Effects of chronic nicotine on glucose utilization in 45 CNS regions were examined using the 2-deoxy-D-[1-14C]glucose technique in rats. Either L-nicotine (1.0 mg/kg) or saline was injected subcutaneously twice daily for 10 days and once the morning of day 11. On the following afternoon, rats received either nicotine challenge (0.3 mg/kg) or saline subcutaneously 2 min before an intravenous pulse of 2-deoxy-D-[1-14C]glucose. Drug-naive rats given nicotine challenge showed increases of glucose utilization in thalamic nuclei and components of the visual system. Tolerance to nicotine challenge in rats given nicotine chronically was seen in the ventral tegmental area, some components of visual pathways, the cerebellum, and vestibular nuclei; no regions showed sensitization. The percent of rats manifesting most nicotine-induced behaviors either increased (Straub tail, locomotor stimulation, tremors) or did not change (ataxia) over the 10 days of chronic treatment. Plasma from rats given nicotine chronically showed low concentrations of nicotine (12 +/- 1 ng/ml) and higher concentrations of cotinine (124 +/- 6 ng/ml) at the time of assay, with no apparent effect of chronic treatment on nicotine levels after the challenge dose. Changes in regional brain activity, as measured by the 2-deoxy-D-[1-14C]glucose technique, generally do not explain the observed sensitization to nicotine in behavioral assays.