This study evaluated the effect of an acute reduction in catecholamine synthesis produced by alpha-methyl-para-tyrosine (AMPT), a tyrosine hydroxylase inhibitor, on cocaine-induced euphoria. In a blinded, placebo-controlled study, AMPT (1 g p.o. T.I.D.) was given to 10 non-treatment-seeking cocaine abusers prior to intranasal administration of 2 mg/kg cocaine. AMPT, but not placebo, reduced plasma levels of the dopamine metabolite homovanillic acid and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol. AMPT also elevated prolactin levels, indicating inhibition of the tuberoinfundibular dopamine system. AMPT pretreatment produced a trend toward diminished cocaine "high" AMPT also tended to lower heart rate and blood pressure responses to cocaine, but had no effect on serum cocaine levels. Although we cannot rule out the therapeutic potential of the depletion strategy, our results with AMPT alone, at this dose, do not strongly support it.