Plasma concentrations of dihydroxyphenylalanine (DOPA) were measured before and during isometric handgrip exercise or mental stress and after coffee drinking or intravenous infusion of desipramine to examine the influence of sympathetic nervous activity on DOPA formation. Sympathetic activity was assessed by the spillover of norepinephrine into plasma. Turnover of norepinephrine was assessed by the plasma concentration of its intraneuronal metabolite, dihydroxyphenylglycol (DHPG). In normal subjects the resting plasma concentration of DOPA was 6.05 +/- 0.16 nmol/L (n = 42). Plasma DOPA level was increased by stimulation of the sympathetic nervous system; handgrip exercise caused a 0.49 +/- 0.07 nmol/L increase (n = 15), mental stress a 0.25 +/- 0.10 nmol/L increase (n = 34), and coffee drinking a 0.85 +/- 0.19 nmol/L increase (n = 9). Desipramine decreased plasma DOPA level by 0.25 +/- 0.06 nmol/L (n = 23). The small but consistent changes in plasma DOPA level during manipulations of sympathetic activity were positively correlated with changes in norepinephrine spillover (r = 0.55, n = 81) and plasma DHPG level (r = 0.66, n = 81). Percentage increases in plasma DOPA level during sympathetic activation were similar to those in plasma DHPG but were a sixth of the percentage increases in norepinephrine spillover. The similar increases in plasma DOPA and DHPG levels indicated that production of DOPA was related to the turnover of norepinephrine in sympathetic nerves. The smaller percentage increases in plasma DOPA (smaller than those in norepinephrine spillover) were consistent with the partial contribution of exocytotic neurotransmitter release to the turnover of norepinephrine in sympathetic nerves.