Skip to main content
SpringerLink
Log in

3,4-Methylenedioxymethamphetamine enhances the release of acetylcholine in the prefrontal cortex and dorsal hippocampus of the rat

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

Abstract

Rationale

The neurochemical effects produced by acute administration of 3,4-methylenedioxymethamphetamine (MDMA) on the monoaminergic systems in the brain are well documented; however, there has been little consideration of the potential effects of MDMA on other neurotransmitter systems.

Objective

The present study was designed to investigate the acute effect of MDMA on cholinergic neurons by measuring acetylcholine (ACh) release in the medial prefrontal cortex (PFC) and dorsal hippocampus, terminal regions of cholinergic projection neurons originating in the basal forebrain.

Methods

In vivo microdialysis and high-performance liquid chromatography with electrochemical detection (HPLC-ED) were used to assess the effects of MDMA on the extracellular concentration of ACh in the PFC and dorsal hippocampus of the rat.

Results

The systemic administration of MDMA (3–20 mg/kg, i.p.) resulted in an increased extracellular concentration of ACh in the PFC and dorsal hippocampus. Reverse dialysis of MDMA (100 μM) into the PFC and hippocampus also increased ACh release in these brain regions. Treatment with parachlorophenylalanine and α-methyl-para-tyrosine, inhibitors of serotonin (5-HT) and dopamine (DA) synthesis, respectively, significantly attenuated the release of ACh stimulated by MDMA in the PFC, but not in the dorsal hippocampus.

Conclusions

MDMA exerts a stimulatory effect on the release of ACh in the PFC and dorsal hippocampus in vivo, possibly by mechanisms localized within these brain regions. In addition, these results suggest that the MDMA-induced release of ACh in the PFC involves both serotonergic and dopaminergic mechanisms.

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
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Acquas E, Fibiger HC (1996) Chronic lithium attenuates dopamine D1-receptor mediated increases in acetylcholine release in rat frontal cortex. Psychopharmacology (Berl) 125(2):162–167

    Article  CAS  Google Scholar 

  • Acquas E, Marrocu P, Pisanu A, Cadoni C, Zernig G, Saria A, DiChiara G (2001) Intravenous administration of ecstasy (3,4-methylenedioxymethamphetamine) enhances cortical and striatal acetylcholine release in vivo. Eur J Pharmacol 418(3):207–211

    Article  PubMed  CAS  Google Scholar 

  • Arnold HM, Fadel J, Sarter M, Bruno JP (2001) Amphetamine-stimulated cortical acetylcholine release: role of the basal forebrain. Brain Res 894(1):74–87

    Article  PubMed  CAS  Google Scholar 

  • Arnold HM, Nelson CL, Sarter M, Bruno JP (2003) Sensitization of cortical acetylcholine release by repeated administration of nicotine in rats. Psychopharmacology (Berl) 165(4):346–358

    CAS  Google Scholar 

  • Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38:1083–1152

    Article  PubMed  CAS  Google Scholar 

  • Beani L, Bianchi C, Giacomelli A, Tamberi F (1978) Noradrenaline inhibition of acetylcholine release from guinea-pig brain. Eur J Pharmacol 48(2):179–193

    Article  PubMed  CAS  Google Scholar 

  • Bianchi C, Spidalieri G, Guandalini P, Tanganelli S, Beani L (1979) Inhibition of acetylcholine outflow from guinea-pig cerebral cortex following locus coeruleus stimulation. Neurosci Lett 14(1):97–100

    Article  PubMed  CAS  Google Scholar 

  • Brodkin J, Malyala A, Nash JF (1993) Effect of acute monoamine depletion on 3,4-methylenedioxymethamphetamine-induced neurotoxicity. Pharmacol Biochem Behav 45(3):647–653

    Article  PubMed  CAS  Google Scholar 

  • Consolo S, Bertorelli R, Russi G, Zambelli M, Ladinsky H (1994) Serotonergic facilitation of acetylcholine release in vivo from rat dorsal hippocampus via serotonin 5-HT3 receptors. J Neurochem 62(6):2254–2261

    PubMed  CAS  Google Scholar 

  • Consolo S, Arnabaldi S, Ramponi S, Nannini L, Ladinsky H, Baldi G (1996) Endogenous 5-HT facilitates in vivo acetylcholine release in rat frontal cortex through 5-HT1B receptors. J Pharmacol Exp Ther 277(2):823–830

    PubMed  CAS  Google Scholar 

  • Darvesh AS, Shankaran M, Gudelsky GA (2002) 3,4-Methylenedioxymethamphetamine produces glycogenolysis and increases the extracellular concentration of glucose in the rat brain. J Pharmacol Exp Ther 301(1):138–144

    Article  PubMed  CAS  Google Scholar 

  • Day J, Fibiger HC (1992) Dopaminergic regulation of cortical acetylcholine release. Synapse 12(4):281–286

    Article  PubMed  CAS  Google Scholar 

  • Day JC, Fibiger HC (1994) Dopaminergic regulation of septohippocampal cholinergic neurons. J Neurochem 63(6):2086–2092

    PubMed  CAS  Google Scholar 

  • Day JC, Tham CS, Fibiger HC (1994) Dopamine depletion attenuates amphetamine-induced increases of cortical acetylcholine release. Eur J Pharmacol 263(3):285–292

    Article  PubMed  CAS  Google Scholar 

  • Day JC, Piazza PV, Le Moal M, Maccari S (1997) Cocaine-induced increase in cortical acetylcholine release: interaction with the hypothalamo–pituitary–adrenal axis. Eur J Neurosci 9(6):1130–1136

    Article  PubMed  CAS  Google Scholar 

  • Fischer HS, Zernig G, Schatz DS, Humpel C, Saria A (2000) MDMA (ecstasy) enhances basal acetylcholine release in brain slices of the rat striatum. Eur J Neurosci 12(4):1385–1390

    Article  PubMed  CAS  Google Scholar 

  • Giovannini MG, Ceccarelli I, Molinari B, Cecchi M, Goldfarb J, Blandina P (1998) Serotonergic modulation of acetylcholine release from cortex of freely moving rats. J Pharmacol Exp Ther 285(3):1219–1225

    PubMed  CAS  Google Scholar 

  • Gough B, Ali SF, Slikker W Jr, Holson RR (1991) Acute effects of 3,4-methylenedioxymethamphetamine (MDMA) on monoamines in the rat caudate. Pharmacol Biochem Behav 39:619–623

    Article  PubMed  CAS  Google Scholar 

  • Green AR, O’Shea E, Colado MI (2004) A review of the mechanisms involved in the acute MDMA (ecstasy)-induced hyperthermic response. Eur J Pharmacol 500(1–3):3–13

    Article  PubMed  CAS  Google Scholar 

  • Gudelsky GA, Nash JF (1996) Carrier-mediated release of serotonin by 3,4-methylenedioxymethamphetamine: implications for serotonin–dopamine interactions. J Neurochem 66(1):243–249

    Article  PubMed  CAS  Google Scholar 

  • Gudelsky GA, Yamamoto BK, Nash JF (1994) Potentiation of 3,4-methylenedioxymethamphetamine-induced dopamine release and serotonin neurotoxicity by 5-HT2 receptor agonists. Eur J Pharmacol 264(3):325–330

    Article  PubMed  CAS  Google Scholar 

  • Hersi AI, Richard JW, Gaudreau P, Quirion R (1995) Local modulation of hippocampal acetylcholine release by dopamine D1 receptors: a combined receptor autoradiography and in vivo dialysis study. J Neurosci 15(11):7150–7157

    PubMed  CAS  Google Scholar 

  • Hirano H, Day J, Fibiger HC (1995) Serotonergic regulation of acetylcholine release in rat frontal cortex. J Neurochem 65(3):1139–1145

    Article  PubMed  CAS  Google Scholar 

  • Imperato A, Obinu MC, Gessa GL (1993) Effects of cocaine and amphetamine on acetylcholine release in the hippocampus and caudate nucleus. Eur J Pharmacol 238(2–3):377–381

    Article  PubMed  CAS  Google Scholar 

  • Johnson MP, Hoffman AJ, Nichols DE (1986) Effects of the enantiomers of MDA, MDMA and related analogues on [3H]serotonin and [3H]dopamine release from superfused rat brain slices. Eur J Pharmacol 132(2–3):269–276

    Article  PubMed  CAS  Google Scholar 

  • Jones BE, Cuello AC (1989) Afferents to the basal forebrain cholinergic cell area from the pontomesencephalic catecholamine, serotonin and acetylcholine neurons. Neuroscience 31(1):37–61

    Article  PubMed  CAS  Google Scholar 

  • Koyama T, Nakajima Y, Fujii T, Kawashima K (1999) Enhancement of cortical and hippocampal cholinergic neurotransmission through 5-HT1A receptor-mediated pathways by BAYx3702 in freely moving rats. Neurosci Lett 265(1):33–36

    Article  PubMed  CAS  Google Scholar 

  • Lebsanft HB, Mayerhofer A, Kovar KA, Schmidt WJ (2003) Is the ecstasy-induced ipsilateral rotation in 6-hydroxydopamine unilaterally lesioned rats dopamine independent? J Neural Transm 110(7):707–718

    PubMed  CAS  Google Scholar 

  • Lehmann J, Nagy JI, Atmadia S, Fibiger HC (1980) The nucleus basalis magnocellularis: the origin of a cholinergic projection to the neocortex of the rat. Neuroscience 5(7):1161–1174

    Article  PubMed  CAS  Google Scholar 

  • Marshall DL, Redfern PH, Wonnacott S (1997) Presynaptic nicotinic modulation of dopamine release in the three ascending pathways studied by in vivo microdialysis: comparison on naïve and chronic nicotine-treated rats. J Neurochem 68(4):1511–1519

    PubMed  CAS  Google Scholar 

  • Nair SG, Gudelsky GA (2004a) Activation of 5-HT2 receptors enhances the release of acetylcholine in the prefrontal cortex and hippocampus of the rat. Synapse 53(4):202–207

    Article  PubMed  CAS  Google Scholar 

  • Nair SG, Gudelsky GA (2004b) Protein kinase C inhibition differentially affects 3,4-methylenedioxymethamphetamine-induced dopamine release in the striatum and prefrontal cortex of the rat. Brain Res 1013(2):168–173

    Article  PubMed  CAS  Google Scholar 

  • Nash JF (1990) Ketanserin pretreatment attenuates MDMA-induced dopamine release in the striatum as measured by in vivo microdialysis. Life Sci 47:2401–2408

    Article  PubMed  CAS  Google Scholar 

  • Nash JF, Brodkin J (1991) Microdialysis studies on 3,4-methylenedioxymethamphetamine-induced dopamine release: effect of dopamine uptake inhibitors. J Pharmacol Exp Ther 259(2):820–825

    PubMed  CAS  Google Scholar 

  • Nash JF Jr, Meltzer HY, Gudelsky GA (1988) Elevation of serum prolactin and corticosterone concentrations in the rat after the administration of 3,4-methylenedioxymethamphetamine. J Pharmacol Exp Ther 245(3):873–879

    PubMed  CAS  Google Scholar 

  • Nelson CL, Burk JA, Bruno JP, Sarter M (2002) Effects of acute and repeated systemic administration of ketamine on prefrontal acetylcholine release and sustained attention performance in rats. Psychopharmacology (Berl) 161(2):168–179

    Article  CAS  Google Scholar 

  • Nelson CL, Sarter M, Bruno JP (2003) Repeated pretreatment with amphetamine sensitizes increases in cortical acetylcholine release. Psychopharmacology (Berl) 151(4):406–415

    Article  Google Scholar 

  • Nichols DE, Lloyd DH, Hoffman AJ, Nichols MD, Yim GK (1982) Effects of certain hallucinogenic amphetamine analogues on the release of [3H]serotonin from rat brain synaptosomes. J Med Chem 25(5):530–535

    Article  PubMed  CAS  Google Scholar 

  • Ohue T, Koshimura K, Akiyama Y, Akihiro I, Kido T, Takagi Y, Miwa S (1992) Regulation of acetylcholine release in vivo from rat hippocampus by monoamines as revealed by novel column-switching HPLC with electrochemical detection. Brain Res 572(1–2):340–344

    Article  PubMed  CAS  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  CAS  Google Scholar 

  • Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic, San Diego, CA

  • Pepeu G, Giovannini MG (2004) Changes in acetylcholine extracellular levels during cognitive processes. Learn Mem 11(1):21–27

    Article  PubMed  Google Scholar 

  • Peters JL, Michael AC (2000) Changes in the kinetics of dopamine release and uptake have differential effects on the spatial distribution of extracellular dopamine concentration in rat striatum. J Neurochem 74(4):1563–1573

    Article  PubMed  CAS  Google Scholar 

  • Quirion R, Richard J, Dam TV (1985) Evidence for the existence of serotonin type-2 receptors on cholinergic terminals in rat cortex. Brain Res 333(2):345–349

    Article  PubMed  CAS  Google Scholar 

  • Reid RT, Lloyd GK, Rao TS (1999) Pharmacological characterization of nicotine-induced acetylcholine release in the rat hippocampus in vivo: evidence for a permissive dopamine synapse. Br J Pharmacol 127(6):1486–1494

    Article  PubMed  CAS  Google Scholar 

  • Ricaurte GA, Yuan J, McCann UD (2000) (+/−)-3,4-Methylenedioxymethamphetamine (ecstasy)-induced serotonin neurotoxicity: studies in animals. Neuropsychobiology 42(1):5–10

    Article  PubMed  CAS  Google Scholar 

  • Rudnick G, Wall SC (1992) The molecular mechanism of “ecstasy” [3,4-methylenedioxymethamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Proc Natl Acad Sci U S A 89(5):1817–1821

    Article  PubMed  CAS  Google Scholar 

  • Saito H, Matsumoto M, Togashi H, Yoshioka M (1996) Functional interaction between serotonin and other neuronal systems: focus on in vivo microdialysis studies. Jpn J Pharmacol 70:203–225

    Article  PubMed  CAS  Google Scholar 

  • Sarter M, Bruno JP (1999) Abnormal regulation of corticopetal cholinergic neurons and impaired information processing in neuropsychiatric disorders. Trends Neurosci 22(2):67–74

    Article  PubMed  CAS  Google Scholar 

  • Sarter M, Bruno JP, Givens B (2003) Attentional functions of cortical cholinergic inputs: what does it mean for learning and memory? Neurobiol Learn Mem 80(3):245–256

    Article  PubMed  CAS  Google Scholar 

  • Scheinin M, Lomasney JW, Hayden-Sixson DM, Schambra UB, Caron MG, Lefkowitz RJ, Fremeau RT Jr (1994) Distribution of alpha 2-adrenergic receptor subtype gene expression in rat brain. Brain Res Mol Brain Res 21(1–2):133–149

    Article  PubMed  CAS  Google Scholar 

  • Singer S, Rossi S, Verzosa S, Hashim A, Lonow R, Cooper T, Sershen H, Lajtha A (2004) Nicotine-induced changes in neurotransmitter levels in brain areas associated with cognitive function. Neurochem Res 29(9):1779–1792

    Article  PubMed  CAS  Google Scholar 

  • Svenningsson P, Tzavara ET, Liu F, Fienberg AA, Nomikos GG, Greengard P (2002) DARPP-32 mediates serotonergic neurotransmission in the forebrain. Proc Natl Acad Sci 99(5):3188–3193

    Article  PubMed  CAS  Google Scholar 

  • Taguchi K, Atobe J, Kato M, Chuma T, Chikuma T, Shigenaga T, Miyatake T (1998) The effect of methamphetamine on the release of acetylcholine in the rat striatum. Eur J Pharmacol 360(2–3):131–137

    Article  PubMed  CAS  Google Scholar 

  • Vizi ES (1980) Modulation of cortical release of acetylcholine by noradrenaline released from nerves arising from the rat locus coeruleus. Neuroscience 5(12):2139–2144

    Article  PubMed  CAS  Google Scholar 

  • Yamaguchi T, Suzuki M, Yamamoto M (1997) Evidence for 5-HT4 receptor involvement in the enhancement of acetylcholine release by p-chloroamphetamine in rat frontal cortex. Brain Res 772(1–2):95–101

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto BK, Spanos LJ (1988) The acute effects of methylenedioxymethamphetamine on dopamine release in the awake-behaving rat. Eur J Pharmacol 148(2):195–203

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto BK, Nash JF, Gudelsky GA (1995) Modulation of methylenedioxymethamphetamine-induced striatal dopamine release by the interaction between serotonin and γ-aminobutyric acid in the substantia nigra. J Pharmacol Exp Ther 273(3):1063–1070

    PubMed  CAS  Google Scholar 

  • Zaborszky L (1989) Afferent connections of the forebrain cholinergic projection neurons, with special reference to monoaminergic and peptidergic fibres. In: Frotscher M, Misgeld U (eds) Central cholinergic synaptic transmission. Birkhauser, Basel, pp 12–32

    Google Scholar 

Download references

Acknowledgements

This work was supported by DA 07427. The contributions of Dr. Lique Coolen in the histological analyses and Dr. Charles Vorhees in the statistical analyses are gratefully appreciated.

Author information

Authors and Affiliations

  1. Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, Cincinnati, OH, 45267, USA

    Sunila G. Nair & Gary A. Gudelsky

Authors
  1. Sunila G. Nair
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gary A. Gudelsky
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gary A. Gudelsky.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nair, S.G., Gudelsky, G.A. 3,4-Methylenedioxymethamphetamine enhances the release of acetylcholine in the prefrontal cortex and dorsal hippocampus of the rat. Psychopharmacology 184, 182–189 (2006). https://doi.org/10.1007/s00213-005-0271-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-005-0271-5

Keywords

Search

Navigation