Δ ⁹ -Tetrahydrocannabinol-induced enhancement of reward responsivity via mesocorticolimbic modulation in squirrel...

Δ ⁹ -tetrahydrocannabinol (THC)-containing products are widely used recreationally, partly due to THC's ability to enhance the appetitive (i.e., rewarding) properties of diverse stimuli. However, the neural mechanisms through which THC modulates reward-related processing remain poorly understood. Here, we used a Pavlovian paradigm in adult squirrel monkeys (3males, 1female) to associate a visual conditioned stimulus (CS ⁺ ) with appetitive food delivery. The modulatory effects of acute THC (1-10μg/kg, i.m.) on behavioral and brain responses to CS ⁺ were evaluated. Event-related functional MRI (fMRI) was employed to characterize the neural correlates of conditioned responding to the CS ⁺ , both in the absence and presence of THC treatment, with preconditioning scans serving as control. Behaviorally, THC (3μg/kg) selectively enhanced conditioned responding to the CS ⁺ without altering responses to the control stimulus (CS ^- ) or increasing baseline consummatory responding, underscoring the specificity of THC's action on reward-associated processes. Consistently, fMRI analyses revealed that THC amplified CS ⁺ -evoked activation within mesocorticolimbic regions, including the anterior cingulate cortex (ACC), striatum, hippocampus, and substantia nigra-ventral tegmental area (SN-VTA), without affecting activity in visual and motor cortices. This finding underscores the selectivity of THC's neuromodulatory effects on reward-related circuitry. Independent of CS exposure, resting-state functional connectivity analyses indicate that THC enhanced mesocorticolimbic network integration, as evident in strengthened SN-VTA-centered connectivity with the ACC, striatum, and hippocampus. Collectively, these findings demonstrate that THC enhances the responses to appetitive stimuli, through selective modulation of mesocorticolimbic circuitry, highlighting the SN-VTA as a pivotal hub for cannabinoid-mediated regulation of incentive salience and motivational drive toward reward-associated stimuli.

THC enhances behavioral and neural responses to rewards through mesocorticolimbic modulation centered on the SN-VTA.