Abstract Studies of the effects of chronic neuroleptic drug treatment have consistently demonstrated enhanced transcription and translation of the preproenkephalin gene in the rat striatum. However, all of these studies have used daily ip drug treatments and none have evaluated the effects of chronic depot neuroleptics. With these drug treatments, dopamine receptor blockade undergoes less variability as a result of sustained steady-state blood levels of the neuroleptic. Therefore, as a result of the increasing utilization of depot neuroleptics therapeutically, we examined the effects of haloperidol decanoate on striatal preproenkephalin mRNA levels. As with daily ip drug injections, the depot preparation was found to increase the levels of this mRNA to an apparent new steady-state level twice that of controls, by 3 days and sustaining this steady-state for the 14 day observation period. These data indicate that both continuous and fluctuating patterns of dopamine receptor blockade result in activation of the preproenkephalin gene.