Cocaine binds to dopamine (DA), serotonin (5-HT) and norepinephrine (NE) transporters blocking the reuptake of these monoamines into presynaptic terminals. As previously reported, continuous infusion of cocaine for seven days or GBR 12909, a selective dopamine uptake inhibitor, produced significant decreases in prodynorphin (PDYN) gene expression in the hypothalamus. Cocaine also produced a significant increase in PDYN mRNA in the caudate putamen, whereas GBR12909 has no effect and the selective serotonin uptake inhibitor fluoxetine decreases PDYN mRNA in the same brain region. The effect of the selective norepinephrine uptake inhibitor nisoxetine was examined on PDYN gene expression. Nisoxetine or vehicle was infused continuously for 7 days via osmotic minipump into male rats. This treatment produced significant increases in PDYN gene expression in the hypothalamus (183% of control), nucleus accumbens (142% of control) and hippocampus (124% of control) and a significant decrease in the caudate putamen (69% of control). These data suggest that nisoxetine affects PDYN gene expression and support a role for NE in the mechanisms underlying the effects of chronic exposure to psychoactive drugs. Moreover, nisoxetine, as well as fluoxetine, decreases PDYN mRNA in the caudate putamen, in contrast to the up-regulation produced by cocaine. Thus, the inhibition of NE uptake alone cannot account for the cocaine-induced increase of PDYN gene expression. These findings suggest that PDYN gene expression regulation by cocaine in the caudate putamen might be due to a combination of effects on two or three monoamine transporters, or to a mechanism unrelated to transporters inhibition.