Skip to main content
SpringerLink
Log in

Effects of exposure to amphetamine derivatives on passive avoidance performance and the central levels of monoamines and their metabolites in mice: Correlations between behavior and neurochemistry

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

Abstract

Rationale

Considerable evidence indicates that amphetamine derivatives can deplete brain monoaminergic neurotransmitters. However, the behavioral and cognitive consequences of neurochemical depletions induced by amphetamines are not well established.

Objectives

In this study, mice were exposed to dosing regimens of 3,4-methylenedioxymethamphetamine (MDMA), methamphetamine (METH), or parachloroamphetamine (PCA) known to deplete the monoamine neurotransmitters dopamine and serotonin, and the effects of these dosing regimens on learning and memory were assessed.

Methods

In the same animals, we determined deficits in learning and memory via passive avoidance (PA) behavior and changes in tissue content of monoamine neurotransmitters and their primary metabolites in the striatum, frontal cortex, cingulate, hippocampus, and amygdala via ex vivo high-pressure liquid chromatography.

Results

Exposure to METH and PCA impaired PA performance and resulted in significant depletions of dopamine, serotonin, and their metabolites in several brain regions. Multiple linear regression analysis revealed that the tissue concentration of dopamine in the anterior striatum was the strongest predictor of PA performance, with an additional significant contribution by the tissue concentration of the serotonin metabolite 5-hydroxyindoleacetic acid in the cingulate. In contrast to the effects of METH and PCA, exposure to MDMA did not deplete anterior striatal dopamine levels or cingulate levels of 5-hydroxyindoleacetic acid, and it did not impair PA performance.

Conclusions

These studies demonstrate that certain amphetamines impair PA performance in mice and that these impairments may be attributable to specific neurochemical depletions.

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
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Achat-Mendes C, Ali SF, Itzhak Y (2005) Differential effects of amphetamines-induced neurotoxicity on appetitive and aversive Pavlovian conditioning in mice. Neuropsychopharmacology 30:1128–1137

    Article  PubMed  CAS  Google Scholar 

  • Achat-Mendes C, Anderson KL, Itzhak Y (2007) Impairment in consolidation of learned place preference following dopaminergic neurotoxicity in mice is ameliorated by N-acetylcysteine but not D1 and D2 dopamine receptor agonists. Neuropsychopharmacology 32:531–541

    Article  PubMed  CAS  Google Scholar 

  • Adriani W, Felici A, Sargolini F, Roullet P, Usiello A, Oliverio A, Mele A (1998) N-methyl-d-aspartate and dopamine receptor involvement in the modulation of locomotor activity and memory processes. Exp Brain Res 123:52–59

    Article  PubMed  CAS  Google Scholar 

  • Ali SF, Newport GD, Holson RR, Slikker W Jr, Bowyer JF (1994) Low environmental temperatures or pharmacologic agents that produce hypothermia decrease methamphetamine neurotoxicity in mice. Brain Res 658:33–38

    Article  PubMed  CAS  Google Scholar 

  • Barrionuevo M, Aguirre N, Del Rio JD, Lasheras B (2000) Serotonergic deficits and impaired passive-avoidance learning in rats by MDEA: a comparison with MDMA. Pharmacol Biochem Behav 65:233–240

    Article  PubMed  CAS  Google Scholar 

  • Belcher AM, Feinstein EM, O’Dell SJ, Marshall JF (2008) Methamphetamine influences on recognition memory: comparison of escalating and single-day dosing regimens. Neuropsychopharmacology 33:1453–1463

    Article  PubMed  CAS  Google Scholar 

  • Bolla KI, McCann UD, Ricaurte GA (1998) Memory impairment in abstinent MDMA (“Ecstasy”) users. Neurology 51:1532–1537

    PubMed  CAS  Google Scholar 

  • Buchert R, Obrocki J, Thomasius R, Vaterlein O, Petersen K, Jenicke L, Bohuslavizki KH, Clausen M (2001) Long-term effects of ‘ecstasy’ abuse on the human brain studied by FDG PET. Nucl Med Commun 22:889–897

    Article  PubMed  CAS  Google Scholar 

  • Colado MI, O’Shea E, Green AR (2004) Acute and long-term effects of MDMA on cerebral dopamine biochemistry and function. Psychopharmacology (Berl) 173:249–263

    Article  CAS  Google Scholar 

  • Fantegrossi WE, Ciullo JR, Wakabayashi KT, De La Garza R 2nd, Traynor JR, Woods JH (2008) A comparison of the physiological, behavioral, neurochemical and microglial effects of methamphetamine and 3,4-methylenedioxymethamphetamine in the mouse. Neuroscience 151:533–543

    Article  PubMed  CAS  Google Scholar 

  • Fuller RW, Hines CW, Mills J (1965) Lowering of brain serotonin level by chloramphetamines. Biochem Pharmacol 14:483–488

    Article  PubMed  CAS  Google Scholar 

  • Fuller RW, Baker JC, Molloy BB (1977) Biological disposition of rigid analogs of amphetamine. J Pharm Sci 66:271–272

    Article  PubMed  CAS  Google Scholar 

  • Gibb JW, Johnson M, Stone D, Hanson GR (1990) MDMA: historical perspectives. Ann N Y Acad Sci 600:601–611, discussion 611–2

    Article  PubMed  CAS  Google Scholar 

  • Gower AJ, Lamberty Y (1993) The aged mouse as a model of cognitive decline with special emphasis on studies in NMRI mice. Behav Brain Res 57:163–173

    Article  PubMed  CAS  Google Scholar 

  • Hanson KL, Luciana M (2004) Neurocognitive function in users of MDMA: the importance of clinically significant patterns of use. Psychol Med 34:229–246

    Article  PubMed  Google Scholar 

  • Hirata H, Ladenheim B, Rothman RB, Epstein C, Cadet JL (1995) Methamphetamine-induced serotonin neurotoxicity is mediated by superoxide radicals. Brain Res 677:345–347

    Article  PubMed  CAS  Google Scholar 

  • Itzhak Y, Achat-Mendes CN, Ali SF, Anderson KL (2004) Long-lasting behavioral sensitization to psychostimulants following p-chloroamphetamine-induced neurotoxicity in mice. Neuropharmacology 46:74–84

    Article  PubMed  CAS  Google Scholar 

  • Kalechstein AD, Newton TF, Green M (2003) Methamphetamine dependence is associated with neurocognitive impairment in the initial phases of abstinence. J Neuropsychiatry Clin Neurosci 15:215–220

    Article  PubMed  CAS  Google Scholar 

  • Kalechstein AD, De La Garza R 2nd, Mahoney JJ 3rd, Fantegrossi WE, Newton TF (2007) MDMA use and neurocognition: a meta-analytic review. Psychopharmacology (Berl) 189:531–537

    Article  CAS  Google Scholar 

  • Kish SJ, Furukawa Y, Ang L, Vorce SP, Kalasinsky KS (2000) Striatal serotonin is depleted in brain of a human MDMA (Ecstasy) user. Neurology 55:294–296

    PubMed  CAS  Google Scholar 

  • Kita T, Wagner GC, Nakashima T (2003) Current research on methamphetamine-induced neurotoxicity: animal models of monoamine disruption. J Pharmacol Sci 92:178–195

    Article  PubMed  CAS  Google Scholar 

  • Krasnova IN, Hodges AB, Ladenheim B, Rhoades R, Phillip CG, Cesena A, Ivanova E, Hohmann CF, Cadet JL (2009) Methamphetamine treatment causes delayed decrease in novelty-induced locomotor activity in mice. Neurosci Res 65:160–165

    Article  PubMed  CAS  Google Scholar 

  • McCann UD, Szabo Z, Scheffel U, Dannals RF, Ricaurte GA (1998) Positron emission tomographic evidence of toxic effect of MDMA (“Ecstasy”) on brain serotonin neurons in human beings. Lancet 352:1433–1437

    Article  PubMed  CAS  Google Scholar 

  • McCann UD, Peterson SC, Ricaurte GA (2007) The effect of catecholamine depletion by alpha-methyl-para-tyrosine on measures of cognitive performance and sleep in abstinent MDMA users. Neuropsychopharmacology 32:1695–1706

    Article  PubMed  CAS  Google Scholar 

  • McCardle K, Luebbers S, Carter JD, Croft RJ, Stough C (2004) Chronic MDMA (ecstasy) use, cognition and mood. Psychopharmacology (Berl) 173:434–439

    Article  CAS  Google Scholar 

  • Miller DB, O’Callaghan JP (1995) The role of temperature, stress, and other factors in the neurotoxicity of the substituted amphetamines 3,4-methylenedioxymethamphetamine and fenfluramine. Mol Neurobiol 11:177–192

    Article  PubMed  CAS  Google Scholar 

  • Myhrer T (2003) Neurotransmitter systems involved in learning and memory in the rat: a meta-analysis based on studies of four behavioral tasks. Brain Res Brain Res Rev 41:268–287

    Article  PubMed  CAS  Google Scholar 

  • O’Callaghan JP, Miller DB (1994) Neurotoxicity profiles of substituted amphetamines in the C57BL/6J mouse. J Pharmacol Exp Ther 270:741–751

    PubMed  Google Scholar 

  • Obrocki J, Schmoldt A, Buchert R, Andresen B, Petersen K, Thomasius R (2002) Specific neurotoxicity of chronic use of ecstasy. Toxicol Lett 127:285–297

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Franklin KBJ (2001) The mouse brain in stereotaxic coordinates, 2nd edn. Academic Press, San Diego

  • Pletscher A, Burkard WP, Bruderer H, Gey KF (1963) Decrease of cerebral 5-hydroxytryptamine and 5-hydroxyindolacetic acid by an arylalkylamine. Life Sci 11:828–833

    Article  PubMed  CAS  Google Scholar 

  • Pletscher A, Bartholini G, Bruderer H, Burkard WP, Gey KF (1964) Chlorinated arylalkylamines affecting the cerebral metabolism of 5-hydroxytryptamine. J Pharmacol Exp Ther 145:344–350

    PubMed  CAS  Google Scholar 

  • Reneman L, Booij J, de Bruin K, Reitsma JB, de Wolff FA, Gunning WB, den Heeten GJ, van den Brink W (2001) Effects of dose, sex, and long-term abstention from use on toxic effects of MDMA (ecstasy) on brain serotonin neurons. Lancet 358:1864–1869

    Article  PubMed  CAS  Google Scholar 

  • Renoir T, Paizanis E, Yacoubi ME, Saurini F, Hanoun N, Melfort M, Lesch KP, Hamon M, Lanfumey L (2008) Differential long-term effects of MDMA on the serotoninergic system and hippocampal cell proliferation in 5-HTT knock-out vs. wild-type mice. Int J Neuropsychopharmacol 11:1149–1162

    Article  PubMed  CAS  Google Scholar 

  • Ricaurte GA (1989) Studies of MDMA-induced neurotoxicity in nonhuman primates: a basis for evaluating long-term effects in humans. NIDA Res Monogr 94:306–322

    PubMed  CAS  Google Scholar 

  • Saadat KS, Elliott JM, Colado MI, Green AR (2006a) The acute and long-term neurotoxic effects of MDMA on marble burying behaviour in mice. J Psychopharmacol 20:264–271

    Article  PubMed  Google Scholar 

  • Saadat KS, Elliott JM, Green AR, Moran PM (2006b) High-dose MDMA does not result in long-term changes in impulsivity in the rat. Psychopharmacology (Berl) 188:75–83

    Article  CAS  Google Scholar 

  • Sanders-Bush E, Bushing JA, Sulser F (1975) Long-term effects of p-chloroamphetamine and related drugs on central serotonergic mechanisms. J Pharmacol Exp Ther 192:33–41

    PubMed  CAS  Google Scholar 

  • Santucci AC, Knott PJ, Haroutunian V (1996) Excessive serotonin release, not depletion, leads to memory impairments in rats. Eur J Pharmacol 295:7–17

    Article  PubMed  CAS  Google Scholar 

  • Schmidt CJ, Levin JA, Lovenberg W (1987) In vitro and in vivo neurochemical effects of methylenedioxymethamphetamine on striatal monoaminergic systems in the rat brain. Biochem Pharmacol 36:747–755

    Article  PubMed  CAS  Google Scholar 

  • Scott JC, Woods SP, Matt GE, Meyer RA, Heaton RK, Atkinson JH, Grant I (2007) Neurocognitive effects of methamphetamine: a critical review and meta-analysis. Neuropsychol Rev 17:275–297

    Article  PubMed  Google Scholar 

  • Simon SL, Dean AC, Cordova X, Monterosso JR, London ED (2010) Methamphetamine dependence and neuropsychological functioning: evaluating change during early abstinence. J Stud Alcohol Drugs 71:335–344

    PubMed  Google Scholar 

  • Steranka LR, Sanders-Bush E (1980) Long-term effects of continuous exposure to amphetamine on brain dopamine concentration and synaptosomal uptake in mice. Eur J Pharmacol 65:439–443

    Article  PubMed  CAS  Google Scholar 

  • Steranka L, Bessent R, Sanders-Bush E (1977) Reversible and irreversible effects of p-chloroamphetamine on brain serotonin in mice. Commun Psychopharmacol 1:447–454

    PubMed  CAS  Google Scholar 

  • Stone DM, Hanson GR, Gibb JW (1987) Differences in the central serotonergic effects of methylenedioxymethamphetamine (MDMA) in mice and rats. Neuropharmacology 26:1657–1661

    Article  PubMed  CAS  Google Scholar 

  • Sugimoto Y, Ohkura M, Inoue K, Yamada J (2001) Involvement of serotonergic and dopaminergic mechanisms in hyperthermia induced by a serotonin-releasing drug, p-chloroamphetamine in mice. Eur J Pharmacol 430:265–268

    Article  PubMed  CAS  Google Scholar 

  • Taghzouti K, Simon H, Louilot A, Herman JP, Le Moal M (1985) Behavioral study after local injection of 6-hydroxydopamine into the nucleus accumbens in the rat. Brain Res 344:9–20

    Article  PubMed  CAS  Google Scholar 

  • Timar J, Gyarmati S, Szabo A, Furst S (2003) Behavioural changes in rats treated with a neurotoxic dose regimen of dextrorotatory amphetamine derivatives. Behav Pharmacol 14:199–206

    Article  PubMed  CAS  Google Scholar 

  • Wang X, Baumann MH, Xu H, Rothman RB (2004) 3,4-Methylenedioxymethamphetamine (MDMA) administration to rats decreases brain tissue serotonin but not serotonin transporter protein and glial fibrillary acidic protein. Synapse 53:240–248

    Article  PubMed  CAS  Google Scholar 

  • Wilson JM, Kalasinsky KS, Levey AI, Bergeron C, Reiber G, Anthony RM, Schmunk GA, Shannak K, Haycock JW, Kish SJ (1996) Striatal dopamine nerve terminal markers in human, chronic methamphetamine users. Nat Med 2:699–703

    Article  PubMed  CAS  Google Scholar 

  • Winsauer PJ, McCann UD, Yuan J, Delatte MS, Stevenson MW, Ricaurte GA, Moerschbaecher JM (2002) Effects of fenfluramine, m-CPP and triazolam on repeated-acquisition in squirrel monkeys before and after neurotoxic MDMA administration. Psychopharmacology (Berl) 159:388–396

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Brendan James Finton

    Present address: Department of Medical and Clinical Psychology, Uniformed Services University, Bethesda, MD, USA

Authors and Affiliations

  1. Division of Neuropharmacology and Neurologic Diseases, Yerkes National Primate Research Center, Yerkes Imaging Center, 954 Gatewood Road, Atlanta, GA, 30322-4250, USA

    Kevin Sean Murnane, Brendan James Finton & Leonard Lee Howell

  2. Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA

    Leonard Lee Howell

  3. Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    William Edward Fantegrossi

  4. Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA

    Shane Alan Perrine & Matthew Peter Galloway

  5. Department of Anesthesiology, Wayne State University School of Medicine, Detroit, MI, USA

    Matthew Peter Galloway

Authors
  1. Kevin Sean Murnane
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shane Alan Perrine
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Brendan James Finton
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Matthew Peter Galloway
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Leonard Lee Howell
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. William Edward Fantegrossi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kevin Sean Murnane.

Additional information

All authors have no conflicts of interest regarding this work. These studies were funded by the National Institutes of Health [DA024760 (SAP), DA 16736 (MPG), DA000517 (LLH), DA020645 (WEF)] and by the Yerkes Base Grant [RR00165 (KSM; LLH; WEF)]. Preliminary findings from these experiments were previously presented at the 2009 scientific meetings of the College on Drug Dependence in Reno, NV, USA by KSM and the Society for Neuroscience in Chicago, IL, USA by SAP.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Figure 1

(DOC 161 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Murnane, K.S., Perrine, S.A., Finton, B.J. et al. Effects of exposure to amphetamine derivatives on passive avoidance performance and the central levels of monoamines and their metabolites in mice: Correlations between behavior and neurochemistry. Psychopharmacology 220, 495–508 (2012). https://doi.org/10.1007/s00213-011-2504-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-011-2504-0

Keywords

Search

Navigation