Geriatric depression exhibits biological and therapeutic differences relative to early-onset depression. We studied olfactory bulbectomy (OBX), a paradigm that shares major features of human depression, in young versus aged rats to determine mechanisms underlying these differences. Young OBX rats showed locomotor hyperactivity and a loss of passive avoidance and tactile startle. In contrast, aged OBX animals maintained avoidance and startle responses but showed greater locomotor stimulation; the aged group also exhibited decreased grooming and suppressed feeding with novel presentation of chocolate milk, effects which were not seen in young OBX. These behavioral contrasts were accompanied by greater atrophy of the frontal/parietal cortex and midbrain in aged OBX. Serotonin transporter sites were increased in the cortex and hippocampus of young OBX rats, but were decreased in the aged OBX group. Cell signaling cascades also showed age-dependent effects, with increased adenylyl cyclase responses to monoaminergic stimulation in young OBX but no change or a decrease in aged OBX. These data indicate that there are biological distinctions in effects of OBX in young and aged animals, which, if present in geriatric depression, provide a mechanistic basis for differences in biological markers and drug responses. OBX may provide a useful animal model with which to test therapeutic interventions for geriatric depression.