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

THC, the psychoactive compound in cannabis, selectively amplifies behavioral and brain responses to cues that predict rewards, without affecting responses to neutral cues or baseline reward consumption. In squirrel monkeys, a low dose of THC (3 μg/kg) increased conditioned approach behavior toward a visual stimulus associated with food delivery. Functional MRI showed that THC enhanced activity in reward-related brain regions—anterior cingulate cortex, striatum, hippocampus, and substantia nigra-ventral tegmental area (SN-VTA)—while leaving visual and motor cortices unaffected. Resting-state connectivity analyses revealed that THC strengthened communication within mesocorticolimbic networks, with the SN-VTA acting as a central hub. These findings indicate that THC boosts incentive salience and motivational drive toward reward-associated stimuli through selective modulation of this circuitry.

Study at a glance

Abstract

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.