).

Results

MDMA-treated rats took longer to find the platform and traveled a greater distance to find the platform at all ages tested in all phases of the MWM. MDMA-treated animals also spent less time in the target quadrant during probe trials. In the CWM, P30 and P40 animals took longer to find the goal and committed more errors in locating the goal, while P180 and P360 MDMA-treated animals performed similarly to SAL-treated animals.

Conclusion

The data suggest that the spatial learning and memory deficits induced by MDMA are long lasting, while the path integration deficits recover over time.

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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  PubMed  CAS  Google Scholar 

  • Bayer SA, Altman J, Russo RJ, Zhang X (1993) Timetables of neurogenesis in the human brain based on experimentally determined patterns in the rat. Neurotoxicology 14:83–144

    PubMed  CAS  Google Scholar 

  • Broening HW, Bacon L, Slikker W Jr (1994) Age modulates the long-term but not the acute effects of the serotonergic neurotoxicant 3,4-methylenedioxymethamphetamine. J Pharmacol Exp Ther 271:285–293

    PubMed  CAS  Google Scholar 

  • Broening HW, Morford LL, Inman-Wood SL, Fukumura M, Vorhees CV (2001) 3,4-Methylenedioxymethamphetamine (ecstasy)-induced learning and memory impairments depend on the age of exposure during early development. J Neurosci 21:3228–3235

    PubMed  CAS  Google Scholar 

  • Burchfield DJ, Lucas VW, Abrams RM, Miller RL, DeVane CL (1991) Disposition and pharmacodynamics of methamphetamine in pregnant sheep. J Am Med Assoc 265:1968–1973

    Article  CAS  Google Scholar 

  • Clancy B, Kersh B, Hyde J, Darlington RB, Anand KJS, Finlay BL (2006) Web-based method for translating neurodevelopment from laboratory species to humans. Neuroinformatics (in press)

  • Cohen MA, Skelton MR, Schaefer TL, Gudelsky GA, Vorhees CV, Williams MT (2005) Learning and memory after neonatal exposure to 3,4-methylenedioxymethamphetamine (ecstasy) in rats: interaction with exposure in adulthood. Synapse 57:148–159

    Article  PubMed  CAS  Google Scholar 

  • Crawford CA, Williams MT, Kohutek JL, Choi FY, Yoshida ST, McDougall SA, Vorhees CV (2006) Neonatal 3,4-methylenedioxymethamphetamine (MDMA) exposure alters neuronal protein kinase A activity, serotonin and dopamine content, and [(35)S]GTPgammaS binding in adult rats. Brain Res 1077:178–186

    Article  PubMed  CAS  Google Scholar 

  • de Quervain DJF, Roozendaal B, McGaugh JL (1998) Stress and glucocorticoids impair retrieval of long-term spatial memory. Nature 394:787–790

    Article  PubMed  CAS  Google Scholar 

  • Etienne AS, Jeffery KJ (2004) Path integration in mammals. Hippocampus 14:180–192

    Article  PubMed  Google Scholar 

  • Figurov A, Pozzo-Miller LD, Olafsson P, Wang T, Lu B (1996) Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature 381:706–709

    Article  PubMed  CAS  Google Scholar 

  • Green AR, Mechan AO, Elliott JM, O’shea E, Colado MI (2003) The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”). Pharmacol Rev 55:463–508

    Article  PubMed  CAS  Google Scholar 

  • Ho E, Karimi-Tabesh L, Koren G (2001) Characteristics of pregnant women who use ecstasy (3, 4-methylenedioxymethamphetamine). Neurotoxicol Teratol 23:561–567

    Article  PubMed  CAS  Google Scholar 

  • Johnston LD, O’Malley PM, Bahman JG, Schulenberg JE (2005a) Monitoring the future national survey results on drug use, 1975–2004. Volume I: secondary school students. National Institute on Drug Abuse, Bethesda, MD

  • Johnston LD, O’Malley PM, Bahman JG, Schulenberg JE (2005b) Monitoring the Future national survey results on drug use, 1975–2004. Volume II: college students and adults ages 19–45. National Institute on Drug Abuse, Bethesda, MD

  • Kirk RE (1993) Experimental design. Brooks/Cole Publishing Company, Pacific Grove, California

    Google Scholar 

  • Koprich JB, Campbell NG, Lipton JW (2003) Neonatal 3,4-methylenedioxymethamphetamine (ecstasy) alters dopamine and serotonin neurochemistry and increases brain derived neurotrophic factor in the forebrain and brainstem of the rat. Brain Res Dev Brain Res 147:177–182

    Article  PubMed  CAS  Google Scholar 

  • Kouimtsidis C, Schifano F, Sharp T, Ford L, Robinson J, Magee C (2006) Neurological and psychopathological sequelae associated with a lifetime intake of 40,000 ecstasy tablets. Psychosomatics 47:86–87

    Article  PubMed  Google Scholar 

  • Linnarsson S, Bjorklund A, Ernfors P (1997) Learning deficit in BDNF mutant mice. Eur J Neurosci 9:2581–2587

    Article  PubMed  CAS  Google Scholar 

  • Mazer C, Muneyyirci J, Taheny K, Raio N, Borella A, Whitaker-Azmitia P (1997) Serotonin depletion during synaptogenesis leads to decreased synaptic density and learning deficits in the adult rat: a possible model of neurodevelopmental disorders with cognitive deficits. Brain Res 760:68–73

    Article  PubMed  CAS  Google Scholar 

  • McElhatton PR, Bateman DN, Evans C, Pughe KR, Worsley AJ (1997) Does prenatal exposure to ecstasy cause congenital malformations? A prospective follow-up of 92 pregnancies. Br J Clin Pharmacol 45:184

    Google Scholar 

  • McElhatton PR, Bateman DN, Evans C, Pughe KR, Thomas SH (1999) Congenital anomalies after prenatal ecstasy exposure. Lancet 354:1441–1442

    Article  PubMed  CAS  Google Scholar 

  • Mordenti J, Chappell W (1989) The use of interspecies scaling in toxicokinetics. In: Yacobi A, Kelly J, Batra V (eds) Toxicokinetics in new drug development. Pergamon, New York pp 42–96

    Google Scholar 

  • Morford LL, Inman-Wood SL, Gudelsky GA, Williams MT, Vorhees CV (2002) Impaired spatial and sequential learning in rats treated neonatally with D-fenfluramine. Eur J Neurosci 16:491–500

    Article  PubMed  CAS  Google Scholar 

  • Rondi-Reig L, Petit GH, Tobin C, Tonegawa S, Mariani J, Berthoz A (2006) Impaired sequential egocentric and allocentric memories in forebrain-specific-NMDA receptor knock-out mice during a new task dissociating strategies of navigation. J Neurosci 26:4071–4081

    Article  PubMed  CAS  Google Scholar 

  • Sapolsky RM, Meaney MJ (1986) Maturation of the adrenocortical stress response: neuroendocrine control mechanisms and the stress hyporesponsive period. Brain Res 396:64–76

    Article  PubMed  CAS  Google Scholar 

  • Sargolini F, Fyhn M, Hafting T, McNaughton BL, Witter MP, Moser MB, Moser EI (2006) Conjunctive representation of position, direction, and velocity in entorhinal cortex. Science 312:758–762

    Article  PubMed  CAS  Google Scholar 

  • Schaefer TL, Ehrman LA, Gudelsky GA, Vorhees CV, Williams MT (2006) A comparison of monoamine and corticosterone levels 24 hours following (+) methamphetamine, (±)3,4-methelynedioxymethamphetamine, cocaine, (+) fenfluramine, or (±)methylphenidate administration in the neonatal rat. J Neurochem 98(5):1369–1378

    Article  PubMed  CAS  Google Scholar 

  • Scholey AB, Parrott AC, Buchanan T, Heffernan TM, Ling J, Rodgers J (2004) Increased intensity of Ecstasy and polydrug usage in the more experienced recreational ecstasy/MDMA users: a WWW study. Addict Behav 29:743–752

    Article  PubMed  Google Scholar 

  • Skelton MR, Blankenmeyer TL, Gudelsky GA, Brown-Strittholt CA, Vorhees CV, Williams MT (2004) Metyrapone attenuates the sequential learning deficits but not monoamine depletions following d,l-fenfluramine administration to adult rats. Synapse 54:214–222

    Article  PubMed  CAS  Google Scholar 

  • Skelton MR, Williams MT, Vorhees CV (2005) Increases in NMDA receptor subunit 1, nitric oxide synthase, and postsynaptic density 95 in adult rats following neonatal MDMA exposure. Society for Neuroscience Abstracts

  • Sodhi MS, Sanders-Bush E (2004) Serotonin and brain development. Int Rev Neurobiol 59:111–174

    Article  PubMed  CAS  Google Scholar 

  • Sprague JE, Preston AS, Leifheit M, Woodside B (2003) Hippocampal serotonergic damage induced by MDMA (ecstasy): effects on spatial learning. Physiol Behav 79:281–287

    Article  PubMed  CAS  Google Scholar 

  • Vorhees CV (1987a) Behavioral teratogenicity of valproic acid: selective effects on behavior after prenatal exposure to rats. Psychopharmacology (Berl) 92:173–179

    CAS  Google Scholar 

  • Vorhees CV (1987b) Maze learning in rats: a comparison of performance in two water mazes in progeny prenatally exposed to different doses of phenytoin. Neurotoxicol Teratol 9:235–241

    Article  PubMed  CAS  Google Scholar 

  • Vorhees CV, Reed TM, Skelton MR, Williams MT (2004) Exposure to 3,4-methylenedioxymethamphetamine (MDMA) on postnatal days 11–20 induces reference but not working memory deficits in the Morris water maze in rats: implications of prior learning. Int J Dev Neurosci 22:247–259

    Article  PubMed  CAS  Google Scholar 

  • Williams MT, Morford LL, McCrea AE, Wood SL, Vorhees CV (2002) Administration of D,L-fenfluramine to rats produces learning deficits in the Cincinnati water maze but not the Morris water maze: relationship to adrenal cortical output. Neurotoxicol Teratol 24:783–796

    Article  PubMed  CAS  Google Scholar 

  • Williams MT, Morford LL, Wood SL, Rock SL, McCrea AE, Fukumura M, Wallace TL, Broening HW, Moran MS, Vorhees CV (2003) Developmental 3,4-methylenedioxymethamphetamine (MDMA) impairs sequential and spatial but not cued learning independent of growth, litter effects or injection stress. Brain Res 968:89–101

    Article  PubMed  CAS  Google Scholar 

  • Williams MT, Schaefer TL, Ehrman LA, Able JA, Gudelsky GA, Sah R, Vorhees CV (2005) 3,4-Methylenedioxymethamphetamine administration on postnatal day 11 in rats increases pituitary-adrenal output and reduces striatal and hippocampal serotonin without altering SERT activity. Brain Res 1039:97–107

    Article  PubMed  CAS  Google Scholar 

  • Winslow JT, Insel TR (1990) Serotonergic modulation of rat pup ultrasonic vocal development: studies with 3,4-methylenedioxymethamphetamine. J Pharmacol Exp Ther 254:212–220

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by NIH grants: DA006733 (CVV) and DA014269 (MTW) and a training grant ES07051 (MRS).

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Authors and Affiliations

  1. Division of Neurology, Cincinnati Children’s Research Foundation, 3333 Burnet Avenue, Cincinnati, OH, 45229-3039, USA

    Matthew R. Skelton, Michael T. Williams & Charles V. Vorhees

  2. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA

    Matthew R. Skelton, Michael T. Williams & Charles V. Vorhees

Authors
  1. Matthew R. Skelton
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  2. Michael T. Williams
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  3. Charles V. Vorhees
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Corresponding author

Correspondence to Charles V. Vorhees.

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Fig. S1

MWM acquisition phase learning curves for P30 (a), P40 (b), P180 (c), and P360 (d) animals. Path length analysis by day show that SAL- and MDMA-treated animals improve their performance each day, although MDMA-treated animals did not learn the task as well (DOC 137 kb)

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Skelton, M.R., Williams, M.T. & Vorhees, C.V. Treatment with MDMA from P11–20 disrupts spatial learning and path integration learning in adolescent rats but only spatial learning in older rats. Psychopharmacology 189, 307–318 (2006). https://doi.org/10.1007/s00213-006-0563-4

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