Endocannabinoid System Modulates Relapse to Methamphetamine Seeking: Possible Mediation by the Arachidonic Acid Cascade

Abstract

We clarified the modulating action of the endocannabinoid system, and its possible mediation by the arachidonic acid cascade, on the reinstatement of methamphetamine (METH)-seeking behavior, using the intravenous self-administration paradigm in rats. Following 12 days of self-administration of METH, the replacement of METH with saline resulted in a gradual decrease in lever press responses (extinction). Under extinction conditions, METH-priming or re-exposure to cues previously paired with METH infusion markedly increased the responses (reinstatement of drug-seeking). The cannabinoid CB1 receptor antagonist, SR141716A, blocked this behavior. Although the cannabinoid agonist, D 8 -tetrahydrocannabinol (THC), had no effects by itself, coadministration of the agonist and METH at small doses reinstated the drug-seeking behavior. THC attenuated the effects of the reinstatement-inducing dose of METH, but enhanced the effect of cues. Either given repeatedly during the extinction or singly, 24 h before the first METH-priming or cues challenge, THC suppressed the reinstatement. In another set of experiments, we found that diclofenac, a cyclooxygenase inhibitor, also attenuated the reinstatement induced by exposure to cues or drug-priming. These results suggest that the endocannabinoid system, through possible mediation by the arachidonic acid cascade, serves as a modulator of the reinstating effects of METH-priming and cues. Extending the current view on the treatment of drug dependence, these results indicate that endocannabinoid-activating substances as well as cyclooxygenase inhibitors may be promising as antirelapse agents.

The effects of varenicline on methamphetamine self-administration and drug-primed reinstatement in male rats

“…Indeed, varenicline has been shown to partially substitute for the discriminative-stimulus effects of meth (Desai & Bergman, 2014). Additionally, the level of responding evoked by meth in a reinstatement test is sensitive to the dose (Anggadiradja et al, 2004; Reichel et al, 2012). The finding that 3.0 mg/kg varenicline had no effect may reflect a summative meth-like dose (i.e., varenicline + meth) that is on the descending portion of the meth-prime reinstatement curve.…”

Extended methamphetamine self-administration enhances reinstatement of drug seeking and impairs novel object recognition in rats

“…administration (0.02 mg/50 μl bolus). We selected this dose based on previous studies of methamphetamine self-administration in rats (Anggadiredja et al 2004a;Roth and Carroll 2004a). During daily sessions, a response on the active lever resulted in a 2-s infusion, followed by a 20-s time-out period to prevent overdose.…”

Effect of Cannabinoid CB1 Receptor Antagonist SR141714A and CB1 Receptor Knockout on Cue-Induced Reinstatement of Ensure® and Corn-Oil Seeking in Mice

“…SR141716A also significantly attenuated relapse to cigarette smoking compared to placebo (STRATUS-US trial; Anthenelli and Despres, 2004). Furthermore, SR141716A is effective in reducing cue-induced reinstatement of cocaine (De Vries et al, 2001), heroin (De Vries et al, 2003), methamphetamine (Anggadiredja et al, 2004), nicotine , ethanol (Economidou et al, 2006), and sucrose Economidou et al, 2006) seeking behavior in rats.…”