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

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.

Early Consumption of Cannabinoids: From Adult Neurogenesis to Behavior

“…Additionally, chronic exposure to THC in adolescent mice increased the percentage of shredding in the nestlet shredding task [ 118 ] and immobility times in adult rats during the forced swim test [ 119 ]. More recently, a study by De Gregorio et al (2020) showed that chronic exposure to low-dose THC in adolescent rats leads to persistent behavioral abnormalities related to some but not all aspects of depressive reactivity [ 120 ]. In particular, THC administration in rats induced some anxiety behaviors (fewer entries into the open arms of the elevated plus maze) and altered serotoninergic neuron firing rate activity [ 120 ].…”

“…More recently, a study by De Gregorio et al (2020) showed that chronic exposure to low-dose THC in adolescent rats leads to persistent behavioral abnormalities related to some but not all aspects of depressive reactivity [ 120 ]. In particular, THC administration in rats induced some anxiety behaviors (fewer entries into the open arms of the elevated plus maze) and altered serotoninergic neuron firing rate activity [ 120 ]. In another study, it was shown that rats treated with chronic THC during adolescence showed a higher level of anxiety-like behaviors, which led to a significant reduction in food intake and body weight [ 121 ].…”

“…Additionally, the long-term effects of perturbation to the ECS will vary depending on the timing and duration of exposure [ 111 ]. Although several studies show that administration of THC during adolescence modifies anxiety behavior, its effect is inconsistent; in this regard, increases [ 117 , 118 ] and decreases [ 119 , 120 , 121 ] in anxiety levels have been reported. These inconsistent results can be explained by the differences in the doses, time of administration, test behaviors assessed after the final administration, and model animal.…”

Editorial: The Endocannabinoid System: Filling the Translational Gap Between Neuroscience and Psychiatry

“…Widely used worldwide, cannabinoids have attracted much attention for their potential role in health and disease, especially in psychiatry (2). Translational research has significantly advanced our understanding of the neuropsychiatric effects of cannabinoids (3)(4)(5)(6). Adopting a translational perspective, the Research Topic presented here brings together up-to-date knowledge of these fascinating and complex chemical substances and how they may modulate mental health.…”

Multimodal MRI data fusion reveals distinct structural, functional and neurochemical correlates of heavy cannabis use

“…6,7 One of the main hypotheses for psychotic disorders implicates different types of cannabis and a dysregulation (aberrant endogenous signalling) between the two main psychoactive components Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). 6,7 Furthermore, THC and CBD might differently interfere with the endocannabinoid and other neurotransmitter systems, 9,10 and hence, both substances have different acute-, residual-and long-term effects on affective, cognitive and sensorimotor functioning. 11 On one side, THC can acutely increase positive mood 12 and reduce anxiety at low doses.…”