Gender-dependent behavioral and biochemical effects of adolescent delta-9-tetrahydrocannabinol in adult maternally deprived rats

Abstract

Preclinical data support the long-term adverse effects on cognition, emotionality, and psychotic-like behaviors of adolescent exposure to natural and synthetic cannabinoids. To investigate whether the long-lasting adverse effects induced by cannabinoids in adolescence are influenced by early-life stress, female and male rats were subjected to 24-h maternal deprivation at postnatal day (PND) 9 and treated with tetrahydrocannabinol (THC) during adolescence (PND 35-45) according to our previously reported protocol. At adulthood, rats were tested in the novel object recognition, social interaction, and forced swim tests, to evaluate possible alterations in recognition memory, social behavior, and coping strategy. Moreover, cannabinoid CB1 receptor density and functionality, as well as NMDA and dopamine D1 and D2 receptor densities were measured through autoradiographic binding studies. In female maternally deprived rats, THC failed to impair recognition memory, counteracted aggressiveness induced by maternal deprivation, whereas no interaction was observed in the passive coping behavior. In males, the association of the two events increased passive coping response without affecting other behaviors. This behavioral picture was accompanied by gender-dependent and region-specific alterations in NMDA, D1 and D2 receptors. In conclusion, this study demonstrates that adolescent THC exposure might have different behavioral outcomes in animals previously exposed to early-life stress compared with non-stressed controls. The interaction between the two events is not univocal, and different combinations may arise depending on the sex of the animals and the behavior considered. Alterations in NMDA, D1 and D2 receptors might be involved in the behavioral responses induced by maternal deprivation and in their modulation by THC.