Tyrosine availability can influence dopamine (DA) synthesis in highly electrophysiologically active DAergic neurons, such as those innervating the medial prefrontal cortex (MPFC).In most brain dopamine (DA) systems, levels of the DA precursor tyrosine do not significantly affect dopaminergic transmission. The availability of tyrosine in the brain normally exceeds the capacity of the enzyme tyrosine hydroxylase (TH) to convert it to DOPA (Carlsson and Lindqvist 1978;Morgenroth et al. 1976;Joh et al. 1978). Since the conversion of DOPA to DA is rapid and efficient, DA synthesis usually depends on TH activity and not on tyrosine levels (Wurtman et al. 1974;Carlsson and Lindqvist 1978). However, precursor dependence of DA synthesis has been demonstrated in the light-activated retina (Fernstrom et al. 1984(Fernstrom et al. , 1986 as well as in striatal DA neurons after administration of haloperidol, spiperone, reserpine or amfonelic acid (Scally et al. 1977;Sved et al. 1979;Fuller and Snoddy 1982) or after marked DA depletion (Melamed et al. 1980). The common feature of these paradigms is a marked increase in the electrophysiological activity of the relevant DA system. Such data suggest that precursor dependence of DA synthesis may be a latent property of all DA neurons, but one which emerges only under conditions of increased dopaminergic activity. (Chiodo et al. 1984;White and Wang 1984), precursor dependence of medial prefrontal cortical (MPFC) DA synthesis might be expected even under basal conditions. Even within the MPFC, however, tight feedback systems limit the ability of exogenous tyrosine administration to augment DA synthesis (Tam et al. 1990). Intriguingly, in rats pretreated with FG-7142, a beta-carboline known to preferentially increase MPFC synthesis, utilization and release Roth 1985, 1990;Bradberry et al. 1991), administration of tyrosine robustly enhances MPFC DA synthesis (Tam et al. 1990). We postulated that such precursor dependence would also be established by other drugs which activate mesocortical dopaminergic activity.The atypical and clinically superior antipsychotic drug, clozapine, has already been demonstrated to preferentially release DA in the prefrontal cortex of the rat (Moghaddam and Bunney 1990; Pehek and Yamamoto 1994;Yamamoto and Cooperman 1995) as well as of the non-human primate (Youngren et al. 1999) and to preferentially activate DA neurons projecting to cortical regions (White and Wang 1983;Goldstein et al. 1993). Accordingly, we postulated that the co-administration of tyrosine and clozapine would potentiate MPFC DA synthesis. We further postulated that if the increased DA synthesis were reflected in increased DA release, then administration of tyrosine to clozapine-pretreated rats would augment MPFC DA levels as measured by in vivo microdialysis. Finally, since haloperidol, but not clozapine, preferentially activates nigrostriatal DA synthesis and release, we anticipated that tyrosine would enhance dialysate DA concentrations in the striatum but not the MPFC of haloperi...