Summary of voxel-based analysis of variance (ANOVA) results. Peak relative cerebral blood volume (rCBV) responses to the nicotine and saline injections in each voxel were evaluated with 4 (DOSE) × 2 (INJECTION) factor ANOVAs. Activated voxels were thresholded for each factor and the interaction effect at pcorrected <0.005. (a) The DOSE main effect of nicotine (0 (saline), 0.03, 0.10, and 0.30 mg/kg) demonstrated widespread brain activation. (b) The INJECTION main effect, which indicates the development of tolerance, is illustrated for the two consecutive injections spaced 25 min apart for either saline or the three doses of nicotine. (c) Significant DOSE × INJECTION interactions were regionally restricted.