Research ReportClozapine and SCH 23390 prevent the spatial working memory disruption induced by Δ9-THC administration into the medial prefrontal cortex

Marijuana (Cannabis sativa) is one of the most widely used illicit drugs in the world. Its use is associated with impairments in cognitive function. We previously reported that Δ9-tetrahydrocannabinol (Δ9-THC), the primary psychoactive component of marijuana, impaired spatial working memory in the radial maze task when injected intracortically (IC) into the medial prefrontal cortex (mPFC) of rats. Here, we used this paradigm to evaluate the involvement of prefrontal dopamine receptors in working memory disruption induced by Δ9-THC. Intracortical pre-treatment of animals with either the D1- or D2-like dopamine receptor antagonists SCH 23390 or clozapine, respectively, significantly reduced the number of errors rats made in the radial maze following treatment with Δ9-THC also administered intracortically. These results were obtained in the absence of locomotor impairment, as evidenced by the time spent in each arm a rat visited. Our findings suggest that prefrontal dopamine receptors are involved in Δ9-THC-induced disruption of spatial working memory. This interaction between the cannabinoid system and dopamine release in the PFC contributes to new directions in research and to treatments for cognitive dysfunctions associated with drug abuse and dependence.

Research Highlights►Δ9-THC acts on CB1r of prefrontal cortex leading to disruption in working memory. ►CB1r is known to have a modulatory role on GABAergic neurons. ►Disruption induced by Δ9-THC may be caused by resultant hyperdopaminergia. ►Dopamine antagonists are able to prevent working memory disruption induced by Δ9-THC.