Age-related changes in CB1 receptor expression and function and the behavioral effects of cannabinoid receptor ligands

Cannabinoid use has increased among aging individuals. However, little information on age-related differences in the behavioral effects of these agents is available. To explore potential differences in the behavioral effects of cannabinoids, we determined effects of Δ⁹-tetrahydrocannabinol (THC, 1–10 mg/kg) or rimonabant (0.3–3.2 mg/kg) on operant fixed-ratio responding (FR10) for food in young adult (6 months) and aged (29 months) rats. THC dose-dependently decreased responding for food. Rimonabant alone had little or no effect on responding up to 1.0 mg/kg, but disrupted responding following a 3.2 mg/kg dose. Rimonabant (1.0 mg/kg) partially antagonized response disruption by THC. These effects were similar in young adult and aged rats. However, aging has been reported to change the neurobiology of cannabinoid CB1 receptors. To confirm our rats exhibited such differences, we assessed CB1 receptor binding sites and function in six subcortical (caudate, nucleus accumbens CA1, and CA2/CA3), and three cortical regions (medial prefrontal, temporal, entorhinal) in young adult (6 months) or aged (26 months) male Lewis rats using quantitative autoradiography. CB1 receptor binding sites were reduced in cortical, but not subcortical brain regions of aged rats. CB1 receptor function, at the level of receptor-G protein interaction, was not different in any region studied. Results indicate that down-regulation of CB1 receptor binding sites observed in cortical regions of aged rats was not accompanied by a commensurate decrease in CB1 receptor-stimulated [³⁵S]GTPγS binding, suggesting a compensatory increase in receptor function in cortical areas. Together, our results provide additional evidence of age-related changes in central CB1 receptor populations. However, the functional compensation for decreased CB1 receptor binding may mitigate changes in behavioral effects of cannabinoids. With the rising use of cannabinoid-based therapeutics among aging populations, further evaluation of age-related changes in the cannabinoid system and the impact of these changes on effects of this class of drugs is warranted.