In this study, we examined the effect of n-methylquipazine (NMQ), which is a putative 5-hydroxytryptamine3(5-HT3)receptor agonist, on the extracellular concentrations of dopamine (DA) and one of its metabolites, dihydroxyphenylacetic acid (DOPAC), in the anterior medial prefrontal cortex (AmPFc) of awake, freely moving rats. The administration of NMQ via the perfusion fluid produced a concentration-dependent (10-1,000 microM) increase in extracellular DA levels in the AmPFc. In contrast, NMQ produced a decrease in the extracellular concentrations of DOPAC. The increase in extracellular DA levels returned to baseline after the removal of NMQ from the perfusate. The increase in extracellular DA levels in the AmPFc produced by 100 microM of NMQ was markedly attenuated by either the coadministration of tetrodotoxin (1 microM), which inhibits axonal impulse flow, or the depletion of extracellular Ca2+ by removing CaCl2 and adding EDTA to the perfusate. The intradialysate administration of the 5-HT3 antagonist BRL 46470A produced a concentration-dependent (10-1,000 microM) decrease in extracellular DA levels, and this effect was reversible on removal from the perfusate. In contrast, ondansetron (500 and 1,000 microM), which is another 5-HT3 receptor antagonist, produced a transient increase followed by a sustained decrease in extracellular DA levels. The preinfusion of 10 microM of BRL 46470 followed by coperfusion of BRL 46470A with 50 or 100 microM of NMQ via the dialysis probe did not significantly attenuate the increase of NMQ in extracellular DA levels in the AmPFc. The administration of the selective 5-HT2 receptor MDL 100907 (1 mg/kg, i.p.) also did not alter the increase in basal DA levels produced by 100 microM of NMQ. The pretreatment of rats with alpha-methyl-p-tyrosine produced a significant attenuation in the NMQ-induced increase in extracellular DA levels, suggesting that the elevation by NMQ of DA levels is dependent on newly synthesized stores of DA. Overall, these results suggest that the increase in AmPFc DA levels by NMQ is probably not mediated by its interaction with the 5-HT3 receptor.