The inhibitory effect of cannabidiol on the rewarding properties of methamphetamine in part mediates by interacting with the hippocampal D1-like dopamine receptors

Cannabidiol (CBD) is a potential treatment to decrease the rewarding properties of psychostimulants. However, the exact mechanism and distinct neuroanatomical areas responsible for the CBD’s effects remain unclear. Indicatively, the D1-like dopamine receptors (D1R) in the hippocampus (HIP) are essential for expressing and acquiring drug-associated conditioned place preference (CPP). Therefore, given that involving D1Rs in reward-related behaviors and the encouraging results of CBD in attenuating the psychostimulant’s rewarding effects, the present study sought to investigate the role of D1Rs of the hippocampal dentate gyrus (DG) in the inhibitory effects of CBD on the acquisition and expression of METH-induced CPP. To this end, over a 5-day conditioning period by METH (1 mg/kg; sc), different groups of rats were given intra-DG SCH23390 (0.25, 1, or 4 μg/0.5 μl, saline) as a D1Rs antagonist before ICV administration of CBD (10 μg/5 μl, DMSO12%). In addition, a different set of animals, after the conditioning period, received a single dose of SCH23390 (0.25, 1, or 4 μg/0.5 μl) before CBD (50 μg/5 μl) administration on the expression day. The results showed that SCH23390 (1 and 4 μg) significantly reduced the suppressive effects of CBD on the acquisition of METH place preference (P < 0.05 and P < 0.001, respectively). Furthermore, the highest dose of SCH23390 (4 μg) in the expression phase remarkably abolished the preventive effects of CBD on the expression of METH-seeking behavior (P < 0.001). In conclusion, the current study revealed that CBD’s inhibitory effect on rewarding properties of METH partially acts through D1Rs in the DG area of the HIP.