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Kittler, Josef T., Elena V. Grigorenko, Chris Clayton, Shou-Yuan Zhuang, Sarah C. Bundey, Michael M. Trower, Don Wallace, Robert Hampson, and Sam Deadwyler. Large-scale analysis of gene expression changes during acute and chronic exposure to Δ9-THC in rats. Physiol Genomics 3: 175–185, 2000.—Large-scale cDNA microarrays were employed to assess transient changes in gene expression levels following acute and chronic exposure to cannabinoids in rats. A total of 24,456 cDNA clones were randomly selected from a rat brain cDNA library, amplified by PCR, and arrayed at high density to investigate differential gene expression profiles following acute (24 h), intermediate (7 days), and chronic (21 days) exposure to Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive ingredient of marijuana. Hippocampal mRNA probes labeled with 33P obtained from both vehicle and Δ9-THC-treated animals were hybridized with identical cDNA microarrays. Results revealed a total of 49 different genes altered by Δ9-THC exposure; of these, 28 were identified, 10 had homologies to expressed sequence tags (ESTs), and 11 had no homology to known sequences in the GenBank database. Chronic or acute cannabinoid receptor activation altered expression of several genes (i.e., prostaglandin D synthase, calmodulin) involved in biochemical cascades of cannabinoid synthesis or cannabinoid effector systems. Other genes [i.e., neural cell adhesion molecule (NCAM), myelin basic protein], whose relation to cannabinoid system function was not immediately obvious, were also significantly altered. Verification of the changes obtained with the large-scale screen was determined by RNA dot blots in different groups of animals treated the same as those in the large-scale screen. Results are discussed in terms of the different types of genes affected at different times during chronic Δ9-THC exposure.