© Copyright 2003 The British Pharmacological Society
University of Surrey
Summer Meeting June 2003
Actions of amphetamine derivatives and cathitone at the noradreline
Linda Cleary & James R Docherty. Department of Physiology, Royal
Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
We have recently
shown that MDMA, MDA, cathinone and to a lesser extent MDEA share with
cocaine an ability to potentiate the contractile actions of noradrenaline
(NA) but not isoprenaline in the 1Hz paced rat right ventricle (Cleary
et al., 2002). It was concluded that these drugs, like cocaine,
prevented the reuptake of noradrenaline into nerve terminals, an action
which could account for the cardiovascular complications associated with
MDMA abuse. The purpose of this study was to directly test the actions
of these compounds at the NA transporter.
Male Wistar rats (250 - 300g) were killed by CO2
overdose and their hearts were quickly removed. For inhibition of [3H]-NA
uptake, left ventricular slices were incubated for 15 minutes at 37oC
in oxygenated Krebs with [3H]-NA 25nM and increasing concentrations of
amphetamine derivatives. Non specific uptake was determined at 4oC.
Displacement of [3H]-Nisoxetine Binding
to the NA transporter was measured by incubating rat cerebral cortex membranes
for 4 hours at 4oC with [3H]-nisoxetine
2nM and increasing concentrations of amphetamine derivatives. Non specific
binding was determined in the presence of desipramine 0.3 µM.
Total specific [3H]-NA uptake was 43.5±2.6
fmol/mg/15min (n=24). All these compounds inhibited uptake of [3H]-NA.
Potency (- log EC50) values were: cocaine
6.16±0.15, cathinone 6.03±0.16, MDMA 6.05±0.07, MDA
5.68±0.06 and MDEA 5.56±0.08. Cocaine, cathinone and MDMA
were signific-antly more potent than MDEA. MDA was significantly less
potent than MDMA and cocaine. Test agents all displaced [3H]-nisoxetine
binding at the rat cerebral cortex NA transporter. MDMA was the least
potent at displacing [3H]-nisoxetine
binding; - log EC50 values: Cocaine 5.04±0.08,
Cathinone 5.40±0.14, MDA 4.66±0.11, MDEA 4.99±0.15,
In rat right ventricular strips, NA increased 1Hz stimulation-evoked contractions
with a pD2 of 7.45±0.12 (n=25). Cocaine, MDMA, MDA and cathinone
(all 10µM) significantly increased the potency of NA to 6.25±0.11,
6.48±0.13, 6.17±0.05 and 6.27±0.10, respectively,
as compared with the effects of vehicle (5.42±0.08) MDEA 10µM
had no effect although 100µM caused a significant increase.
In NA uptake studies, MDEA was the least potent and also had low potency
functionally in the paced right ventricle. In [3H]-nisoxetine
displacement studies, MDMA was significantly less potent than the other
drugs but not in functional studies. Other studies report a poor correlation
between inhibition of binding and inhibition of uptake at the NA transporter
(Eshleman et al., 1999). In conclusion, cardiac actions of amphetamine
derivatives may involve competitive blockade of the NA transporter. This
action may result in cardiac morbidity as previously shown for cocaine.
Supported by the Irish Heart Foundation.
Cleary, L. et al. (2002) Eur. J. Pharmacol. 451,
Eshleman A.J. et al. (1999) J. Pharmacol. exp. Ther.