Mechanism of the protective effect of reserpine on aggregated mice treated with (+)-amphetamine

Abstract Experiments were made to see if the effect of reserpine in protecting aggregated mice from the toxic effect of (+)-amphetamine depended on the hypothermia or on the depletion of brain noradrenaline it induces. In aggregated mice, a 7 mg/kg dose of amphetamine elevated body temperature, lowered the level of brain noradrenaline and caused 100% mortality. In reserpinized aggregated mice, amphetamine did not cause hyperthermia or any further depletion of brain noradrenaline. Prevention of the hypothermic effect of reserpine by keeping amphetamine-treated reserpinized animals at a higher environmental temperature markedly lowered the protective effect of reserpine. When also the depletion of noradrenaline by reserpine was antagonized by dopa, reserpine no longer protected aggregated mice from the toxic effect of amphetamine. The lowering of 5-hydroxytryptamine content brought about by reserpine remained unaltered during these procedures. Complete protection against amphetamine toxicity was also offered by α-methyl-1-tyrosine in doses which lowered brain noradrenaline to almost the same extent as reserpine, but which did not lower temperature or brain 5-hydroxytryptamine. When the body temperature of aggregated mice with brain noradrenaline lowered by α-methyl-1-tyrosine was elevated by subjecting the animals to heat stress, the protective effect was reduced. Hypothermia induced by reserpine could thus be related to its noradrenaline-depleting action. The results show that both properties contribute to reserpine's protective action. However, the abolition by dopa of this protective effect of reserpine and the complete protection offered by α-methyl-1-tyrosine without hypothermia suggest that depletion of brain noradrenaline plays the more important role in the protective effect of reserpine.