Mid-aged rats were either adrenalectomized and chronically maintained, or left intact and treated daily for a 9- to 10-month period with a potent analog of the peptide adrenocorticotropin (residues 4 to 9), which has some stimulant properties, or with the neural stimulant pentylenetetrazole. All three treatments reduced hippocampal morphologic correlates of brain aging (neuronal loss, glial reactivity). The pentylenetetrazole and peptide treatments also improved reversal learning. These results suggest that certain endogenous peptides, with stimulant properties, may also exert long-term, trophic effects on brain structure and function.