Pre-administration of alpha-2-adrenoceptor antagonists potentiates amphetamine-induced tachycardia in anaesthetized mice

Minna Kurttila and Ewen MacDonald, Department of Pharmacology & Toxicology, University of Kuopio, P.O. Box 1627, FI-70211 Kuopio, Finland.

It was recently noted that 50 minutes after a single treatment with amphetamine (AMP, 10 mg/kg) there was a 20% decline in noradrenaline (NA) levels in various brain regions in mice lacking alpha-2A-adrenoceptors but no decline in wild-type mice (Lähdesmäki et al. 2004). It was proposed that in normal mice, the initial AMP-induced release of NA activated pre-synaptic alpha-2A-adrenoceptors which then prevented further depletion of transmitter stores. Wild-type mice pre-treated with atipamezole (1 mg/kg) (a non-subtype selective alpha-2-antagonist) also exhibited significant declines in NA (> 20%) when challenged 10 minutes later with AMP. We hypothesized that should this interaction also occur in peripheral tissues, then there should be physiological consequences.

A total of 30 mice, males and females (C57BL/6J strain, weight range 20-31 grams) were deeply anaesthetized with pentobarbitone (100 mg/kg i.p.) and artificially respirated with air. Needle electrodes were inserted under the skin in all four limbs to record ECG from which the heart rate was extracted (Hugo Sachs ECG electrodes linked to Haemodyn software). About ten minutes later, the mice were injected i.p. with either saline or an alpha-2-antagonist (atipamezole 1 mg/kg or idazoxan 1 mg/kg) and exactly 10 minutes subsequently were challenged with AMP (10 mg/kg, i.p.) with controls receiving an equivalent volume of saline. Heart rate was followed for the next 50 minutes. Differences between groups were statistically assessed by Mann-Whitney U-test with Bonferroni correction; values of P<0.05 considered significant.

Neither of the alpha-2-antagonists evoked any major change in heart rate on their own. AMP caused a rapid and prolonged tachycardia but this was potentiated if the mice had been pretreated with either of the alpha-2-antagonists (Table 1).

Table 1: Heart rate (HR ± s.e. mean) and amphetamine-induced tachycardia in mice pretreated 10 minutes previously with atipamezole or idazoxan (both 1 mg/kg)

Results are means ± s.e. mean (* P<0.05; **P<0.01, Mann-Whitney U-test)

In conclusion, pretreatment with an alpha-2-adrenoceptor antagonist potentiated AMP-induced tachycardia. This confirms the neurochemical data obtained by Lähdesmäki et al. (2004). While we believe that this interaction is pharmacodynamic in nature (i.e. mediated through the alpha-2A-adrenoceptor), it is theoretically possible that the interaction is due to some, as yet unrecognized, ability of alpha-2-antagonists to block or delay the metabolism/excretion of amphetamine.

Lähdesmäki J. et al. (2004) Psychopharmacol, 29, 1282-1293.