The role of fatty acid amide hydrolase inhibition in nicotine reward and dependence

Abstract

The endogenous cannabinoid anandamide (AEA) exerts the majority of its effects at CB1 and CB2 receptors and is degraded by fatty acid amide hydrolase (FAAH). FAAH KO mice and animals treated with FAAH inhibitors are impaired in their ability to hydrolyze AEA and other non-cannabinoid lipid signaling molecules, such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). AEA and these other substrates activate non-cannabinoid receptor systems, including TRPV1 and PPAR-α receptors. In this mini review, we describe the functional consequences of FAAH inhibition on nicotine reward and dependence as well as the underlying endocannabinoid and non-cannabinoid receptor systems mediating these effects. Interestingly, FAAH inhibition seems to mediate nicotine dependence differently in mice and rats. Indeed, pharmacological and genetic FAAH disruption in mice enhances nicotine reward and withdrawal. However, in rats, pharmacological blockade of FAAH significantly inhibits nicotine reward and has no effect in nicotine withdrawal. Studies suggest that non-cannabinoid mechanisms may play a role in these species differences.

Figure 1

PF-3845 enhances nicotine CPP in mice. Pretreatment with the FAAH enzyme inhibitor PF-3845 (10mg/kg i.p.) or vehicle, given 2 h before an inactive dose of nicotine (0.1mg/kg s.c.) significantly enhances nicotine preference. *p<0.05 vs all treatment groups. Data are expressed as means ± SEM of 6–8mice. See Merritt et al. (2008) for nicotine CPP methods.

Figure 2

WY14643 blocks nicotine CPP in mice. Pretreatment with the PPAR-α agonists WY14643 (1mg/kg i.p.) or vehicle, given 15 min before an active dose of nicotine (0.5mg/kg s.c.) significantly blocks nicotine preference. *p<0.05 vs all treatment groups. Data are expressed as means ± SEM of 6–8mice. See Merritt et al. (2008) for nicotine CPP methods.