Inhibition of Anandamide Hydrolysis by Cyclohexyl Carbamic Acid 3′-Carbamoyl-3-yl Ester (URB597) Reverses Abuse-Related Behavioral and Neurochemical Effects of Nicotine in Rats

Abstract

Emerging evidence suggests that the rewarding, abuse-related effects of nicotine are modulated by the endocannabinoid system of the brain. For example, pharmacological blockade or genetic deletion of cannabinoid CB 1 receptors can reduce or eliminate many abuse-related behavioral and neurochemical effects of nicotine. Furthermore, doses of ⌬ 9 -tetrahydrocannabinol and nicotine that are ineffective when given alone can induce conditioned place preference when given together. These previous studies have used systemically administered CB 1 receptor agonists and antagonists and gene deletion techniques, which affect cannabinoid CB 1 receptors throughout the brain. A more functionally selective way to alter endocannabinoid activity is to inhibit fatty acid amide hydrolase (FAAH), thereby magnifying and prolonging the effects of the endocannabinoid anandamide only when and where it is synthesized and released on demand. Here, we combined behavioral and neurochemical approaches to evaluate whether the FAAH inhibitor URB597 (cyclohexyl carbamic acid 3Ј-carbamoyl-3-yl ester) could alter the abuse-related effects of nicotine in rats. We found that URB597, at a dose (0.3 mg/kg) that had no behavioral effects by itself, prevented development of nicotine-induced conditioned place preference (CPP) and acquisition of nicotine self-administration. URB597 also reduced nicotine-induced reinstatement in both CPP and self-administration models of relapse. Furthermore, in vivo microdialysis showed that URB597 reduced nicotine-induced dopamine elevations in the nucleus accumbens shell, the terminal area of the brain's mesolimbic reward system. These findings suggest that FAAH inhibition can counteract the addictive properties of nicotine and that FAAH may serve as a new target for development of medications for treatment of tobacco dependence.Nicotine, the main psychoactive component of tobacco, plays a major role in tobacco dependence by acting directly as a reinforcer of drug-seeking and drug-taking behavior (Le Foll and Goldberg, 2006). In rats, nicotine can reinforce drug self-administration behavior (Corrigall and Coen, 1989) and induce conditioned place preference (CPP) (Le Foll and Goldberg, 2005), and it can trigger relapse to previously acquired drug-seeking behavior (Shaham et al., 1997). Nicotine's rewarding effects are believed to stem from its ability to activate the mesolimbic dopaminergic system by enhancing firing rate and burst firing of dopaminergic neurons in the ventral tegmental area (VTA) (Mereu et al., 1987) and increasing dopamine release in terminal areas, especially in the nucleus accumbens shell (Pontieri et al., 1996).Recent findings suggest that behavioral and motivational

Hub and switches: endocannabinoid signalling in midbrain dopamine neurons

“…Whether the phosphorylation leads to a reduced ion influx into the DA cell or to fewer nAChRs expressed on the surface of DA cell membranes, the outcome appears as a diminished/abolished response of VTA DA neurons to nicotine, as well as to endogenous acetylcholine [42]. This scenario would provide a plausible cellular mechanism for the lack of effect of nicotine in increasing extracellular DA levels in the shell of the NAcc following URB597 treatment [40]. Accordingly, synthetic PPARa ligands, such as lipid lowering fibrates, prevent nicotine-induced excitation of DA cells and increases of extracellular DA levels in the NAcc shell [73].…”

“…However, because DA neurons might be sensitized to priming with drugs or with drug-associated cues, and might trigger reinstatement, one possibility is that potentiation of endocannabinoid signalling (rather than an indiscriminate activation of CB1 receptors by exogenous agonists) might blunt their stimulus-driven responses by selectively suppressing glutamate release from impinging excitatory axons. Accordingly, cue-induced reinstatement to nicotine self-administration is particularly sensitive to blockade by both FAAH inhibition, AM404 and VDM11 [40,107,108]. In regards to this, it must be pointed out that inhibition of FAAH enhances NAE levels that could depress responses to nicotine via modulation of nAChRs (see above).…”

“…Nonetheless, previous anatomical, biochemical and electrophysiological studies have provided compelling evidence that the N-acylethanolamine anandamide and the endogenous ligands to peroxisome-proliferatoractivated receptor-alpha (PPARa; i.e. oleoylethanolamide, OEA; palmitoylethanolamide, PEA), as well as the endocannabinoid/vanilloid N-arachidonoyldopamine (NADA) are also present within the VTA [31,34,[38][39][40][41][42][43], thus suggesting discrete physiological roles for each endocannabinoid and cognate molecule in the modulation of DA neuron and its related behaviour.…”

The Volitional Nature of Nicotine Exposure Alters Anandamide and Oleoylethanolamide Levels in the Ventral Tegmental Area

“…For example, although synthetic CB 1 agonists increase nicotine SA and enhance nicotine-seeking behavior (Gamaleddin et al, 2012), these nicotine-related behaviors are generally attenuated by enhancing endogenous eCB tone (eg, eCB clearance inhibition) (Forget et al, 2009;Gamaleddin et al, 2011;Scherma et al, 2008). The distinction between these influences may arise, in part, from differential regional patterns of CB1 activation.…”

“…Moreover, in contrast to CB 1 -selective agonists, manipulations such as FAAH inhibition also enhance signaling through non-CB receptors (PPAR a , TRPV 1 , and so on) that may counter or modify the effects of concurrent CB 1 receptor signaling. Because the nature of nicotine-induced alterations in eCB signaling may differ at various stages of nicotine exposure (eg, acquisition vs maintenance of drug intake; dependence), and nicotineinduced eCB alterations may differ from eCB disruptions associated with nicotine-seeking behavior (induced by cues, drug priming, and/or stress), it is not surprising that the influence of eCB clearance inhibition on nicotine-related behaviors varies among these distinct phases of nicotine use (Forget et al, 2009;Scherma et al, 2008).…”