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Using a mouse brain cDNA microarray consisting of 2688 gene sequences, which include unknown sequences with the empirical possibility of expression in the brain, the effects of repeated toxic doses of intraperitoneal (i.p.) cocaine (40 mg kg-1, 4 days) on the expression profile of the cerebral genes were investigated. The modifications in this profile caused by buprenorphine (BUP) (0.25 mg kg-1 i.p., 4 days), a protective drug against cocaine, were also examined. In the cocaine group, the expression levels reached the recommended increased levels (≥2 times the control value in the saline-treated control group) in 24.0% of the genes but were equal to or less than the recommended attenuation levels (≤0.5 times the control value) in 14.0% of the genes. In the cocaine–BUP group, the expression levels of the other 15.4% of the total genes were increased and those of the other 18.2% of the total genes were attenuated. However, corresponding to the BUP-attenuated mortality rate and severity of seizures, the expression levels of 80.1% of the cocaine-modified genes with above-background levels recovered to the recommended normal levels (>0.5 and <2 times the control value). Although statistically significant modifications in the expression of cocaine- or BUP-related brain-region-specific genes were not proved using whole cerebrums, including many unknown genes, our results suggest that the expression of genes related to neuronal cell damage, including non-peculiar genes related to the damage accompanying convulsive seizures and malignant tumors, were normalized and the genes related to the protection of neural cells were induced by BUP. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]