Altered gene expression in striatal projection neurons in CB1 cannabinoid receptor knockout mice.

The basal ganglia, a brain structure critical for sensorimotor and motivational aspects of behavior, contain very high levels of CB1 cannabinoid receptors. These receptors are activated by endogenous lipophilic ligands, and they are thought to mediate behavioral effects of cannabinoid drugs. To evaluate the role of the endogenous cannabinoid system in the regulation of basal ganglia pathways, we have investigated the effects of targeted deletion of CB1 receptors on gene expression of various neuropeptides and transmitter-related enzymes in basal ganglia neurons. Mice without CB1 receptors are extremely hypoactive in a test for exploratory behavior (open-field test), showing markedly reduced locomotion and rearing. These CB1 mutants display significantly increased levels of substance P, dynorphin, enkephalin, and GAD 67 mRNAs in neurons of the two output pathways of the striatum that project to the substantia nigra and the globus pallidus. Our findings demonstrate that elimination of CB1 receptors results in behavioral abnormalities and functional reorganization of the basal ganglia.