Chronoamperometry was used in combination with monoamine-selective electrodes to monitor, in nucleus accumbens (NAcc) and prefrontal cortex (PFC) of freely behaving rats, changes in dopamine (DA)-like electrochemical signals elicited by unilateral ventral tegmental microinjections of the selective mu-opioid receptor agonist D-Ala, N-Me-Phe-Gly-Ol-Enkephalin (DAMGO; 0.01, 0.1, and 1.0 nmol). The results show that DAMGO dose-dependently increased electrochemical signals both in Nacc and PFC within a few minutes of injection. While DAMGO elicited signal increases of comparable amplitudes in both regions, the increases recorded in PFC were significantly longer lasting than those in NAcc; at the highest dose tested (1.0 nmol), DAMGO produced signal increases that lasted (mean +/- sem) 129 +/- 7.3 min in PFC and 96 +/- 12.5 min in NAcc. Pretreatment with the opioid receptor antagonist, naloxone (2 mg/kg, sc), significantly attenuated the peak amplitude and reduced the duration of DAMGO-induced (0.1 nmol) signal increases both in PFC and NAcc. In contrast, pretreatment with apomorphine (50 micrograms/kg, sc), a D1/D2 DA receptor agonist, significantly reduced the duration and the rate of rise of the signal increases in both regions but had little effect on the peak increases in signal. Unilateral ventral tegmental DAMGO administration (0.01, 0.1, and 1.0 nmol) also caused dose-dependent increases in contraversive circling the duration of which approximated that of the signal increases recorded in NAcc. However, differences in the time courses of DAMGO-induced contraversive circling and signal increases in NAcc suggest that the behavioral stimulant effect of ventral tegmental mu-opioid receptor activation may not be mediated exclusively by meso-NAcc DA neurons. The results of this study suggest that enkephalins modulate the activity of meso-PFC DA neurons and that behaviorally relevant activation of mu-opioid receptors in the ventral tegmental area increases DA transmission in PFC to a same, if not to a greater extent as in NAcc. These findings are discussed in relation to evidence indicating that the response of meso-NAcc DA neurons to a variety of stimuli, including drugs of abuse, is indirectly regulated by a DA-sensitive neurons in PFC.