Cocaine-induced Fos expression in the rat brain: Modulation by prior Δ-tetrahydrocannabinol exposure during adolescence and sex-specific effects.

It has been suggested that cannabis consumption during adolescence may be an initial step to cocaine use in adulthood. Indeed, previous preclinical data show that adolescent exposure to cannabinoids (both natural and synthetic) potentiates cocaine self-administration in rats. Here we aimed at gaining a deeper understanding of the cellular activation patterns induced by cocaine as revealed by Fos imaging and how these patterns may change due to adolescent exposure to THC. Male and female Wistar rats were administered every other day THC (3 mg/kg i.p.) or vehicle from postnatal day 28-44. At adulthood (PND90) they were given an injection of cocaine (20 mg/kg i.p.) or saline and sacrificed 90 min later. Cocaine-induced Fos activation was measured by immunohistochemistry as an index of cellular activation. We found that cocaine-induced activation in the motor cortex was stronger in THC-exposed rats. Moreover, there was significant sex-dependent interaction between cocaine and adolescent THC exposure in the dorsal hypothalamus, suggesting that cocaine induced a more robust cellular activation in THC-exposed females but not in THC-treated males. Other THC- and cocaine-induced effects were also evident. These results add to the previous literature suggesting that the behavioral, cellular, molecular, and brain-activating actions of cocaine are modulated by early experience with cannabinoids and provide additional knowledge that may explain the enhanced actions of cocaine in rats exposed to cannabinoids during their adolescence.