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Neurochemical and behavioural characterisation of alkoxyamphetamine derivatives in rats

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Abstract

The clinical utility of amphetamine and amphetamine analogues has been jeopardized by a number of side effects and toxicity, partly due to complex mechanisms of action. While some of the analogues have been individually characterised, there is still need for comparative studies, in particular, on their efficacy to release dopamine and 5-hydroxytryptamine, further enlightening some of the synaptic mechanisms conveying their actions. Thus, we have compared four alkoxyamphetamine derivatives,i.e.,p-methoxyamphetamine;p-methoxymethamphetamine; methylenedioxyamphetamine, methylenedioxymethamphetamine, using methamphetamine, and D-amphetamine, as reference substances, on rotational behaviour and releasing mechanisms studied within vivo microdialysis in rats.

All alkoxylated-derivatives produced a long-lasting rotational behaviour at 10 mg/kg s.c., but the reference substances produced a strong rotation already at 2 mg/kg s.c. in 6-hydroxydopaminelesioned rats. At the concentration of 100 μM, the alkoxylated-derivatives were equipotent to evoke dopamine and 5-hydroxytryptamine release in rat neostriatum, while D-amphetamine and methamphetamine were more efficient on dopamine release. Pre-treatment with methamphetamine or the alkoxylated-derivatives produced a remarkable decrease of the effect of K+-depolarisation on both dopamine and 5-hydroxytryptamine release.

The insertion of a methoxy or a methylenedioxy group on the benzene ring of D-amphetamine or methamphetamine, or N-methylation of the Damphetamine molecule alters the selectivity of the compounds. The efficacy of the alkoxylated-derivatives on dopamine and 5-hydroxytryptamine release was similar, but stimulated less dopamine release and produced less rotational behaviour than Damphetamine and methamphetamine. The lower efficacy of K+-depolarisation following pre-treatments with the derivatives suggests an impairment of releasable monoamine stores. The present observations can enlighten the mechanisms of action of drugs showing a high risk for abuse among young populations.

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Abbreviations

5-HIAA:

5-hydroxyindoleacetic acid

5-HT:

5-hydroxytryptamine (serotonin)

6-OHDA:

6-hydroxydopamine

D-AMPH:

D-amphetamine

DA:

dopamine

DOPAC:

dihydroxyphenylacetic acid

HPLC:

highperformance liquid chromatography

HVA:

homovanillic acid

MDA:

methylenedioxyamphetamine

MDMA:

methylenedioxymethamphetamine (Ecstasy)

METH:

methamphetamine

PMA:

para-methoxyamphetamine

PMMA:

para-methoxymethamphetamine

References

  • Abekawa T, T Ohmori and T Koyama (1994) Effects of repeated administration of a high dose of methamphetamine on dopamine and glutamate release in rat striatum and nucleus accumbens.Brain Res. 643, 276–281.

    Article  PubMed  CAS  Google Scholar 

  • Axt KJ and ME Molliver (1991) Immunohistochemical evidence for methamphetamine-induced serotonergic axon loss in the rat brain.Synapse 9, 302–313.

    Article  PubMed  CAS  Google Scholar 

  • Brown JM, GR Hanson and AE Fleckenstein (2000) Methamphetamine rapidly decreases vesicular dopamine uptake.J. Neurochem. 74, 2221–2223.

    Article  PubMed  CAS  Google Scholar 

  • Brunswick DJ, S Benmassour, SM Tejami-Butt and M Hauptmann (1992) Effects of high-dose methamphetamine on monoamine uptake sites in rat brain measured by quantitative autoradiography.Synapse 11, 287–293.

    Article  PubMed  CAS  Google Scholar 

  • Buchanan JF and CR Brown (1988) “Designer drugs” a problem in clinical toxicology.Med. Toxicol. 3, 1–17.

    CAS  Google Scholar 

  • Burrows KB, WL Nixdorf and BK Yamamoto (2000) Central administration of methamphetamine synergizes with metabolic inhibition to deplete striatal monoamines.J. Pharmacol. Exp. Ther. 292, 853–860.

    PubMed  CAS  Google Scholar 

  • Bustamante D, Y Zhi-Bing, MN Castel, S Johansson, M Goiny, L Terenius, T Hökfelt and M Herrera-Marschitz (2002) Effect of repeated methamphetamine treatment on neurotransmitter release in substantia nigra and neostriatum of the rat.J. Neurochem. 83, 645–654.

    Article  PubMed  CAS  Google Scholar 

  • Bustamante D, G Díaz-Véliz, C Paeile, G Zapata-Torres and BK Cassels (2004) Analgesic and behavioral effects of amphetamine, p-methoxyamphetamine and N-alkyl-p-methoxyamphetamine derivatives.Pharmacol. Biochem. Behav. 79, 199–212.

    Article  PubMed  CAS  Google Scholar 

  • Butcher SP, IS Fairbrother, JS Kelly and GW Arbuthnott (1988) Amphetamine-induced release in the rat striatum: an in vivo microdialysis study.J. Neurochem. 50, 346–355.

    Article  PubMed  CAS  Google Scholar 

  • Byard RW, J Gilbert, R James and RJ Lokan (1998) Amphetamine derivate fatalities in South-Australia. Is “ecstasy” the culprit?Am. J. For. Med. Pathol. 19, 261–265.

    Article  CAS  Google Scholar 

  • de la Torre R, J Ortuño, M Mas, M Farre and J Segura (1999) Fatal MDMA intoxication.Lancet 353, 593.

    PubMed  Google Scholar 

  • Eisch AJ, SJ O’Dell and JF Marshall (1996) Striatal and cortical NMDA receptors are altered by a neurotoxic regimen of methamphetamine.Synapse 22, 217–225.

    Article  PubMed  CAS  Google Scholar 

  • Felgate HE, PD Felgate, RA James, DN Sims and DC Vozzo (1998) Recent paramethoxyamphetamine deaths.J. Anal. Toxicol. 22, 69–172.

    Google Scholar 

  • Fibiger HC and EG McGeer (1971) Effect of acute and chronic methamphetamine treatment on tyrosine hydroxylase activity in brain and adrenal medulla.Eur. J. Pharmacol. 16, 176–180.

    Article  PubMed  CAS  Google Scholar 

  • Fleckenstein AE, RR Metzger, JW Gibb and GR Hanson (1997) A rapid and reversible change in dopamine transporters induced by methamphetamine.Eur. J. Pharmacol. 323, 9–10.

    Article  Google Scholar 

  • Frey K, M Kilbourn and T Robinson (1997) Reduced striatal vesicular monoamine transporters after neurotoxic but not after behaviorally-sensitizing doses of methamphetamine.Eur. J. Pharmacol. 334, 273–279.

    Article  PubMed  CAS  Google Scholar 

  • Fuxe K and U Ungerstedt (1970) Histochemical biochemical and functional studies on central monoamine neurons after acute and chronic amphetamine administration, In:Amphetamine and Related Compounds (Costa E, Ed.) (Raven Press:New York), pp 257–288.

    Google Scholar 

  • Gough B, SZ Imam, B Blough, W Slikker Jr and SF Ali (2002) Comparative effects of substituted amphetamines (PMA, MDMA, and METH) on monoamines in rat caudate: a microdialysis study.Ann. NYAcad. Sci. 965, 410–420.

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Haughey JM, AE Fleckenstein, RR Metzger and GR Hanson(2000) The effects of methamphetamine on serotonin transporter activity: role of dopamine and hyperthermia.J. Neurochem. 75, 1608–1617.

    Article  PubMed  CAS  Google Scholar 

  • Herrera-Marschitz M and U Ungerstedt (1984a) Evidence striatal efferents relate to different dopamine receptors.Brain Res. 323, 269–278.

    Article  PubMed  CAS  Google Scholar 

  • Herrera-Marschitz M and U Ungerstedt (1984b) Evidence that apomorphine and pergolide induce rotation in rats by different actions on D1 and D2 receptor sites.Eur. J. Pharmacol. 98, 165–176.

    Article  PubMed  CAS  Google Scholar 

  • Herrera-Marschitz M, H Utsumi and U Ungerstedt (1990) Scoliosis in rats with experimentally-induced hemiparkinsonism: dependence upon striatal dopamine denervation.J. Neurol. Neurosurg. Psychiatr. 53, 39–43.

    Article  PubMed  CAS  Google Scholar 

  • Herrera-Marschitz M, JJ Meana, WT O’Connor, M Goiny, MS Reid and U Ungerstedt (1992) Neuronal dependence of extracellular dopamine, acetylcholine, glutamate, aspartate and gammaaminobutyric acid (GABA) measured simultaneously from rat neostriatum usingin vivo microdialysis, reciprocal interactions.Amino Acids 2, 157–179.

    Article  CAS  Google Scholar 

  • Herrera-Marschitz M, Z-B You, M Goiny, JJ Meana, R Silveira, O Godukhin, Y Chen, S Espinoza, E Pettersson, F Loidl, G Lubec, K Andersson, I Nylander, L Terenius and U Ungerstedt (1996) On the origin of extracellular glutamate levels monitored in the basal ganglia byin vivo microdialysis.J. Neurochem. 66, 1726–1735.

    PubMed  CAS  Google Scholar 

  • Holson RR, JF Bowger, P Clausing and B Bough (1996) Methamphetamine-stimulated striatal dopamine release declines rapidly over time following microdialysis probe insertion.Brain Res. 739, 301–307.

    Article  PubMed  CAS  Google Scholar 

  • Hotchkiss AJ and JW Gibb (1980) Long-term effects of multiple doses of methamphetamine on tryptophan hydroxylase and tyrosine hydroxylase activity in rat brain.J. Pharmacol. Exp. Ther. 214, 257–260.

    PubMed  CAS  Google Scholar 

  • Johansen SS, AC Hansen, IB Muller, JB Lundemose and MB Franzmann (2003) Three fatal cases of PMA and PMMA poisoning in Denmark.J. Anal Toxicol. 27, 253–256.

    PubMed  CAS  Google Scholar 

  • Johnson M, AA Letter, K Merchant, GR Hanson and JW Gibb (1988) Effects of 3,4-methylenedioxyamphetamine and 3,4-methylenedioxymethamphetamine isomers on central serotonergic, dopaminergic and nigral neurotensin systems of the rat.J. Pharmacol. Exp. Ther. 244, 977–982.

    PubMed  CAS  Google Scholar 

  • Kalant H (2001) The pharmacology and toxicology of ecstasy (MDMA) and related drugs.Can. Med. J. Assn. 165, 917–928.

    CAS  Google Scholar 

  • Kleven MS and LS Seiden (1992) Methamphetamine-induced neurotoxicity: structure activity relationships.Ann. NY Acad. Sci. 654, 292–301.

    Article  PubMed  CAS  Google Scholar 

  • Kraner JC, DJ McCoy, MA Evans, LE Evans and BJ Sweeney (2001) Fatalities caused by the MDMA-related drug paramethoxyamphetamine (PMA).J. Anal. Toxicol. 25, 645–648.

    PubMed  CAS  Google Scholar 

  • Kuczenski R and DS Segal (1992) Differential effects of methamphetamine and dopamine uptake blockers (cocaine, nomifensine) on caudate and accumbens dialysate dopamine and 3-methoxytyramine.J. Pharmacol. Exp. Ther. 262, 1085–1094.

    PubMed  CAS  Google Scholar 

  • Kuczenski R, D Segal, AK Cho and W Melega (1995) Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioural responses to the stereoisomers of amphetamine and methamphetamine.J. Neurosci. 15, 1308–1317.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Marek GJ, G Vosmer and LS Seiden (1990) Dopamine uptake inhibitors block long-term neurotoxic effects of methamphetamine upon dopaminergic neurons.Brain Res. 513, 274–279.

    Article  PubMed  CAS  Google Scholar 

  • Marshall JF, SJ O’Dell and FB Weihmuller (1993) Dopamine-glutamate interactions in methamphetamine-induced neurotoxicity.J. Neural Transm. 91, 241–254.

    Article  CAS  Google Scholar 

  • Martin TL (2001) Three cases of fatal paramethoxyamphetamine overdose.J. Anal. Toxicol. 25, 649–651.

    PubMed  CAS  Google Scholar 

  • Nash JF and BK Yamamoto (1992) Methamphetamine neurotoxicity and striatal glutamate release: comparison to 3,4-methylenedioxymethamphetamine.Brain Res. 581, 237–243.

    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.

    PubMed  CAS  Google Scholar 

  • Nixdorf WL, KB Burrows, GA Gudelsky and BK Yamamoto (2001) Enhancement of 3,4-methylenedioxymethamphetamine neurotoxicity by energy inhibitor malonate.J. Neurochem. 77, 647–654.

    Article  PubMed  CAS  Google Scholar 

  • O’Dell SJ, FB Weihmuller and JF Marshall (1991) Multiple methamphetamine injections induce marked increases in extracellular striatal dopamine which correlate with subsequent neurotoxicity.Brain Res. 564, 256–260.

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G and C Watson (1982)The Rat Brain in Stereotaxic Coordinates (Academic Press:San Diego, CA).

    Google Scholar 

  • Peat MA, PF Warren, C Bakhit and JW Gibb (1985) The acute effects of methamphetamine and p-chloro-amphetamine on the cortical serotonergic system of the rat brain: evidence for differences in the effects of methamphetamine and amphetamine.Eur. J. Pharmacol. 116, 11–16.

    Article  PubMed  CAS  Google Scholar 

  • Pentney AR (2001) An exploration of the history and controversies surrounding MDMA and MDA.J. Psychoactive Drugs 33, 213–221.

    PubMed  CAS  Google Scholar 

  • Pu C and CV Vorhees (1993) Developmental dissociation of methamphetamine-induced depletion of dopaminergic terminals and astrocytes reaction in rat striatum.Dev. Brain Res. 72, 325–328.

    Article  CAS  Google Scholar 

  • Pu C, EJ Fisher, GP Cappon and CV Vorhees (1994) The effects of amfonelic acid, a dopamine uptake inhibitor, on methamphetamine-induced dopamine terminal degeneration and astrocytic response in rat striatum.Brain Res. 649, 217–224.

    Article  PubMed  CAS  Google Scholar 

  • Randrup AS and I Munkvad (1966) Role of catecholamines in the amphetamine excitatory response.Nature 211, 540.

    Article  PubMed  CAS  Google Scholar 

  • Ricaurte GA, CR Schuster and LS Seiden (1980) Long-term effects of repeated methylamphetamine administration on dopamine and serotonin neurons in the rat brain: a regional study.Brain Res. 193, 153–163.

    Article  PubMed  CAS  Google Scholar 

  • Sabol KE, JT Roach, SL Broom, C Ferreira and MM Preau (2001) Long-term effects of a high-dose methamphetamine regimen on subsequent methamphetamine-induced dopamine releasein vivo.Brain Res. 892, 122–129.

    Article  PubMed  CAS  Google Scholar 

  • Schmidt CJ (1987) Acute administration of methylenedioxyamphetamine: comparison with the neurochemical effects of itsN-desmethyl andN-ethyl analogues.Eur. J. Pharmacol. 136, 81–88.

    Article  PubMed  CAS  Google Scholar 

  • Schmidt CJ and JW Gibb (1985) Role of the dopamine uptake carrier in the neurotoxic response to methamphetamine: effect of amfonelic acid.Eur. J. Pharmacol. 109, 73–80.

    Article  PubMed  CAS  Google Scholar 

  • Seiden LS, CR Fischman and CR Schuster (1976) Long-term methamphetamine-induced changes in brain catecholamines in tolerant rhesus monkeys.Drug Alcohol Dependend. 1, 215–219.

    Article  CAS  Google Scholar 

  • Sonsalla PK, WJ Nicklas and RE Heikkila (1989) Role for excitatory amino acids in methamphetamine-induced nigrostriatal dopaminergic toxicity.Science 243, 398–400.

    Article  PubMed  CAS  Google Scholar 

  • Steele TD, JC Katz and GA Ricaurte (1992) Evaluation of the neurotoxicity of N-methyl-1-(4-methoxyphenyl)-2-aminopropane (para-methoxymethamphetamine, PMMA).Brain Res. 589, 349–352.

    Article  PubMed  CAS  Google Scholar 

  • Stephans SE and BK Yamamoto (1994) Methamphetamineinduced neurotoxicity: roles for glutamate and dopamine efflux.Synapse 17, 203–209.

    Article  PubMed  CAS  Google Scholar 

  • Stone DM, DC Stahl, GR Hanson and JW Gibb (1986) The effects of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4- methylenedioxyamphetamine (MDA) on monoaminergic systems in the brain.Eur. J. Pharmacol. 128, 41–48.

    Article  PubMed  CAS  Google Scholar 

  • Stone DM, M Johnsson, GR Hanson and JW Gibb (1987) A comparison of the neurotoxic potential of methylenedioxyamphetamine (MDA) and its N-methylated and N-ethylated derivatives.Eur. J. Pharmacol. 134, 245–248.

    Article  PubMed  CAS  Google Scholar 

  • Tseng L-F, MK Menon and HH Loh (1976) Comparative actions of the monomethoxyamphetamines on the release and uptake of biogenic amines in brain tissue.J. Pharmacol. Exper. Ther. 197, 263–271.

    CAS  Google Scholar 

  • Ungerstedt U (1971) Striatal dopamine release after amphetamine or nerve degeneration revealed by rotationalbehaviour.Acta Physiol. Scand. 367, 49–68.

    CAS  Google Scholar 

  • Ungerstedt U and GW Arbuthnott (1970) Quantitative recording of rotational behaviour in rats after 6-hydroxydopamine lesions of the nigrostriatal dopamine system.Brain Res. 24, 485–493.

    Article  PubMed  CAS  Google Scholar 

  • Ungerstedt U, M Herrera-Marschitz, U Jungnelius, L Ståhle, U Tossman and T Zetterström (1982) Dopamine synaptic mechanisms reflected in studies combining behavioural recordings and brain dialysis.Adv. Biosci. 37, 219–231.

    CAS  Google Scholar 

  • Zetterström T, T Sharp, CA Marsden and U Ungerstedt (1983)In vivo measurement of dopamine and its metabolites studied by intracerebral dialysis: changes after D-amphetamine.J. Neurochem. 41, 1769–1773.

    Article  PubMed  Google Scholar 

  • Zetterström T, M Herrera-Marschitz and U Ungerstedt (1986) Simultaneous measurement of dopamine release and rotational behaviour in 6-hydroxydopamine denervated rats using intracerebral dialysis.Brain Res. 376, 1–7.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Programme of Molecular & Clinical Pharmacology, ICBM, Medical Faculty, University of Chile, Santiago, Chile

    Cesar A. Romero, Diego A. Bustamante, Bruce Cassels & Mario Herrera-Marschitz

  2. Department of Chemistry, Faculty of Sciences, University of Chile, Santiago, Chile

    Gerald Zapata-Torres & Bruce Cassels

  3. CBB-Millennium Institute, University of Chile, Santiago, Chile

    Gerald Zapata-Torres & Bruce Cassels

  4. Department. of Physiology & Pharmacology, Karolinska Institutet, Stockholm, Sweden

    Michel Goiny

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  1. Cesar A. Romero
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  2. Diego A. Bustamante
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  3. Gerald Zapata-Torres
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  4. Michel Goiny
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  5. Bruce Cassels
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  6. Mario Herrera-Marschitz
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Correspondence to Mario Herrera-Marschitz.

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Romero, C.A., Bustamante, D.A., Zapata-Torres, G. et al. Neurochemical and behavioural characterisation of alkoxyamphetamine derivatives in rats. neurotox res 10, 11–22 (2006). https://doi.org/10.1007/BF03033330

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