Adolescent THC impacts on mPFC dopamine-mediated cognitive processes in male and female rats

Adolescent use of cannabis is linked to later-life changes in cognition, learning, and memory. Rodent models suggest this could be a causal effect of Δ ⁹ -tetrahydrocannabinol (THC) influencing the development of circuits underlying these processes, especially for the prefrontal cortex (PFC) which undergoes maturation during adolescence. Here we examined how two weeks of daily exposure to THC (5mg/kg IP) during adolescence persistently impacts cognitive processes involving mPFC dopamine. In male and female Long Evans rats treated in adolescence with THC or vehicle, we quantify acquisition of, and stable performance in two mPFC dopamine-dependent cognitive tasks—attentional set shifting and probability-based reward discounting. We also determined how acute pharmacological or chemogenetic augmentation of dopamine signaling impacts cognition in both groups and both sexes. We found that adolescent THC (AdoTHC) sex-dependently impacts acquisition of cue-guided instrumental reward seeking, but has minimal effects on set-shifting or probability discounting in either sex. When we challenged dopamine circuits by acutely potentiating monoamine signaling with amphetamine (0, 0.25, 0.5 mg/kg) during probability discounting, we confirmed prior findings that amphetamine reduced discounting of improbable reward options, and further showed that this amphetamine effect was more robust in rats with a history of adolescent THC. We next asked whether this potentiated effect of amphetamine involves AdoTHC impacts on dopamine circuits in particular, by attempting to recapitulate the amphetamine effect using more specific chemogenetic stimulation of VTA dopamine neurons. In contrast, we found that neither acute chemogenetic stimulation of VTA dopamine neurons (using a Cre-dependent DREADD in tyrosine hydroxylase:Cre rats), nor pathway-specific chemogenetic stimulation of these neurons’ projection to mPFC in particular impacted probability discounting, suggesting that AdoTHC’s potentiation of amphetamine effects may reflect alterations of non-VTA dopamine neurons influenced by amphetamine. Results confirm the marked specificity in the cognitive processes impacted by adolescent THC exposure, and suggest that some persistent effects of adolescent THC may alter cognitive responses to amphetamine in a manner independent of VTA dopamine projections to mPFC.