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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

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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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  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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