Large-scale analysis of gene expression changes during acute and chronic exposure to Δ⁹-THC in rats

Abstract

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 Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the psychoactive ingredient of marijuana. Hippocampal mRNA probes labeled with (33)P obtained from both vehicle and Delta(9)-THC-treated animals were hybridized with identical cDNA microarrays. Results revealed a total of 49 different genes altered by Delta(9)-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 Delta(9)-THC exposure.

Adolescent Rats Find Repeated Δ9-THC Less Aversive Than Adult Rats but Display Greater Residual Cognitive Deficits and Changes in Hippocampal Protein Expression Following Exposure

“…Previous studies have noted altered regulation of ubiquitin-conjugating enzyme 24 h after D 9 -THC administration (Kittler et al, 2000;Grigorenko et al, 2002) and the current study extends this to 17 days posttreatment. Expression of this protein may indicate disruption of cell proliferation and repair resulting from drug exposure during the adolescent period.…”

“…MBP is a major constituent of the myelin sheath that allows fast saltatory conduction of nerve pulses (Vanrobaeys et al, 2005). Previous studies employing microarray techniques have demonstrated downregulated MBP expression immediately after chronic D 9 -THC administration (Kittler et al, 2000;Grigorenko et al, 2002). Again, the current study is of interest as it shows such effects more than 2 weeks after D 9 -THC exposure, and only in rats exposed to D 9 -THC during the adolescent period.…”

“…They may also protect denatured proteins from aggregation and then promote refolding (Sargent et al, 1989). Microarray studies with cannabinoids have reported altered expression of related mRNAs, including heat shock 27 kDa protein 3 (Parmentier-Batteur et al, 2002) and 70 kDa heat shock protein (Kittler et al, 2000;Grigorenko et al, 2002). A disruption in the expression of these proteins could promote degenerative changes.…”

“…Previous studies have utilized cDNA microarray to assess changes of gene expression profiles induced by cannabinoids in the CNS and suggest a variety of gene expression changes following chronic cannabinoid treatment (Kittler et al, 2000;Grigorenko et al, 2002;Parmentier-Batteur et al, 2002). However, to our knowledge, no previous study has analyzed brain protein expression profiles of chronic cannabinoid-exposed rats.…”

Differential Roles of CB1 and CB2 Cannabinoid Receptors in Mast Cells

“…G␤␥ may transduce cannabinoid signals to phosphatidylinositol (PI) 4 3-kinase and mitogen-activated protein kinases (6). Cannabinoid regulation of the CREB and NF-B are among the few transcriptional effects of cannabinoid exposure that have been documented in immune cell contexts (6,(17)(18)(19)(20)(21).…”