Comparative effect of amphetamine, phenylethylamine and related drugs on dopamine efflux, dopamine uptake and mazindol binding

We quantified the effects amphetamine (AMPH), phenylethylamine (PEA), tyramine (TYR), octopamine (OCT) and DA, on initial rates of DA uptake (striatal minces), binding of [3H]mazindol to the neuronal uptake (NU) site (striatal membranes) and on DA and dihydroxyphenylacetic acid (DOPAC) efflux (striatal slices). In general, the order of potency for the three paradigms was: AMPH > DA = TYR = PEA > OCT. The K(m) values for uptake were positively correlated with the K(i) values for inhibition of mazindol binding (r = 0.91; P < .01) and with the potencies to induce DA efflux (r = 0.96; P < .005). Potencies for inhibition of mazindol binding and for eliciting DA efflux also were highly correlated (r = 0.92; P < .01). Correlations were lost if data for nomifensine (NOM), a NU inhibitor, were included in the analysis. Despite the significant correlations, AMPH, TYR, PEA and OCT were 10 to 20 times more potent in inhibiting NU than in eliciting efflux or inhibiting mazindol binding. Conversely, the potency of NOM to inhibit mazindol binding was 10 and 800 times greater than that required to inhibit NU or to elicit DA release, respectively. NOM inhibited competitively AMPH-induced DA release. These results suggest that: 1) AMPH-like drugs bind to and are likely to be transported by the NU carrier, and 2) inward transport of these agents appears to have multiple effects (e.g., an increase in intracellular Na+ and Cl-) that act cooperatively to increase V(max) and reduce K(m) for the outward, carrier-mediated DA transport. AMPH, TYR, PEA and OCT had qualitatively similar effects on endogenous DA and [3H]DA release. Momoamine oxidase inhibition potentiated these effects. All these agents released more endogenous DA from control than from reserpine-treated slices. In control slices, TYR and OCT increased DA and reduced DOPAC efflux; whereas AMPH and PEA increased DA and reduced DOPAC efflux, except at high concentrations in which DOPAC efflux also was increased. After reserpine, these agents reduced DOPAC efflux in proportion to the increased DA efflux. In summary, we propose that AMPH-like drugs increase DA efflux from a single cytoplasmic pool maintained by DA synthesis and spontaneous and drug-induced efflux of DA from storage vesicles. The magnitude of drug induced DA efflux depends on several factors: 1) the ability to act as a substrate for the NU carrier and thus increase cytoplasmic DA efflux via accelerated exchange diffusion (AMPH > TYR = PEA > OCT); 2) the ability to increase DA efflux from storage vesicles (TYR > OCT > AMPH > PEA); and 3) the ability of drugs to inhibit monoamine oxidase or to compete with DA for deamination (AMPH > TYR = PEA = OCT).