Enkephalin and other brain peptides previously have been shown to be active in the dopa potentiation test which may be considered an animal model of mental depression. A recently described model of passive immobility during swimming, also sensitive to tricyclic antidepressants, was therefore used to study a large number of naturally occurring peptides and some of their analogues. It was found that several enkephalins with no opiate activity after peripheral injection reduced the immobility and thus increased the activity of swimming rats. alpha-MSH, but not its 4--10 core or a 4--9 analogue, also caused significantly more swimming than did the diluent control. As we have previously found in several animal and clinical studies, a smaller dose of MIF-I was more effective than larger doses. The results confirm our concept of the CNS actions of brain peptides and support the suggestion that some of them, like the enkephalins, might be useful after peripheral administration in mental depression or other CNS disorders.