Delta‐9‐tetrahydrocannabinol potentiates fear memory salience through functional modulation of mesolimbic dopaminergic activity states

Chronic or acute exposure to delta‐9‐tetrahydrocannabinol (THC), the main psychoactive compound in cannabis, has been associated with numerous neuropsychiatric side‐effects, including dysregulation of emotional processing and associative memory formation. Clinical and preclinical evidence suggests that the effects of THC are due to the ability to modulate mesolimbic dopamine (DA) activity states in the nucleus accumbens (NAc) and ventral tegmental area (VTA). Nevertheless, the mechanisms by which THC modulates mesolimbic DA function and emotional processing are not well understood. Using an olfactory associative fear memory procedure combined with in vivo neuronal electrophysiology, we examined the effects of direct THC microinfusions targeting the shell region of the NAc (NASh) and examined how THC may modulate the processing of fear‐related emotional memory and concomitant activity states of the mesolimbic DA system. We report that intra‐NASh THC dose‐dependently potentiates the emotional salience of normally subthreshold fear conditioning cues. These effects were dependent upon intra‐VTA transmission through GABAergic receptor mechanisms and intra‐NASh DAergic transmission. Furthermore, doses of intra‐NASh THC that potentiated fear memory salience were found to modulate intra‐VTA neuronal network activity by increasing the spontaneous firing and bursting frequency of DAergic neurones whilst decreasing the activity levels of a subpopulation of putative GABAergic VTA neurones. These findings demonstrate that THC can act directly in the NASh to modulate mesolimbic activity states and induce disturbances in emotional salience and memory formation through modulation of VTA DAergic transmission.