SPECIES-DEPENDENT RESPONSIVENESS TO NON-AMPHETAMINE CENTRAL STIMULANTS - RELATIONSHIP BETWEEN UPTAKE AND RELEASE OF BRAIN DOPAMINE

Amfonelic acid (AFA), a potent nonamphetamine central stimulant in man and the rat, has little or no stimulatory effect in the rabbit. AFA and other nonamphetamine stimulants inhibit the accumulation of dopamine (DA) by both rat and rabbit striatal synaptosomes, suggesting that DA uptake inhibition does not cause stimulation. While AFA raises DA metabolites in rat striatum, no effect was seen in the rabbit. The marked potentiation by AFA of haloperidol''s ability to increase brain DA metabolism in the rat does not occur in the rabbit. Haloperidol, which raises brain DA metabolite concentrations in both species, lowers DA concentration in the rabbit, but not in the rat; this species difference was seen after tyrosine hydroxylase inhibition. Apparently there is a more rapid exchange between storage and releasable DA pools in the rabbit. The ability of DA uptake inhibitors to evoke stimulation in the rat but not the rabbit may be due to a DA interpool regulatory mechanism in the rat such that free axoplasmic DA may regulate DA transfer from a storage to a releasable pool. AFA, by inhibiting DA reuptake, would reduce axoplasmic DA levels and reduce inhibition of interpool transfer. Since interpool movement of DA appears to occur more readily in the rabbit, the proposed interpool regulatory mechanism may not exist or is not a rate-limiting step in the rabbit DA system. Inhibition of DA reuptake in the rabbit would not cause potentiation of DA overflow.