Transcriptional regulation is central to the long-term effects of drugs of abuse. Activation of the extracellular signal-regulated kinase (ERK1/2) pathway underlies plasticity changes that accompany drug use. One target of ERK1/2 activation is the Ets-like transcription factor Elk-I. We show here that nicotine modulates Elk-I in the rat hippocampus in a spatially and temporally specific manner. In-vitro nicotine (1 mu M) activated Elk-I in hippocampal slices. In-vivo acute nicotine (0.4 mg/kg) activated Elk-I in the CAI area but not in the dentate gyrus. Chronic nicotine for 14 days changed the level of total Elk-I but not its phosphorylation state. Thus, Elk-I regulation of transcriptional events may contribute to nicotine-induced changes in the hippocampus.