Sex, drugs, and adult neurogenesis: Sex‐dependent effects of escalating adolescent cannabinoid exposure on adult hippocampal neurogenesis, stress reactivity, and amphetamine sensitization

Abstract

Cannabinoid exposure during adolescence has adverse effects on neuroplasticity, emotional behavior, cognition, and reward sensitivity in adult rats. We investigated whether escalating doses of the cannabinoid receptor 1 (CB1 R) agonist, HU-210, in adolescence would affect adult hippocampal neurogenesis and behavioral processes putatively modulated by hippocampal neurogenesis, in adult male and female Sprague-Dawley rats. Escalating doses of HU-210 (25, 50, and 100 µg/kg), or vehicle were administered from postnatal day (PND) 35 to 46. Animals were left undisturbed until PND 70, when they were treated with 5-bromo-2-deoxyuridine (BrdU; 200 mg/kg) and perfused 21 days later to examine density of BrdU-ir and BrdU/NeuN cells in the dentate gyrus. In another cohort, hypothalamic-pituitary-adrenal (HPA) axis reactivity to an acute restraint stress (30 min; PND 75) and behavioral sensitization to d-amphetamine sulfate (1-2 mg/kg; PND 105-134) were assessed in adulthood. Adolescent HU-210 administration suppressed the density of BrdU-ir cells in the dentate gyrus in adult male, but not adult female rats. Adolescent HU-210 administration also induced significantly higher peak corticosterone levels and reminiscent of the changes in neurogenesis, this effect was more pronounced in adult males than females. However, adolescent cannabinoid treatment resulted in significantly higher stereotypy scores in adult female, but not male, rats. Thus, adolescent CB1 R activation suppressed hippocampal neurogenesis and increased stress responsivity in adult males, but not females, and enhanced amphetamine sensitization in adult female, but not male, rats. Taken together, increased CB1 R activation during adolescence results in sex-dependent, long-term, changes to hippocampal structure and function, an effect that may shed light on differing vulnerabilities to developing disorders following adolescent cannabinoid exposure, based on sex.

Consequences of adolescent use of alcohol and other drugs: Studies using rodent models

“…Findings of long-lasting neural and behavioral consequences of adolescent exposure to THC and a variety of synthetic CB agonists have emerged with a variety of measures; these findings have been reviewed recently in several excellent reviews to which the reader can refer for additional information, critique and references (Trezza et al, 2008; Renard et al, 2014; Higuera-Matas et al, 2015; Lubman et al, 2015). Although not commonly assessed, where examined, observed effects of adolescent CB exposure have sometimes been found to be sex-specific (e.g., Lee et al, 2014; Higuera-Matas et al, 2015; see Viveros et al, 2011, for review) and generally not evident after comparable exposures in adulthood (e.g., Viveros et al, 2012). Periods of particular vulnerability during adolescence have been little investigated to date, with work suggesting that early/mid adolescence (e.g., P35–40 and P40–45) is a time of greater vulnerability than during late adolescence (P50–55 or later) (Cass et al, 2014) contrasting with other findings that effects are more pronounced with exposures during late adolescence/emerging adulthood (P40–65) than during the juvenile-to-mid-adolescent period (P15–40) or in adulthood (>P70) (see Schneider, 2008).…”

Sex differences in drug addiction and response to exercise intervention: From human to animal studies

“…It was also reported that estradiol-induced neurogenesis and neuroprotection depended on the activation of either estrogen receptor subtype within the brain (Nilsen et al , 2000; Suzuki et al , 2007; Saleh et al , 2013). Young male rats showed delayed neurogenesis in the hippocampus after repeated exposure to cannabinoid compared to young female rats (Lee et al , 2014). Many studies have demonstrated that exercise can reduce the symptoms of drug addiction by ameliorating cognitive decline via the promotion of neurogenesis and activation of new neurons in the hippocampus.…”

Developmental regulation of fear learning and anxiety behavior by endocannabinoids

“…On a behavioral level, adolescent THC exposure reduces stress‐coping behavior in the forced swim test in adult female rats, impairs spatial working memory in adult males and leads to anhedonia in both adult males and females as measured by the sucrose preference test (Rubino et al ). Neural consequences of adolescent cannabinoid exposure include differential reductions in amygdalar and hippocampal CB 1 R binding and signaling capacity in adult males and females (Rubino et al ), decreases in markers of neuroplasticity such as synaptophysin and PSD 95 in the PFC of females (Rubino et al ), dendritic atrophy and reduced number of spines in hippocampal neurons in males (Rubino et al ) and reductions in cell proliferation (Realini et al ) and survival (Lee et al ) in the dentate gyrus of the hippocampus in adult female and male rats. Chronic administration of the FAAH inhibitor URB‐597 in adulthood reverses effects induced by adolescent THC administration such as reductions in stress‐coping and increases in anxiety behaviors in female rats (Realini et al ) as well as decreases in hippocampal CB 1 R expression in male rats (Marco et al ).…”