Acute infusions of THC directly into the prefrontal cortex of rats produce anxiety-like effects without impairing executive function, while CBD infusions impair attentional set-shifting and spatial working memory without affecting anxiety or sociability. CBD reverses cognitive impairments caused by glutamatergic antagonism in the prefrontal cortex and blocks the anxiety-inducing properties of THC, suggesting CBD's therapeutic effects may only emerge during pathological states. These opposing effects are mediated through dissociable CB1 and 5-HT1A receptor signaling mechanisms within the prefrontal cortex.
Adolescent exposure to THC, the main psychoactive component of cannabis, increases the risk of later neuropsychiatric symptoms, and the medial prefrontal cortex is a key brain region involved. The antioxidant N-acetylcysteine (NAC) prevented cognitive, synaptic, neuronal, and neurochemical deficits caused by chronic adolescent THC exposure in a rodent model. This suggests that THC-induced oxidative stress contributes to neuropsychiatric risk and identifies NAC as a potential preventive treatment.
Adolescent female rats exposed to THC gained weight slower than controls during treatment. In adulthood, they showed no behavioral abnormalities in tests of locomotion, sensorimotor gating, memory, or anxiety. However, long-lasting molecular adaptations occurred: altered expression of estrogen receptor-α and fatty acid amid hydrolase in the hypothalamus and hippocampus, along with enduring changes in hippocampal oscillatory patterns. These sex-specific adaptations may protect females against the long-term behavioral abnormalities consistently seen in male cohorts.
In rats, THC infused directly into the medial prefrontal cortex (PFC) caused strong panic-like responses, while CBD did not affect panic but blocked the formation of associative fear memories and impaired latent inhibition and oddity discrimination. CBD counteracted THC-induced panic and prevented THC-driven phosphorylation of ERK1/2. CBD's effects on perception and latent inhibition depended on 5-HT1A receptor transmission and were accompanied by reduced phosphorylation of p70S6K, independently of THC. The findings suggest dissociable molecular mechanisms: THC promotes panic via ERK1/2 phosphorylation, while CBD impairs perceptive functions via 5-HT1A receptors and reduced p70S6K phosphorylation.