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

Converging evidence suggests that the endocannabinoid system is an important constituent of neuronal substrates involved in brain reward processes and emotional responses to stress. Here, we evaluated motivational effects of intravenously administered anandamide, an endogenous ligand for cannabinoid CB1-receptors, in Sprague-Dawley rats, using a place-conditioning procedure in which drugs abused by humans generally produce conditioned place preferences (reward). Anandamide (0.03-3 mg/kg intravenous) produced neither conditioned place preferences nor aversions. However, when rats were pre-treated with the fatty acid amide hydrolase (FAAH) inhibitor URB597 (cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester; 0.3 mg/kg intraperitoneal), which blocks anandamide's metabolic degradation, anandamide produced dose-related conditioned place aversions. In contrast, URB597 alone showed no motivational effects. Like URB597 plus anandamide, the synthetic CB1-receptor ligand WIN 55,212-2 (50-300 microg/kg, intravenous) produced dose-related conditioned place aversions. When anxiety-related effects of anandamide and URB597 were evaluated in a light/dark box, both a low anandamide dose (0.3 mg/kg) and URB597 (0.1 and 0.3 mg/kg) produced anxiolytic effects when given alone, but produced anxiogenic effects when combined. A higher dose of anandamide (3 mg/kg) produced anxiogenic effects and depressed locomotor activity when given alone and these effects were potentiated after URB597 treatment. Finally, anxiogenic effects of anandamide plus URB597 and development of place aversions with URB597 plus anandamide were prevented by the CB1-receptor antagonist AM251 (3 mg/kg intraperitoneal). Thus, additive interactions between the effects of anandamide on brain reward processes and on anxiety may account for its aversive effects when intravenously administered during FAAH inhibition with URB597.

Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of anandamide (a cannabinoid CB 1 -receptor ligand) and oleoylethanolamide and palmitoylethanolamide (OEA and PEA, ligands for a-type peroxisome proliferatoractivated nuclear receptors, PPAR-a) when and where they are naturally released in the brain. Using a passive-avoidance task in rats, we found that memory acquisition was enhanced by the FAAH inhibitor URB597 or by the PPAR-a agonist WY14643, and these enhancements were blocked by the PPAR-a antagonist MK886. These findings demonstrate novel mechanisms for memory enhancement by activation of PPAR-a, either directly by administering a PPAR-a agonist or indirectly by administering a FAAH inhibitor.Peroxisome proliferator-activated receptor-a (PPAR-a) is a ligandactivated transcriptional factor that regulates the expression of genes involved in lipid utilization, fatty acid oxidation, and inflammation (van Raalte et al. 2004;LoVerme et al. 2006). Immunolocalization studies of PPAR-a in the adult rat brain suggest that this nuclear receptor might have specific functions in regulating expression of genes involved in cholinergic neurotransmission and learning and memory processes (Moreno et al. 2004;Cimini et al. 2005). For example, there are high concentrations of PPAR-a receptors in the hippocampus and amygdala (Moreno et al. 2004). However, the potential involvement of PPAR-a in learning and memory processes has not been systematically investigated.Endogenous ligands for PPAR-a include the lipid mediators N-oleoylethanolamide (OEA) and N-palmitoylethanolamide (PEA). In addition, anandamide (N-arachidonoylethanolamine), which has primarily been studied as an endogenous ligand for G-proteincoupled cannabinoid CB 1 receptors that mediate the behavioral effects of cannabis and its active constituent D 9-tetrahydrocannabinol (THC) (Devane et al. 1992;Solinas et al. 2008), has recently begun to receive attention as a potential endogenous PPAR-a ligand (O'Sullivan 2000;Mackie and Stella 2006;Sun et al. 2007). OEA has primarily been studied as a satiety factor (Rodriguez de Fonseca et al. 2001;Fu et al. 2003) and PEA as an anti-inflammatory factor (Kuehl et al. 1957;Calignano et al. 1998;Jaggar et al. 1998). OEA and PEA are structurally similar to anandamide but do not bind to or activate cannabinoid CB 1 receptors. Anandamide, OEA, and PEA are all inactivated primarily by the intracellular serine enzyme, fatty acid amide hydrolase (FAAH) (Cravatt and Lichtman 2002;Fegley et al. 2005). Consequently, selective FAAH-inhibiting drugs such as cyclohexyl carbamic acid 39-carbamoyl-3-yl ester (URB597) increase endogenous levels of anandamide, OEA, and PEA in the brain (Fegley et al. 2005;Piomelli et al. 2006).In the present experiments, the effects of FAAH inhibition on learning and memory processes and the involvement of cannabinoid CB 1 receptors and PPAR-a nuclear receptors in those effects were studied using a passive-avoidance procedure in rats. FAAH inhibition was accomplished by administering U...

Rationale-Endocannabinoids are involved in a variety of behavioral and physiological processes that are just beginning to be understood. In the 5-choice serial reaction-time task, exogenous cannabinoids have been found to alter attention, but endocannabinoids such as anandamide have not been studied.Objectives-We used this task to evaluate the effects of anandamide in rats. Since anandamide is a ligand for not only cannabinoid receptors, but also transient receptor potential vanilloid 1 (TRPV1) receptors, and as recently suggested, peroxisome proliferator-activated nuclear receptor-α (PPARα), we also determined whether anandamide's effects in this task were mediated by each of these receptors.Methods-Whenever one of five holes was illuminated for 2 s, a food pellet was delivered if a response occurred in that hole during the light or within 2 s after the light.Results-Anandamide increased omission errors and decreased responding during inter-trial intervals. These effects were blocked by the TRPV1 antagonist capsazepine, but not by the cannabinoid-receptor antagonist rimonabant or the PPARα antagonist MK886. Testing with openfield activity and food consumption procedures in the same rats suggested that the disruption of operant responding observed in the attention task was not due to motor depression, anxiety, decreased appetite, or an inability to find and consume food pellets.Conclusions-The vanilloid-dependent behavioral disruption induced by anandamide was specific to the operant attention task. These effects of anandamide resemble effects of systemicallyCorresponding author: Steven R. Goldberg, Preclinical Pharmacology Section, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Biomedical Research Center 05A711, 251 Bayview Blvd., Baltimore, MD, 21224, USA. E-mail: E-mail: sgoldber@mail.nih.gov. NIH Public AccessAuthor Manuscript Psychopharmacology (Berl). Author manuscript; available in PMC 2010 April 1. Published in final edited form as:Psychopharmacology (Berl Anandamide is an endogenous neurotransmitter that has primarily been studied as an endocannabinoid acting at the CB 1 cannabinoid receptor (Devane et al. 1992;Palmer et al. 2002). However, anandamide is also a ligand for the transient receptor potential vanilloid 1 (TRPV1) receptor (Starowicz et al. 2007;Zygmunt et al. 1999) and has recently been reported to be a ligand for the peroxisome proliferator-activated receptor-α (PPARα; O'Sullivan 2007; Sun et al. 2006). The contributions of these cannabinoid and non-cannabinoid receptors to the behavioral effects of anandamide are just beginning to be studied. It has been shown that exogenous CB 1 -receptor agonists can impair attention under certain conditions (Arguello and Jentsch 2004;Verrico et al. 2004), but the effects of anandamide on attention have not been studied. Therefore, in the present study we used a five-choice serial reaction-time task (5-CSRTT; Robbins 2002) to investigate the attentional effects of anandamide in rats. After...

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