Antagonism of the CB(1) cannabinoid receptor (CB(1) receptor) by rimonabant (SR141716) reduces self-administration of alcohol and other drugs of abuse in animal models. These findings suggest that the CB(1) receptor may be a target for genetic differences that modify the salient features of rewarding drugs. In the present study, wild-type (CB(1) (+/+)) are compared to transgenic mice deficient in CB(1) receptors (CB(1) (-/-)). 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 CB(1) (-/-) striatum increases when compared to CB(1) (+/+). Real-time PCR analyses to evaluate D(2) and D(4) dopamine receptor gene expression in striatum isolated from CB(1) (+/+) and CB(1) (-/-) revealed a nearly 2-fold increase in D(4) receptor mRNA in the striatum from CB(1) (-/-) mice and no significant change in D(2) expression. In contrast, treatment of C57BL/6 mice with the CB(1) receptor antagonist, rimonabant, produced a reduction of both D(2) and D(4) dopamine receptor expression in the striatum. These data suggest that genetic differences in CB(1) receptor may exert a modulatory effect on D(4) dopamine receptor and opioid peptide gene expression.