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Neurotoxicity Research

, Volume 10, Issue 1, pp 11–22 | Cite as

Neurochemical and behavioural characterisation of alkoxyamphetamine derivatives in rats

  • Cesar A. Romero
  • Diego A. Bustamante
  • Gerald Zapata-Torres
  • Michel Goiny
  • Bruce Cassels
  • Mario Herrera-Marschitz
Article

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.

Keywords

Amphetamine Ecstasy Drug abuse Rotation Microdialysis Rat 

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

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Copyright information

© Springer 2006

Authors and Affiliations

  • Cesar A. Romero
    • 1
  • Diego A. Bustamante
    • 1
  • Gerald Zapata-Torres
    • 2
    • 3
  • Michel Goiny
    • 4
  • Bruce Cassels
    • 1
    • 2
    • 3
  • Mario Herrera-Marschitz
    • 1
  1. 1.Programme of Molecular & Clinical Pharmacology, ICBM, Medical FacultyUniversity of ChileSantiagoChile
  2. 2.Department of Chemistry, Faculty of SciencesUniversity of ChileSantiagoChile
  3. 3.CBB-Millennium InstituteUniversity of ChileSantiagoChile
  4. 4.Department. of Physiology & PharmacologyKarolinska InstitutetStockholmSweden

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