Spontaneous Withdrawal from THC during Adolescence: Sex Differences in Locomotor Activity and Anxiety.

Abstract

Research suggests that the use and abuse of marijuana can be especially harmful if it occurs during adolescence, a period of vast developmental changes throughout the brain. Because of the localization of cannabinoid receptors within the limbic system (Rossi et al., 2009; Katona et al., 2001), and the established effects of cannabinoids on emotional states/anxiety levels of rats and humans, we wanted to study the sex- and dose-related effects of Δ9-tetrahydrocannabinol (THC, the main psychoactive component in marijuana) on behavior and anxiety in a spontaneous withdrawal paradigm. Male and female Sprague Dawley rats were administered 2, 7.5 or 15 mg/kg THC or vehicle from postnatal day 35-41, a period approximating mid-adolescence in humans. Locomotor activity, anxiety-related behaviors, corticosterone and neurosteroid levels were measured during drug administration and subsequent drug abstinence. THC caused significant dose-dependent locomotor depression during drug administration. Locomotor depression initially abated upon drug cessation, but then re-emerged by the end of the 2-week drug abstinence period and was greater in female rats than male rats. We also found the development of sensitization to the locomotor-depressing effects of THC in middle- and high-dose rats and the subsequent development of tolerance in high-dose rats. The high dose of THC increased anxiety-like behaviors while the low dose decreased anxiety-like behaviors during the drug administration period, with females more sensitive to the anxiogenic effects of THC. During drug abstinence, females were again especially sensitive to the anxiogenic effects of THC, while THC had an anxiolytic-like effect on males. Measurements of plasma corticosterone and neurosteroid levels during the drug abstinence period may help to explain sex differences in these results. In conclusion, this study demonstrates sexually-dimorphic effects of THC on anxiety-related behaviors and locomotor activity after cessation of THC administration, information that may be useful in the development of therapeutic remedies for clinical marijuana withdrawal.