Physical activity and antidepressant treatment have each separately been of significant interest for the management of Alzheimer's disease (AD); particularly the behavioral problems associated with this dementing disorder. We have found that combined antidepressant treatment and physical activity have an additive, potentiating effect on BDNF mRNA expression within several areas of the rat hippocampus. During the 20-day experimental period, animals were treated daily with imipramine (15 mg/kg) or tranylcypromine (7.5 mg/kg) by intraperitoneal injection. Exercising rat groups were given access to running wheels for the duration of the experiment. BDNF mRNA levels were assessed in several cell groups of the hippocampus by in situ hybridization, using a [35S] labelled riboprobe complementary to the full-length BDNF sequence, and computer-assisted densitometry. The combination of physical activity and antidepressant treatment for the 20-day period led to a significant potentiation of full-length BDNF mRNA levels within the dentate gyrus and CA 1, CA 3, and CA 4 cellular fields, above the levels obtained with each intervention alone. These results provide impetus for the study of physical exercise as a potential enhancer of treatment response to antidepressants.