Early rapid response genes such as c-fos are activated in the central nervous system by a variety of agents including psychostimulants. In the present studies, we investigated changes in c-fos mRNA content in several brain regions of the rat in response to nicotine. A single injection of nicotine ip increased the c-fos mRNA content within 30 min and returned toward baseline by 120 min. Significant elevations were induced by 0.5 mg/kg bw nicotine in the medial habenula and by 1.0 mg/kg in the hippocampus, dentate gyrus, and piriform cortex. At 1.0 mg/kg, significantly greater increases in c-fos mRNA levels were present in medial habenula and hippocampus compared to dentate gyrus and in dentate gyrus compared to piriform cortex. Moreover, at 1.0 mg/kg nicotine, increases were significantly less in cerebellar cortex and cingulate gyrus, and these were not dose-dependent. Mecamylamine, a nicotinic cholinergic receptor antagonist, significantly attenuated or eliminated c-fos mRNA response to 1.5 mg/kg nicotine in all regions, except in the cerebellar cortex. Desensitization of the c-fos mRNA response to nicotine was investigated by administering two injections of 2.0 mg/kg nicotine 2 h apart. In the hippocampus, dentate gyrus, and piriform cortex, the first dose of nicotine significantly reduced the c-fos mRNA response to a second dose. The magnitude of desensitization ranged from 43% (piriform cortex) to 81% (hippocampus). In summary, nicotine rapidly elevated the c-fos mRNA content in several rat brain regions. The sensitivity of this response to nicotine and development of desensitization differed among the regions.