The nature of the functional relationships between areas of prefrontal cortex and ventral striatum remain undefined. This study was designed to examine functional interactions between activity in two areas of prefrontal cortex, the prelimbic (PL) and agranular insular (AI) areas, and ventral striatal (VS) dopamine (DA) function. Interactions were assessed using a Fixed Interval (FI) schedule of reinforcement shown previously in our laboratory to be modulated by VS DA function. The study compared changes in FI performance following intra-VS DA antagonist injections alone (SCH23390 + eticlopride) to those observed when either saline or saline + lidocaine were injected into prefrontal cortex after the intra-VS DA antagonist injections. The intra-VS DA antagonists alone decreased FI response rates and increased postreinforcement pause times at both dose combinations (1/0.1 and 3/0.3 microg of SCH23390/eticlopride per side). Neither saline nor saline + lidocaine injected into the PL area of prefrontal cortex altered the effects of intra-VS DA antagonists on FI performance. Saline administration into the AI area of prefrontal cortex, however, eliminated the FI rate-decreasing effects of intra-VS DA antagonists. The agent or mechanism of this effect, whether it be saline, the act of inserting the cannulae into the cortical tissue, or the act of injecting fluid into this tissue, is not clear. This effect of AI saline was prevented by coadministration of lidocaine with saline into AI. These results, coupled with those from a previous experiment examining lesion effects in PL and AI on FI performance (Evans SB, Cory-Slechta DA. The effects of temporary lesions of the insular and medial prefrontal cortex on fixed-interval schedule-controlled behavior in the rat, Soc Neurosci Abstr 1996;22(1):159) suggest that PL might exert a tonic influence on VS DA function, since FI response rates gradually increase over a 2-week period following lesions of PL. In contrast, AI, although not normally modulating FI performance, can apparently influence VS DA function, possibly when alterations in activity are invoked in AI.