Mepirapim, a Novel Synthetic Cannabinoid, Induces Addiction-Related Behaviors through Neurochemical Maladaptation in the Brain of Rodents

Abstract

Mepirapim is a synthetic cannabinoid that has recently been abused for recreational purposes. Although serious side effects have been reported from users, the dangerous pharmacological effects of Mepirapim have not been scientifically demonstrated. In this study, we investigated the addictive potential of Mepirapim through an intravenous self-administration test and a conditioned place preference test in rodents. Moreover, to determine whether the pharmacological effects of Mepirapim are mediated by cannabinoid receptors, we investigated whether Mepirapim treatment induces cannabinoid tetrad symptoms in mice. Lastly, to identify Mepirapim induced neurochemical maladaptation in the brains of mice, we performed microdialysis, western blots and neurotransmitter enzyme-linked immunosorbent assays. In the results, Mepirapim supported the maintenance of intravenous self-administration and the development of conditioned place preference. As a molecular mechanism of Mepirapim addiction, we identified a decrease in GABAeric signalling and an increase in dopaminergic signalling in the brain reward circuit. Finally, by confirming the Mepirapim-induced expression of cannabinoid tetrad symptoms, we confirmed that Mepirapim acts pharmacologically through cannabinoid receptor one. Taken together, we found that Mepirapim induces addiction-related behaviours through neurochemical maladaptation in the brain. On the basis of these findings, we propose the strict regulation of recreational abuse of Mepirapim.

Designer Drug, 25D-NBOMe, Has Reinforcing and Rewarding Effects through Change of a Dopaminergic Neurochemical System

“…Experimental animals were selected for each behavior test in accordance with the method described in a previous study. 46 Male Sprague-Dawley rats (7 weeks old, 250∼270 g) were purchased from Orient Bio Co., Ltd (Seoul, Korea), and were used for the IVSA test and microdialysis. The rats were housed one rat per cage (26 × 42 × 18 cm) and had free access to food and water except during food training.…”

“…An IVSA test was performed to assess the reinforcing effects of 25D-NBOMe according to previous studies. , …”

“…Western blot analysis was performed to confirm the changes in protein expression caused by 25D-NBOMe treatment in the mouse NAc according to previous research. , Brain samples from mice in the saline, 25D-NBOMe (1 mg/kg), and methamphetamine (1 mg/kg) groups from the CPP test were used for western blot analysis ( n = 5–7). Samples of all the mice were taken 24 h after the last drug or saline treatment, and NAc core and shell were taken for the western blot.…”

“…Microdialysis was performed to confirm the neurochemical changes in neurotransmitters and their metabolites in the rat NAc shell after 25D-NBOMe treatment ( n = 3–5 per group) according to previous studies. , …”

“…As described in the previous study, food training was performed after a week of acclimation to facilitate the acquisition of operant responding. 46 Before beginning food training, the rats were deprived of food for 12 h and then trained to press a lever to obtain 45 mg of food pellets (Bio-Serv, Frenchtown, NJ, USA) in standard operant chambers connected to a food pellet dispenser until the desired criteria were satisfied (80 food pellets over 3 consecutive days) in 1 h daily sessions.…”