Effects of acute and repeated dosing of the synthetic cannabinoid CP55,940 on intracranial self-stimulation in mice

Abstract

Background Synthetic cannabinoids have emerged as a significant public health concern. To increase the knowledge of how these molecules interact on brain reward processes, we investigated the effects of CP55,940, a high efficacy synthetic CB1 receptor agonist, in a frequency-rate intracranial self-stimulation (ICSS) procedure. Methods The impact of acute and repeated administration (seven days) of CP55,940 on operant responding for electrical brain stimulation of the medial forebrain bundle was investigated in C57BL/6J mice. Results CP55,940 attenuated ICSS in a dose-related fashion (ED50 (95% C.L.) = 0.15 (0.12–0.18) mg/kg). This effect was blocked by the CB1 receptor antagonist rimonabant. Tolerance developed quickly, though not completely, to the rate-decreasing effects of CP55,940 (0.3 mg/kg). Abrupt discontinuation of drug did not alter baseline responding for up to seven days. Moreover, rimonabant (10 mg/kg) challenge did not alter ICSS responding in mice treated repeatedly with CP55,940. Conclusions The finding that CP55,940 reduced ICSS in mice with no evidence of facilitation at any dose is consistent with synthetic cannabinoid effects on ICSS in rats. CP55,940-induced ICSS depression was mediated through a CB1 receptor mechanism. Additionally, tolerance and dependence following repeated CP55,940 administration were dissociable. Thus, CP55,940 does not produce reward-like effects in ICSS under these conditions.

Antinociceptive and Abuse Potential Effects of Cannabinoid/Opioid Combinations in a Chronic Pain Model in Rats

“…The current study showed that CP55940 produced dose-dependent depression of ICSS in rats. Similar results have been previously reported in mice and rats [44,45]. In addition, other CB1 agonists produced similar effects in ICSS such as Δ9-tetrahydrocannabinol and WIN55,212-2 ((R)-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate) [31,46].…”

Effects of repeated treatment with methcathinone, mephedrone, and fenfluramine on intracranial self-stimulation in rats

“…with mu opioid receptor agonists like morphine (Legakis and Negus 2018;Miller et al 2015a;Reid 1987;Wiebelhaus et al 2016) or high nicotine doses (Freitas et al 2016)], (2) tolerance to ICSS depression without emergence of ICSS facilitation [e.g. with cannabinoid receptor agonists like Δ9-tetrahydrocannabinol (Grim et al 2015;Kwilasz and Negus 2012), the N-methyl-Daspartate glutamate receptor antagonist ketamine (Hillhouse et al 2014), and the delta opioid receptor agonist SNC80 (Negus et al 2012)], or (3) sustained ICSS depression [e.g. with the kappa agonist salvinorin A (Potter et al 2011), the dopamine D2 agonist quinpirole (Negus et al 2012), and the serotonin 5HT1A/2A receptor agonist flibanserin (Lazenka et al 2016)].…”

Neuropharmacology of New Psychoactive Substances (NPS): Focus on the Rewarding and Reinforcing Properties of Cannabimimetics and Amphetamine-Like Stimulants

“…Differences in developing tolerance to depression of ICSS after repeated exposure to cannabinoids have been reported. Tolerance is completely developed after repeated exposure to Δ 9 -THC (Kwilasz and Negus, 2012 ) but partially developed after CP55940 (Grim et al, 2015 ), and not developed after WIN55212-2 administration (Mavrikaki et al, 2010 ), suggesting that the different affinity of Δ 9 -THC vs. SC for the CB1 receptors could play a role in developing this tolerance (Grim et al, 2015 ).…”