AM404 attenuates reinstatement of nicotine seeking induced by nicotine-associated cues and nicotine priming but does not affect nicotine- and food-taking

Abstract

Multiple studies suggest a pivotal role of the endocannabinoid system in the regulation of the reinforcing effects of various substances of abuse. Different approaches have been used to modulate endocannabinoid neurotransmission including the use of endogenous cannabinoid anandamide reuptake inhibitors. Previously, the effects of one of them, N-(4-hydroxyphenyl)-arachidonamide (AM404), have been explored in rodents trained to self-administer ethanol and heroin, producing some promising results. Moreover, AM404 attenuated the development and reinstatement of nicotine-induced conditioned place preference (CPP). In this study, we used the nicotine intravenous self-administration procedure to assess the effects of intraperitoneal administration of 0, 1, 3 and 10 mg/kg AM404 on nicotine-taking and food-taking behaviors under fixed-ratio and progressive-ratio schedules of reinforcement, as well as on reinstatement of nicotine-seeking induced by nicotine priming and by presentation of nicotine-associated cues. The ability of AM404 to produce place preference was also evaluated. AM404 did not produce CPP and did not modify nicotine-taking and food-taking behaviors. In contrast, AM404 dose-dependently attenuated reinstatement of nicotine-seeking behavior induced by both nicotine-associated cues and nicotine priming. Our results indicate that AM404 could be a potential promising therapeutic option for the prevention of relapse to nicotine-seeking in abstinent smokers.

Dissociating the role of endocannabinoids in the pleasurable and motivational properties of social play behaviour in rats

“…These findings are in line with previous studies showing that treatment with URB597 does not affect responding for food (Adamcyk et al, 2009; Kangas et al, 2016; Oleson et al, 2012), nicotine (Forget et al, 2009; Scherma et al, 2008), heroin (Solinas et al, 2005), anandamide, THC and cocaine (Adamcyk et al, 2009; Justinova et al, 2008) in rats and non-human primates. Similarly, inhibiting the reuptake of anandamide with AM404 had no effect on responding for food in rats (Gamaleddin et al, 2013). Together, these data show that increasing anandamide tone through inhibition of its degradation or reuptake does not profoundly alter the incentive motivational properties of rewards.…”

Acute and chronic modulation of striatal endocannabinoid‐mediated plasticity by nicotine

“…Associations between behavioral responses to nicotine and the eCB system have previously been shown with respect to reward, conditioning and drug reinstatement (Castane et al 2002;Cohen et al 2002;Merritt et al 2008;Gamaleddin et al 2013). Inhibition of eCB signaling attenuates nicotine-induced activation of the mesolimbic dopamine system, reduces self-administration and inhibits acquisition and expression of nicotineinduced place preference (Castane et al 2002;Cohen et al 2002;Cheer et al 2007;Hadjiconstantinou & Neff 2011).…”

“…Inhibition of eCB signaling attenuates nicotine-induced activation of the mesolimbic dopamine system, reduces self-administration and inhibits acquisition and expression of nicotineinduced place preference (Castane et al 2002;Cohen et al 2002;Cheer et al 2007;Hadjiconstantinou & Neff 2011). On the opposite, activation of CB1Rs or inhibition of eCB metabolism enhances nicotine self-administration and expression of nicotine-induced place preference (Merritt et al 2008;Gamaleddin et al 2013). Interestingly, eCB levels are altered by acute and repeated nicotine exposure (Gonzalez et al 2002;Buczynski, Polis, & Parsons 2013), and the endogenous ligand for the nicotinic acetylcholine receptor (nAChR), acetylcholine, appears to regulate eCB-mediated plasticity in the striatum (eCB-LTD) (Partridge et al 2002;Adermark 2011).…”

Cannabinoid-Nicotine Interactions

“…These findings suggest that anandamide might counteract the addictive effect of nicotine. However, inhibition of anandamide uptake failed to reduce nicotine taking behavior in rats trained to self-administer nicotine under fixed-ratio or progressive-ratio schedules [137,138].…”

“…In reinstatement models of relapse in rats, anandamide uptake inhibitors dosedependently reduced nicotine seeking induced by nicotine-conditioned stimuli or by nicotine priming, [137,138] (see Table 13.3). Moreover, AM404 prevented the development of nicotine-induced CPP and impeded nicotine-induced reinstatement of extinguished CPP [74].…”