Adolescent Response to THC: Greater Learning Impairment and Lesser Cannabinoid CB1 Receptor Desensitization in Adolescents than Adults.
Adolescence is a behaviorally well-defined developmental period during which experimentation with illicit drugs such as marijuana is common. While the lasting effects of adolescent marijuana use have been studied in humans and in animal models, relatively little is known about the acute response to marijuana in adolescents. It is known that adolescent rats are more impaired by the psychoactive ingredient in marijuana, delta-9 tetrahydrocannabinol (THC), than adults in a water maze spatial learning task. However, what causes this greater sensitivity to THC-induced learning impairment is not understood. We characterized adolescent (postnatal day 30-35) and adult (postnatal day 70-75) rat cannabinoid CB1 receptor number, distribution, and functional coupling in the hippocampus, the brain which may be the site at which THC impairs spatial learning impairment. Next, we elucidated the time course of hippocampal CB1 receptor desensitization in adolescents and adults in response to daily treatment with 10 mg/kg THC. Finally, we characterized the development of tolerance to the learning impairment caused by THC in adolescent and adult rats by pre-treating them for five days with 10 mg/kg THC, and measuring learning performance in the Morris water maze. Our results indicate that agonist stimulation of the CB1 receptor in adolescent hippocampus produces less functional coupling to G proteins than adults. Also, adolescent hippocampal CB1 receptors desensitize less rapidly in response to 10 mg/kg THC treatment than those in adults. Finally, adolescent rats do not become tolerant to the learning impairment effects of 10 mg/kg THC after five days of pre-treatment, while adults do. We conclude that adolescents may be more impaired by THC than adults as a result of more slowly desensitizing hippocampal CB1 receptors, which may be due to
lesser functional CB1-G protein coupling in adolescents.
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