Neuroleptic drugs increase the level of alpha-melanotropin (alpha-MSH) in the blood of the rat. We have investigated whether neuroleptic-like peptides, the gamma-type endorphins, also affect alpha-MSH release. A structure-activity study revealed that (des-enkephalin)-gamma-endorphin (DE gamma E, beta-LPH-(66-77), beta-endorphin-(6-17)) is able to increase plasma alpha-MSH levels after intracerebroventricular injection, while the longer gamma-type endorphins, i.e. gamma E (beta-LPH-(61-77)), beta-endorphin-(1-17)), and DT gamma E (beta-LPH-(62-77), beta-endorphin-(2-17)) were without effect in the dosage used. A dose-response study revealed a more or less bell-shaped relationship for the effect of DE gamma E on plasma alpha-MSH levels. The effect of DE gamma E could not be counteracted by apomorphine or naloxone. The observations indicate that DE gamma E increases plasma alpha-MSH levels in a way distinct from that of haloperidol and the opiate peptide beta-endorphin. On the other hand, a time-course of plasma alpha-MSH levels after DE gamma E administration resembled the one which has been seen after haloperidol injection. From experiments performed on pituitary neurointermediate lobes incubated in vitro, it seems not likely that DE gamma E acts directly on the dopamine receptors of the pituitary in affecting alpha-MSH release. In conclusion, it appears that DE gamma E affects alpha-MSH levels in plasma in a way distinct from that of the neuroleptic drug haloperidol and of the opiate-peptide beta-endorphin.