Stress-induced neuronal atrophy and death in the hippocampus may play an important role in the etiology of clinical depression. Conventional antidepressants can stimulate hippocampal neurogenesis after chronic administration. AMPA receptor potentiators (ARPs) such as LY392098 and LY451616 are active in both the forced swim test and the tail suspension test, two behavioral despair procedures widely used to predict antidepressant efficacy. Unlike traditional antidepressants, this group of compounds does not affect extracellular concentrations of biogenic amines. In this study, we investigated the effect of LY451646 on progenitor cell proliferation in adult rat hippocampus. Male Sprague-Dawley rats (n = 4-5 per group) received either single or chronic (21 days) doses of LY451646 (0.025-0.5 mg/kg). Bromodeoxyuridine (BrdU) injections and immunohistochemistry were performed 30 min and 24 h after the last drug injection, respectively. Results show that chronic LY451646 treatment increased progenitor cell proliferation (approximately 45%) in the dentate gyrus in a dose-dependent manner. This upregulation of BrdU labeling appeared as an increase in the number of cells arranged in clusters. Similarly, a significant increase in the number of cells in clusters was observed after a single injection of LY451646 (0.05 mg/kg), although the increase in total number of BrdU-positive cells (approximately 30%) did not reach statistical significance. This is the first in vivo study showing the modulation of progenitor cell proliferation by an ARP. These findings suggest that the antidepressant-like activity of ARPs in animals may be attributed, at least in part, to the regulation of progenitor cell proliferation in the hippocampus.