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

Chronic exposure to a low dose of THC (1 mg/kg) during adolescence in rats leads to depressive-like behaviors (increased immobility in the forced swim test and anhedonia in the sucrose preference test) and anxiety-like behavior (fewer open-arm entries in the elevated plus maze). Adult exposure also produces anxiety but not depressive-like behaviors. Both adolescent and adult THC exposure reduce the activity of serotonin neurons in the dorsal raphe, while noradrenergic neurons in the locus coeruleus remain unaffected. These findings suggest that the serotonin system is vulnerable to chronic low-dose THC, and that adolescents are particularly susceptible to THC-induced depressive effects.

Study at a glance

Abstract

BACKGROUND: Chronic exposure to the Δ9-tetrahydrocannabinol (THC), the main cannabis pharmacological component, during adolescence has been shown to be associated with an increased risk of depression and suicidality in humans. AIMS: Little is known about the impact of the long-term effects of chronic exposure to low doses of THC in adolescent compared to adult rodents. METHODS: THC (1mg/kg i.p., once a day) or vehicle was administered for 20 days in both adolescent (post-natal day, PND 30-50) and young adult rats (PND 50-70). After a long washout period (20 days), several behavioral paradigms and electrophysiological recordings of serotonin (5-HT) and norepinephrine (NE) neurons were carried out. RESULTS: Adolescent THC exposure resulted in depressive lbehaviors: a significant decrease in latency to first immobility in the forced swim test, increased anhedonia in the sucrose preference test. Decrease entries in the open arm were observed in the elevated plus maze after adolescent and adult exposure, indicating anxiousphenotype. A significant reduction in dorsal raphe serotonergic neural activity without changing locus coeruleus noradrenergic neural activity was found in THC adolescent and adult exposure. CONCLUSIONS: Altogether, these findings suggest that low doses of chronic THC exposure during the developmental period and adulthood could result in increased vulnerability of the 5-HT system and anxiety symptoms; however, depressive phenotypes occur only after adolescent, but not adult exposure, underscoring the higher vulnerability of young ages to the mental effects of cannabis.