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

Adolescent exposure to THC, the main psychoactive component of cannabis, persistently alters dopamine-dependent cognitive functions in a sex-specific manner in rats. Adult rats treated with THC during adolescence showed reduced acquisition of cue-guided reward seeking, but minimal changes in set-shifting or decision-making under uncertainty. When given amphetamine, these rats were more sensitive to its effects on reducing preference for improbable rewards compared to controls. Directly stimulating dopamine neurons in the ventral tegmental area or their projections to the medial prefrontal cortex did not affect decision-making in control rats, but slightly disrupted choices in THC-exposed rats. These results indicate that adolescent THC exposure has specific, lasting effects on cognition and amphetamine sensitivity that may not involve direct dopamine pathway changes.

Study at a glance

Abstract

Rationale: -tetrahydrocannabinol (THC) influences development of circuits underlying these processes, especially in the prefrontal cortex, which matures during adolescence. Objective: We determined how 14 daily THC injections (5mg/kg) during adolescence persistently impacts medial prefrontal cortex (mPFC) dopamine-dependent cognition. Methods: In adult Long Evans rats treated as adolescents with THC (AdoTHC), we quantify performance on two mPFC dopamine-dependent reward-based tasks-strategy set shifting and probabilistic discounting. We also determined how acute dopamine augmentation with amphetamine (0, 0.25, 0.5 mg/kg), or specific chemogenetic stimulation of ventral tegmental area (VTA) dopamine neurons and their projections to mPFC impacts probabilistic discounting. Results: AdoTHC sex-dependently impacts acquisition of cue-guided instrumental reward seeking, but has minimal effects on set-shifting or probabilistic discounting in either sex. When we challenged dopamine circuits acutely with amphetamine during probabilistic discounting, we found reduced discounting of improbable reward options, with AdoTHC rats being more sensitive to these effects than controls. In contrast, neither acute chemogenetic stimulation of VTA dopamine neurons nor pathway-specific chemogenetic stimulation of their projection to mPFC impacted probabilistic discounting in control rats, although stimulation of this cortical dopamine projection slightly disrupted choices in AdoTHC rats. Conclusions: These studies confirm a marked specificity in the cognitive processes impacted by AdoTHC exposure. They also suggest that some persistent AdoTHC effects may alter amphetamine-induced cognitive changes in a manner independent of VTA dopamine neurons or their projections to mPFC.