A recent hypothesis of the pathogenesis of schizophrenia posits a developmentally-specific dysfunction of the dopaminergic innervation of the prefrontal cortex (PFC; Weinberger, 1987; Berman and Weinberger, 1990). It has been difficult to reconcile this hypothesis with the observation that all clinically effective antipsychotic drugs used for the treatment of schizophrenia block dopamine D2 receptors (see Deutch et al., 1991a). A resolution between the suggestion of functional dopamine (DA) "depletion" in the PFC and enhanced subcortical DA function was offered by studies of Carter, Pycock, and associates (Carter and Pycock, 1980; Pycock et al., 1980a, b). These investigators reported that depletion of DA in the rat PFC enhanced DA utilization in subcortical sites such as the nucleus accumbens septi (NAS) and striatum. Thus, a functional deficit in DA neurotransmission in the PFC would increase subcortical DA turnover, and the D2 receptor blockade induced by antipsychotic drugs would counteract the increase in dopaminergic tone in subcortical sites. This hypothesis has been particularly influential because it incorporates both an explanation for negative symptoms, which are thought to reflect cortical dysfunction (a derangement in DA transmission in the PFC), and the efficacy of antipsychotic drugs in the treatment of positive symptoms (arising from increases in subcortical DA tone). As attractive as this hypothesis has been, the physiological underpinnings that subserve such system interactions have remained elusive. Pycock, Carter, and colleagues (Carter and Pycock, 1980; Pycock et al., 1980a, b) reported that 6-hydroxydopamine (6-OHDA) lesions of the PFC increase DA levels and DA turnover in the striatum; certain aspects of their findings have been confirmed (Martin-Iversen et al., 1986; Leccese and Lyness, 1987; Haroutounian et al., 1988). However, other groups have been unable to confirm either the biochemical or behavioral findings of Pycock and associates (Joyce et al., 1983; Oades et al., 1986; Deutch et al., 1990). Moreover, Pycock and colleagues did not observe consistent effects of PFC DA deafferentation on various indices of subcortical DA function (Carter and Pycock, 1980; Pycock et al., 1980a, b). In light of the importance that such DA system interactions may have in the pathogenesis of schizophrenia, we have reinvestigated the effects of cortical DA lesions on subcortical DA function.