The effects of fatty acid amide hydrolase inhibitors on maintenance of cocaine and food self-administration and on reinstatement of cocaine-seeking and food-taking behavior in rats.

Some empirical evidence suggests that the endocannabinoids (eCB) (e.g. anandamide) may play an important role in cocaine addiction. The eCB act as a retrograde messengers activating CB receptors at the presynaptic membrane and are degraded by enzymatic actions of fatty acid amide hydrolase (FAAH). The present study aimed to examine the effect of the FAAH inhibitors, phenylmethylsulphonyl fluoride (PMSF; i.p.) or cyclohexylcarbamic acid 3-carbamoyl biphenyl-3-yl ester (URB597; i.p.) on the cocaine- or food-maintained self-administration as well as on the cocaine-seeking or food-taking behaviors in rats. Male Wistar rats were implanted with a catheter (iv.) and trained to self-administer cocaine (0.5 mg/kg/infusion) on a fixed ratio 5 schedule of reinforcement with a conditioned stimulus (tone+light). After self-administration stabilized, extinction/reinstatement procedures were carried out during which the rats were tested for the response reinstatement induced by cocaine (10 mg/kg, ip) or a cue (light+tone). The food (sweetened milk) self-administration and extinction/reinstatement procedures were conducted in a manner resembling cocaine self-administration. Neither PMSF (30-120 mg/kg) nor URB597 (0.1-3 mg/kg) affected cocaine self-administration. PMSF, 60 mg/kg, significantly reduced cocaine-induced reinstatement and at 120 mg/kg (combined with the challenge dose of cocaine) it evoked behavioral disruption. PMSF (60-120 mg/kg) dose-dependently inhibited cue-induced reinstatement. URB597 (1-3 mg/kg) attenuated both cocaine- and cue-induced drug-seeking behaviors. PMSF (60 mg/kg) decreased food self-administration. Toward reinstatement of food-taking behavior PMSF (60-120 mg/kg) and URB597 (3 mg/kg) showed inhibitory effects. Our results indicate that FAAH inhibitors could be potent modulators of motivational and conditioned aspects of goal-directed behaviors with less prominent effects on consumatory behaviors.