The effect of atipamezole and amphetamine combination on the noradrenaline concentration in hypothalamus, spleen and heart of mice

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

In the past few years, we have been examining the interaction between the alpha-2-adrenoceptor blocking drugs (such as atipamezole, ATI) and the stimulant, amphetamine (AMP). This stems from an observation in alpha-2A-knock-out mice; administration of AMP caused a major decline in central noradrenaline (NA) levels within 50 min (Lähdesmäki et al. (2004). This finding could be duplicated in wild-type mice by injecting them with ATI 10 min prior to AMP. In a parallel communi-cation, we will describe that this injection schedule can cause a severe tachycardia, much greater than that of AMP alone (Kurttila & MacDonald, this meeting).

This study had two principal aims; 1) to ensure that the central effects of the ATI/AMP interaction could be duplicated in the mouse strain to which we have access (C57BL/6J strain, females, weight range 23-30 grams) and 2) to examine the effects of the interaction in two peripheral tissues, heart and spleen. The mice were divided into four groups (n= 5) receiving first either saline or ATI (1 mg/kg, i.p.) followed 10 min later by saline or AMP (10 mg/kg, i.p.). Fifty min later the mice were euthanized by CO2 inhalation and the tissues excised for assay of NA and adrenaline (ADR) by the standard HPLC-EC procedure (after alumina extraction for the peripheral tissues). Statistical analysis was Mann-Whitney test with Bonferroni correction and p<0.05 considered significant.

The ATI/AMP combination significantly depleted hypothalamic NA but not heart NA levels. In spleen, there was a trend to a decrease in NA, this being significant when the results were expressed as nmol/spleen (spleen weight tended to decrease with all drug treatments). There was a major accumulation of ADR in the hearts of the mice treated with the drug combination. (Table 1).

Table 1: Concentrations of noradrenaline in hypothalamus, heart and spleen and concentration of adrenaline in heart fifty minutes after administration of AMP (10 mg/kg) in mice pretreated with ATI (1 mg/kg) or saline

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

In conclusion, the combination of ATI and AMP leads to depletion of NA in hypothalmus and to some extent, in spleen. In contrast, there is no evidence for depletion of NA in heart. However, some of the NA measured there may derived from adrenal gland, since the heart level of ADR had more than doubled in mice receiving the drug combination. This ADR must have been released from adrenal medulla and been taken up from the blood by the cardiac muscle.

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