Effects of Δ-9-tetrahydrocannabinol during the peripubertal period in the rat with a focus on early life experience.

Abstract

Marijuana is the most commonly abused illicit substance in the United Sates. Additionally, in 2012, almost 60% of all first time marijuana users were under the age of 18. Adolescents who use marijuana are more likely to exhibit anxiety, depression and other mood disorders including psychotic-like symptoms, with earlier onset of use correlating with more severe effects. Furthermore, the stress history of the user can also affect the behavioral response to cannabis. Therefore, we hypothesize that rats will differ in their behavioral and physiological response to adolescent Δ-9-tetrahydrocannabinol (THC, the primary psychoactive substance in marijuana) based on their early life experience. To examine the effect of early life experience on adolescent THC, we exposed adolescent (postnatal day (P) 29-38) male and female rats, that were either shipped from a supplier on P14 or born in our vivarium, to once daily injections of 3mg/kg THC. Shipping and transport are known stressors which could contribute to the disparate findings among behavioral studies of adolescent cannabinoid exposure. Indeed, our findings suggest that shipped males are more sensitive to the anxiolytic-like and antidepressant-like effects of THC, as measured by the elevated plus maze (EPM) and forced swim test (FST), respectively, during the early drug abstinence period. This effect was not observed in vivarium reared males or females of either origin. As well, no effect of THC was observed in any group with respect to pre-pulse inhibition, a measure of sensorimotor gating which has been shown to be abnormal in psychotic patients. To take into consideration the onset of puberty occurs earlier (~P30) in female rats than in male rats (~P40) and that this might affect the behavioral response to THC, we repeated the study, dosing female rats between P21-30 (pre-puberty) and male rats between P39-48 (puberty). Indeed, the pre-pubertal females showed similar effects as the pre-pubertal (P29-38) males, exhibiting reduced anxious-like behavior on the EPM. This was not observed in the pubertal males. Finally, to investigate possible underlying biochemical correlates of these behaviors, plasma corticosterone levels were obtained either immediately following the FST or after 24 hours in the home cage. Additionally, brain sections were analyzed using in situ hybridization and CP55,940 stimulated [35S]GTPgammaS binding studies. Exposure to the FST increased plasma corticosterone levels in all groups regardless of treatment, sex or origin. No treatment or origin effect was observed at baseline. However, at both time points females overall had higher corticosterone levels than males. Within the animals examined, THC increased CB1R mRNA expression in females but not males, while CP55,940 stimulated [35S]GTPgammaS binding was decreased in females and unaffected in males. Although the effects of this low dose of THC during adolescence are subtle, the results suggest that both males and females are more susceptible to changes in emotional behavior when exposure occurs just prior to the onset of puberty. Additionally, biochemical changes following THC exposure are sex specific, indicating unique changes in the endocannabinoid system during the early drug abstinence period. This suggests that THC interacts with the developing endocannabinoid system differently in males and females during the peri-pubertal period. Further understanding of the sex differences in response to adolescent THC could lead to more targeted and sex-specific treatments for marijuana dependence.