Previous studies have identified deficiencies in the mesocorticolimbic dopamine (DA) systems of alcohol-preferring (P) rats. This study uses quantitative microdialysis to compare the extracellular levels of DA in the medial prefrontal cortex (MPF) of P rats and outbred Wistar rats and also compares the effects of systemic ethanol administration on DA levels in the MPF using traditional microdialysis. In experiment 1, male Wistar and P rats were implanted with loop-style microdialysis probes and later perfused at 0.5 microl/min with artificial cerebrospinal fluid for 120 min prior to five baseline (20-min) sample collections. Three concentrations (5, 10, and 20 nM) of DA were then perfused in random order for 100 min each. Samples (20-min) were collected and stored at -70 degrees C until assayed using high performance liquid chromatography/electrochemical detection (HPLC/EC), and the data were analyzed using the quantitative no-net-flux (NNF) method. In experiment 2, male Wistar and P rats were implanted with dialysis probes aimed at the MPF. After collecting four baseline samples, all rats were injected (i.p.) with one dose of either 0.9% saline or 2.0 g/kg ethanol. Microdialysis samples were collected at 20-min intervals and stored at -70 degrees C until analyzed by HPLC/EC. NNF microdialysis yielded significantly (P<.05) lower extracellular DA concentrations in the MPF of P rats compared to Wistar rats (2.0+/-0.4 vs. 4.8+/-0.4 nM, respectively). The extraction fractions were not different between the P and Wistar groups (69+/-3 vs. 65+/-3%, respectively). No significant change in extracellular DA levels was observed in P rats or Wistar rats after either saline or 2g/kg ethanol. The lower extracellular concentrations of DA in the MPF of P rats compared to Wistar rats, without a difference in the extraction fraction, suggest that DA neurotransmission is lower in the MPF of the P rat. This lower DA neurotransmission could be a result of reduced activity of the DA neurons projecting to the MPF, reduced excitatory or increased inhibitory tone occurring locally within the MPF, and/or reduced DA innervation to the MPF. The lack of effect of systemic EtOH administration on extracellular DA levels in the MPF suggests that unlike the mesolimbic DA system, the mesocortical DA system is not responsive to acute EtOH administration.