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. 2015 Aug;40(9):2185-97.
doi: 10.1038/npp.2015.62. Epub 2015 Mar 10.

Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse

Zuzana Justinova  1 , Leigh V Panlilio  1 , Guillermo Moreno-Sanz  2 , Godfrey H Redhi  1 , Alessia Auber  1 , Maria E Secci  1 , Paola Mascia  1 , Tiziano Bandiera  3 , Andrea Armirotti  3 , Rosalia Bertorelli  3 , Svetlana I Chefer  4 , Chanel Barnes  1 , Sevil Yasar  5 , Daniele Piomelli  6 , Steven R Goldberg  1
Affiliations

Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse

Zuzana Justinova et al. Neuropsychopharmacology. 2015 Aug.

Abstract

Inhibition of the enzyme fatty acid amide hydrolase (FAAH) counteracts reward-related effects of nicotine in rats, but it has not been tested for this purpose in non-human primates. Therefore, we studied the effects of the first- and second-generation O-arylcarbamate-based FAAH inhibitors, URB597 (cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester) and URB694 (6-hydroxy-[1,1'-biphenyl]-3-yl-cyclohexylcarbamate), in squirrel monkeys. Both FAAH inhibitors: (1) blocked FAAH activity in brain and liver, increasing levels of endogenous ligands for cannabinoid and α-type peroxisome proliferator-activated (PPAR-α) receptors; (2) shifted nicotine self-administration dose-response functions in a manner consistent with reduced nicotine reward; (3) blocked reinstatement of nicotine seeking induced by reexposure to either nicotine priming or nicotine-associated cues; and (4) had no effect on cocaine or food self-administration. The effects of FAAH inhibition on nicotine self-administration and nicotine priming-induced reinstatement were reversed by the PPAR-α antagonist, MK886. Unlike URB597, which was not self-administered by monkeys in an earlier study, URB694 was self-administered at a moderate rate. URB694 self-administration was blocked by pretreatment with an antagonist for either PPAR-α (MK886) or cannabinoid CB1 receptors (rimonabant). In additional experiments in rats, URB694 was devoid of THC-like or nicotine-like interoceptive effects under drug-discrimination procedures, and neither of the FAAH inhibitors induced dopamine release in the nucleus accumbens shell--consistent with their lack of robust reinforcing effects in monkeys. Overall, both URB597 and URB694 show promise for the initialization and maintenance of smoking cessation because of their ability to block the rewarding effects of nicotine and prevent nicotine priming-induced and cue-induced reinstatement.

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Figures

Figure 1
Figure 1
Effect of URB597 or URB694 administration on FAAH activity and levels of FAEs in the brain of monkeys. (a, b) Inhibition of brain (a, cerebellum) and liver (b) FAAH activity 1 h after URB597, URB694 (both 1 mg/kg), or vehicle IV administration. (c–f) Midbrain concentrations of anandamide (c; AEA), 2-arachidonoylglycerol (d; 2-AG), PEA (e), and OEA (f) 1 h after vehicle, URB597, or URB694 (both 1 mg/kg) IV administration. Results are expressed as means±SEM (n=4–6). ***P<0.001 post hoc comparisons with vehicle (VEH) conditions, Tukey’s test.
Figure 2
Figure 2
Effect of URB597 or URB694 on nicotine self-administration in squirrel monkeys under a fixed-ratio 10 (FR10) schedule. (a–f) Pretreatment with URB597 or URB694 (both 1 mg/kg IV, 30 min before the session) caused significant (all p’s <0.01) rightward shifts of the nicotine dose–response curves compared with vehicle (V) pretreatment. Number of nicotine injections per 1-h session (a, d), overall response rates in the presence of the green light signaling nicotine availability (b, e), and total nicotine intake per session (c, f) are shown as a function of the nicotine dose (abscissae log scale). Each data point represents the mean±SEM of the last three sessions under each nicotine condition and under vehicle conditions (n=4). *P<0.05, **p<0.01, post hoc comparisons of the effects of pretreatment with URBs vs vehicle treatment within each nicotine dose, Tukey’s test.
Figure 3
Figure 3
Effect of different doses of URB597 or URB694 on self-administration of peak nicotine dose and reversal of these effects by PPAR-α antagonist MK886. (a, b) The 5-day treatment with URB597 (a; 0.1–1.0 mg/kg IV) or URB694 (b; 0.03–1.0 mg/kg IV) significantly decreased the number of 30 μg/kg injections of nicotine self-administered during 1 h sessions by squirrel monkeys under a fixed-ratio 10 (FR10) schedule (sessions 4–8) compared with vehicle treatment (sessions 1–3 and 9–11). (c, d) The blockade of nicotine self-administration by URB597 (c, 1 mg/kg) or URB694 (d; 1 mg/kg) was significantly reversed by MK866 (0.3 or 1 mg/kg IM, 45 min before the session). Number of nicotine injections per 1 h session is shown over consecutive sessions. Each data point represents the mean±SEM (n=3–4). *P<0.05, **p<0.01, post hoc vs the mean of the last three sessions with vehicle pretreatment (sessions 1–3), Bonferroni test.
Figure 4
Figure 4
Effect of URB597 or URB694 on relapse to nicotine seeking in abstinent squirrel monkeys. (a, b) During extinction, vehicle was substituted for nicotine. Treatment with URB597 (a) or URB694 (b; both 1 mg/kg IV, 30 min before the session) blocked the reinstatement of extinguished nicotine-seeking responses produced by a nicotine-priming injection (0.1 mg/kg IV, immediately before the session), and this effect was prevented by pretreatment with MK886 (1 mg/kg IM, 45 min before the session). **P<0.01, post hoc vs ‘vehicles+vehicle priming’ ##p<0.01, post hoc vs ‘vehicles+nicotine priming’, $$p<0.01, post hoc vs ‘URB 1+nicotine priming’, Tukey’s test. (c, d) During extinction, injection-paired visual cues and response-contingent IV nicotine injections were removed. Treatment (the same as in a and b) with URB597 (c) or URB694 (d) blocked the reinstatement of extinguished nicotine-seeking responses induced by reintroduction of visual cues and IV saline injections. The effect of URB694, but not URB597, was partially reversed by pretreatment with MK886. *P<0.05, **p<0.01, post hoc vs ‘vehicles+no cues’ ##p<0.01, post hoc vs ‘vehicles+cues’, $$p<0.01, post hoc vs ‘URB 1+cues’, Tukey’s test. Total numbers of lever presses produced per 1 h session are shown (a–d). Each bar represents mean±SEM (n=4). ‘0 mg/kg’ represents vehicle in all panels.
Figure 5
Figure 5
Self-administration of URB694 under FR10 schedule in anandamide-experienced squirrel monkeys. (a–c) Effects of varying injection doses on self-administration of URB694. Number of URB694 injections per 1 h session (a), overall rates of responding in the presence of the green light signaling drug availability (b), and total URB694 intake per session (c) are shown as a function of injection dose (abscissae log scale). The baseline responding for 30 μg/kg injections of anandamide is also shown. Each point represents the mean±SEM (n=4) of the last three sessions under each dose condition and under a vehicle (V) condition. *P<0.05; **p<0.01, post hoc vs the vehicle condition, Bonferroni test. (d, e) Acquisition of URB694 self-administration. Number of injections per session (d) and overall rates of responding (e) during anandamide (30 μg/kg/injection) self-administration (sessions 1–5), vehicle extinction (sessions 6–10), and URB694 (1 μg/kg/injection) self-administration (sessions 11–15) are shown. Points represent means±SEM (n=4). *P<0.05, **p<0.01, post hoc vs the mean of the last three sessions of anandamide self-administration (sessions 3–5); #p<0.05, ##p<0.01, post hoc vs the mean of the last three sessions of vehicle extinction (sessions 8–10), Bonferroni test. (f, g) Blockade of URB694 self-administration by pretreatment with rimonabant or MK886. Number of injections per session (f) and overall rates of responding (g) during URB694 (1 μg/kg/injection) self-administration are shown after IM pretreatment with vehicles (sessions 1–3 and 9–11), 1 mg/kg of rimonabant, or 1 mg/kg of MK886 (both sessions 4–8). Points represent means±SEM (n=4). *P<0.05, **p<0.01, post hoc vs the mean of the last three sessions of vehicle pretreatment (sessions 1–3), Bonferroni test.
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