Further studies on the long-term depletion of striatal dopamine in iprindole-treated rats by amphetamine.

(+) Amphetamine was more potent (-) amphetamine in causing persistent depletion of striatal dopamine in iprindole-treated rats. This effect of amphetamine was not mimicked by EXP561, a structurally related compound that is more potent than amphetamine as an inhibitor of dopamine uptake. The depletion of striatal dopamine at 1 week after amphetamine injection in iprindole-treated rats was prevented by amfonelic acid, an inhibitor of uptake into dopamine neurons. The depletion of dopamine by amphetamine was prevented when amfonelic acid was given at the same time as amphetamine or as long as 4 hr after amphetamine but not when amfonelic acid was given 24-48 hr after amphetamine. Amfonelic acid antagonized the depletion of dopamine by amphetamine but not the depletion of serotonin by p-chloroamphetamine; fluoxetine antagonized the depletion of serotonin by p-chloroamphetamine but not the depletion of dopamine by amphetamine. Pretreatment with alpha-methyl-tyrosine to block dopamine synthesis antagonized the persistent depletion of dopamine by amphetamine, but pretreatment with an inhibitor of monoamine oxidase to increase that dopamine concentration had no effect. The possibility that prolonged release of dopamine from intraneuronal storage granules leads to deleterious effects on dopamine neurons is discussed.