CB1 knockout mice display significant changes in striatal opioid peptide and D4 dopamine receptor gene expression

Antagonism of the CB1 cannabinoid receptor (CB1 receptor) by rimonabant (SR141716) reduces self-administration of alcohol and other drugs of abuse in animal models. These findings suggest that the CB1 receptor may be a target for genetic differences that modify the salient features of rewarding drugs. In the present study, wild-type (CB1 (+/+)) are compared to transgenic mice deficient in CB1 receptors (CB1 (−/−)). The goal was to investigate the influences of the cannabinoid receptor system on opioid peptide gene expression and on dopamine receptor gene expression which is commonly influenced by substances of abuse. We demonstrate using reverse transcription and real-time polymerase chain reaction (PCR) that striatal mRNA for preproenkephalin (PPENK) and preprodynorphin (PPDYN) in the CB1 (−/−) striatum increases when compared to CB1 (+/+). Real-time PCR analyses to evaluate D2 and D4 dopamine receptor gene expression in striatum isolated from CB1 (+/+) and CB1 (−/−) revealed a nearly 2-fold increase in D4 receptor mRNA in the striatum from CB1 (−/−) mice and no significant change in D2 expression. In contrast, treatment of C57BL/6 mice with the CB1 receptor antagonist, rimonabant, produced a reduction of both D2 and D4 dopamine receptor expression in the striatum. These data suggest that genetic differences in CB1 receptor may exert a modulatory effect on D4 dopamine receptor and opioid peptide gene expression.