Effects of Chronic Exposure to Low-Dose delta-9-Tetrahydrocannabinol in Adolescence and Adulthood on Serotonin/Norepinephrine Neurotransmission and Emotional Behavior

Background: Chronic exposure to D9-tetrahydrocannabinol (THC), the main pharmacological component of cannabis, during adolescence has been shown to be associated with an increased risk of depression and suicidality in humans. Little is known about the impact of the long-term effects of chronic exposure to low doses of THC in adolescent compared with adult rodents. Methods: THC (1 mg/kg i.p., once per day) or vehicle was administered for 20 days in both adolescent (post-natal day 30-50) and young adult rats (post-natal day 50-70). After a long washout period (20 days), behavioral tests and electrophysiological recordings of serotonin and norepinephrine neurons were carried out. Results: Adolescent THC exposure resulted in depressive behaviors: decreased latency to first immobility in the forced swim test and increased anhedonia in the sucrose preference test. Decreased entries in the open arms were observed in the elevated plus maze after adolescent and adult exposure, indicating an anxious phenotype. A significant reduction in dorsal raphe serotonergic neural activity without a change in locus coeruleus noradrenergic neural activity was found after adolescent and adult exposure. Conclusions: Altogether, these findings suggest that chronic low-dose THC exposure during the critical developmental period of adolescence and during adulthood could result in increased vulnerability of the serotonin system accompanied by anxiety symptoms. However, depressive phenotypes occur only after adolescent exposure but not after adult exposure, underscoring the greater vulnerability of young ages to the mental effects of cannabis.