Title: SELECTIVE (+)‐AMPHETAMINE NEUROTOXICITY ON STRIATAL DOPAMINE NERVE TERMINALS IN THE MOUSE
Abstract: Infusion of large doses of (+)‐amphetamine continuously for 7 days by means of osmotic minipumps caused a long‐lasting reduction of endogenous dopamine levels, dopamine nerve terminals demonstrated histochemically and [ 3 H]‐noradrenaline uptake in vitro in the striatum of mice. The effect was dose‐dependent, fully developed after 4 days and selective for striatal dopamine up to a dose of (+)‐amphetamine of 25 μg/h. Higher doses, which produced increased mortality, also affected dopamine levels in the olfactory tubercle as well as noradrenaline in several regions. Fluorescence histochemical studies using the Falck‐Hillarp technique disclosed catecholamine accumulations in the striatum after (+)‐amphetamine; a sign of neurotoxic damage. No effects on the dopamine cell bodies were noted. There were also no indications of neurotoxic damage to noradrenaline or 5‐hydroxytryptamine neurones induced by (+)‐amphetamine. Large doses of (−)‐amphetamine were without effect, demonstrating that the long‐lasting impairment of transmitter uptake‐storage mechanism in striatal dopamine nerve terminals is selective for (+)‐amphetamine. There was a slow gradual recovery of endogenous dopamine and [ 3 H]‐noradrenaline uptake in the striatum with time, which was almost complete 6 months after the (+)‐amphetamine administration. The results give further evidence for the view that (+)‐amphetamine in large doses can have a selective neurotoxic action on a vulnerable population of a dopamine nerve terminals in the striatum. The results suggest in addition that there is a slow regrowth and regeneration with time of damaged dopamine nerve terminals.