Mesocortical dopamine (DA) neurons projecting to the prefrontal and cingulate cortices possess a faster basal firing rate and exhibit more bursting than other midbrain DA neurons. Thus, we examined whether tyrosine administration could preferentially affect DA synthesis in these DA neurons. Tyrosine administered at doses as low as 25 mg/kg significantly increased in vivo tyrosine hydroxylation in the prefrontal and cingulate cortices without affecting it in other mesocortical, mesolimbic, and nigrostriatal DA terminal fields examined. Further studies in the mesoprefrontal DA neurons showed that tyrosine administered at higher doses of 50 mg/kg initially enhanced tyrosine hydroxylation and elevated endogenous DA levels within 60 min. The resultant increases in DA levels appeared to feedback and normalize prefrontal tyrosine hydroxylase activity. The levels of DA metabolites in the prefrontal cortex were unaltered by doses of tyrosine from 25-200 mg/kg, suggesting that the functional transmitter outflow from these DA neurons is not normally affected by precursor administration under resting conditions. However, when these mesocortical DA neurons were pharmacologically activated following administration of the anxiogenic beta-carboline, FG7142, tyrosine administration (25 mg/kg) was effective in increasing DA metabolite levels in the prefrontal cortex. These results thus suggest that enhanced activity of the mesoprefrontal DA neurons renders these DA neurons much more dependent up on tyrosine availability for maintenance of transmitter output.