Large-scale analysis of gene expression changes during acute and chronic exposure to Delta(9)-THC in rats

Large-scale cDNA microarrays were employed to assess transient changes in g ene expression levels following acute and chronic exposure to cannabinoids in rats. A total of 24,456 cDNA clones were randomly selected from a rat br ain cDNA library, amplified by PCR, and arrayed at high density to investig ate differential gene expression profiles following acute (24 h), intermedi ate (7 days), and chronic (21 days) exposure to Delta(9)-tetrahydrocan-nabi nol (Delta(9)-THC), the psychoactive ingredient of marijuana. Hippocampal m RNA probes labeled with P-33 obtained from both vehicle and Delta(9)-THC-tr eated animals were hybridized with identical cDNA microarrays. Results reve aled a total of 49 different genes altered by Delta(9)-THC exposure; of the se, 28 were identified, 10 had homologies to expressed sequence tags (ESTs) , and 11 had no homology to known sequences in the GenBank database. Chroni c or acute cannabinoid receptor activation altered expression of several ge nes (i.e., prostaglandin D synthase, calmodulin) involved in biochemical ca scades of cannabinoid synthesis or cannabinoid effector systems. Other gene s [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 l arge-scale screen was determined by RNA dot blots in different groups of an imals treated the same as those in the large-scale screen. Results are disc ussed in terms of the different types of genes affected at different times during chronic Delta(9)-THC exposure.