Long-term hippocampal glutamate synapse and astrocyte dysfunctions underlying the altered phenotype induced by adolescent THC treatment in male rats

Mechanisms Underlying Sex Differences in Cannabis Use

“…In the glutamate system, adult female rats, with cannabinoid exposure in adolescence, showed reduced NMDA receptor density [41, 68] and reduced glutamate release in hippocampus [68], compared to control females. Adult male rats with cannabinoid exposure in adolescence, in contrast, have shown enhanced NMDA subunit GluN2B expression and AMPA subunit expression compared to control males [69]. In the GABAergic system, both sexes have shown elevated GABA release in adulthood, after cannabinoid exposure in adolescence, but female rats specifically show enhanced hippocampal GABA-A receptor expression compared to control females [68].…”

“…Some groups reported no effects of adolescent cannabinoid exposure in rodents on anxiety in adolescence [146] or adulthood [61, 69], and others reported a male-specific reduction in anxiety or anxious behavior with cannabinoid exposure [147–149]. Adequate comparison of conflicting results is limited, however, as these studies vary in their administered cannabinoid (i.e., CP 55,940 vs. THC) which may impact potency of effect at the receptor level.…”

“…Cannabinoid exposure in males, in contrast, has been shown to decrease depressive-like behavior [149, 165]. Conflicting evidence does exist, however, as elevated depressive symptoms in both sexes [41], or no effects in males [69], have been reported. Altogether, cannabis use correlates with several measures of depression in humans, cannabinoid exposure has mixed effects on depressive symptoms in preclinical animal models, and varied sex-specific associations between cannabis use and depression emerge across studies, necessitating further inclusion of females in studies of depression in cannabis use.…”

New vistas on cannabis use disorder

“…In a first study, adolescent THC treatment was shown to increase the levels of the astrocyte marker glial fibrillary acidic protein (GFAP) in the hilus of the dentate gyrus of both male and female rats (Lopes-Rodriguez et al 2014). More recently, Zamberletti et al (2016), using the same treatment protocol previously applied to females (Zamberletti et al 2015), demonstrated that the behavioral phenotype triggered by adolescent THC treatment in male rats overlaps only partially with the one present in females, being characterized by poorer memory performance and psychotic-like behaviors, without alterations in the emotional component that instead were observed in females. Interestingly, when the authors looked at the possible molecular underpinnings of this phenotype, sex-differences were observed, in terms of brain region affected and profile of pro-neuroinflammatory biomarkers.…”

The long-term cognitive consequences of adolescent exposure to recreational drugs of abuse

“…For instance, repetitive THC exposure in adolescent female rodents led to reductions in pre-and postsynaptic markers of neuroplasticity and total and basal dendritic length in the prefrontal cortex in adulthood, indicating multiple potential changes in cortical organization (Rubino et al 2009a). Conversely, reports examining similar outcomes in male adolescents are conflicting, with some reporting reductions in postsynaptic markers and dendritic count and length (Renard et al 2016) and others reporting no change (Zamberletti et al 2016). It should be noted, however, that the discrepancies in male prefrontal cortex outcomes may be a byproduct of different drugs used, as Renard et al (2016) administered a synthetic cannabinoid agonist and Zamberletti et al (2016) administered THC.…”