Maria Scherma

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.

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 CB1 receptors can reduce or eliminate many abuse-related behavioral and neurochemical effects of nicotine. Furthermore, doses of Δ9-tetrahydrocannabinol and nicotine that are ineffective when given alone can induce conditioned place preference when given together. These previous studies have used systemically administered CB1 receptor agonists and antagonists and gene deletion techniques, which affect cannabinoid CB1 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 3′-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 brains 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.

Endocannabinoid system and opioid addiction: Behavioural aspects

Cannabinoids produce a variety of pharmacological effects very similar to those elicited by opioids. Direct and indirect interactions with opioid system have been proposed to explain some cannabinoid effects such as analgesia and attenuation of opioid-withdrawal syndrome, and evidence has been provided in support to the notion that rewarding properties of cannabinoids and opioids might be functionally linked. In particular, a growing body of studies points to an important role of the endogenous cannabinoid system in the modulation of opioid rewarding and addictive effects. The current review examines progresses in the past few years in the elucidation of cannabinoid-opioid interactions in drug abuse and dependence, focusing on recent findings from behavioural studies using different animal models of addiction. Specifically, here we review data on the behavioural aspects (i.e., drug abuse, dependence, tolerance, sensitization, relapse and drug vulnerability) of the specific, often reciprocal, cross-talk between cannabinoids and opioids with particular reference to the role of the endocannabinoid system in opioid addiction. The potential biochemical mechanisms involved in these pharmacological interactions are discussed together with possible therapeutic implications in the pharmacotherapy of opioid dependence. However, individuation of the precise anatomical substrates and molecular mechanisms of such interaction still remains a complex and challenging field for future research.

Blockade of Nicotine Reward and Reinstatement by Activation of Alpha-Type Peroxisome Proliferator-Activated Receptors

BACKGROUND Recent findings indicate that inhibitors of fatty acid amide hydrolase (FAAH) counteract the rewarding effects of nicotine in rats. Inhibition of FAAH increases levels of several endogenous substances in the brain, including the endocannabinoid anandamide and the noncannabinoid fatty acid ethanolamides oleoylethanolamide (OEA) and palmitoylethanolamide, which are ligands for alpha-type peroxisome proliferator-activated nuclear receptors (PPAR-α). Here, we evaluated whether directly acting PPAR-α agonists can modulate reward-related effects of nicotine. METHODS We combined behavioral, neurochemical, and electrophysiological approaches to evaluate effects of the PPAR-α agonists [[4-Chloro-6-[(2,3-dimethylphenyl)amino]-2-pyrimidinyl]thio]acetic acid (WY14643) and methyl oleoylethanolamide (methOEA; a long-lasting form of OEA) on 1) nicotine self-administration in rats and squirrel monkeys; 2) reinstatement of nicotine-seeking behavior in rats and monkeys; 3) nicotine discrimination in rats; 4) nicotine-induced electrophysiological activity of ventral tegmental area dopamine neurons in anesthetized rats; and 5) nicotine-induced elevation of dopamine levels in the nucleus accumbens shell of freely moving rats. RESULTS The PPAR-α agonists dose-dependently decreased nicotine self-administration and nicotine-induced reinstatement in rats and monkeys but did not alter food- or cocaine-reinforced operant behavior or the interoceptive effects of nicotine. The PPAR-α agonists also dose-dependently decreased nicotine-induced excitation of dopamine neurons in the ventral tegmental area and nicotine-induced elevations of dopamine levels in the nucleus accumbens shell of rats. The ability of WY14643 and methOEA to counteract the behavioral, electrophysiological, and neurochemical effects of nicotine was reversed by the PPAR-α antagonist 1-[(4-Chlorophenyl)methyl]-3-[(1,1-dimethylethyl)thio]-a,a-dimethyl-5-(1-methylethyl)-1H-Indole-2-propanoic acid (MK886). CONCLUSIONS These findings indicate that PPAR-α might provide a valuable new target for antismoking medications.

Nicotinic α7 Receptors as a New Target for Treatment of Cannabis Abuse

Increasing use of cannabis makes the search for medications to reduce cannabis abuse extremely important. Here, we show that homomeric α7 nicotinic receptors are novel molecular entities that could be targeted in the development of new drugs for the treatment of cannabis dependence. In rats, systemic administration of the selective α7 nicotinic acetylcholine receptor antagonist methyllycaconitine (MLA), but not the selective heteromeric non-α7 nicotinic acetylcholine receptor antagonist dihydrobetaerythroidine, (1) antagonized the discriminative effects of δ-9-tetrahydrocannabinol (THC), the main active ingredient in cannabis, (2) reduced intravenous self-administration of the synthetic cannabinoid CB1 receptor agonist WIN55,212-2 [(R)-(+)-[2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone, mesylate salt], and (3) decreased THC-induced dopamine elevations in the shell of the nucleus accumbens. Altogether, our results indicate that blockade of α7 nicotinic receptors reverses abuse-related behavioral and neurochemical effects of cannabinoids. Importantly, MLA reversed the effects of cannabinoids at doses that did not produce depressant or toxic effects, further pointing to α7 nicotinic antagonists as potentially useful agents in the treatment of cannabis abuse in humans.

Baclofen prevents drug-induced reinstatement of extinguished nicotine-seeking behaviour and nicotine place preference in rodents

The gamma-aminobutyric acid(GABA)-B receptor agonist baclofen is known to reduce drug intake in both animals and humans and to prevent reinstatement of cocaine-, opioid-, and alcohol-seeking in rats after a period of extinction, but its effect on nicotine reinstatement is unknown. This study investigated the effect of baclofen on nicotine-seeking reinstatement both using the extinction/reinstatement model of nicotine self-administration and conditioned place preference (CPP). Results showed that in rats previously trained to intravenously self-administer nicotine (30 microg/kg/inf) under a FR-1 schedule of reinforcement, acute nicotine (0.15 mg/kg) priming effectively reinstates nicotine-seeking behaviour following extinction. At doses used in this study (up to 2.5 mg/kg) baclofen alone did not affect locomotor activity and did not reinstate responding. However, baclofen dose-dependently attenuated drug-induced reinstatement of nicotine-seeking in rats. Moreover, baclofen (1.25 mg/kg) completely blocked nicotine-induced reinstatement of extinguished nicotine (0.3 mg/kg) CPP in mice. Altogether, our results showed that baclofen is able to antagonise reinstatement of nicotine-seeking and CPP triggered by nicotine primings, suggesting its potential clinical utility as an anti-relapse agent.

Reducing cannabinoid abuse and preventing relapse by enhancing endogenous brain levels of kynurenic acid

In the reward circuitry of the brain, α-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of Δ9-tetrahydrocannabinol (THC), marijuanas main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of α7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates cannabinoid-induced increases in extracellular dopamine in reward-related brain areas. In the self-administration model of drug abuse, Ro 61-8048 reduced the rewarding effects of THC and the synthetic cannabinoid WIN 55,212-2 in squirrel monkeys and rats, respectively, and it also prevented relapse to drug-seeking induced by reexposure to cannabinoids or cannabinoid-associated cues. The effects of enhancing endogenous KYNA levels with Ro 61-8048 were prevented by positive allosteric modulators of α7nAChRs. Despite a clear need, there are no medications approved for treatment of marijuana dependence. Modulation of KYNA offers a pharmacological strategy for achieving abstinence from marijuana and preventing relapse.

Nicotinic Facilitation of Δ9-Tetrahydrocannabinol Discrimination Involves Endogenous Anandamide

Systemic administration of the main active ingredient in cannabis, Δ9-tetrahydrocannabinol (THC), alters extracellular levels of acetylcholine in several brain areas, suggesting an involvement of the cholinergic system in the psychotropic effects of cannabis. Here, we investigated whether drugs acting at either nicotinic or muscarinic receptors can modulate the discriminative effects of THC. In rats that had learned to discriminate effects of 3 mg/kg i.p. injections of THC from injections of vehicle, the nicotinic agonist nicotine (0.1-0.56 mg/kg subcutaneous) and the muscarinic agonist pilocarpine (0.3-3 mg/kg i.p.) did not produce THC-like effects, but they both potentiated the discriminative effects of low doses of THC (0.3-1 mg/kg). Neither the nicotinic antagonist mecamylamine (1-5.6 mg/kg i.p.) nor the muscarinic antagonist scopolamine (0.01-0.1 mg/kg i.p.) altered the discriminative effects of THC, but they blocked the potentiation of discriminative effects of THC by nicotine and pilocarpine, respectively. The cannabinoid CB1 antagonist rimonabant (1 mg/kg i.p.) reversed nicotine- but not pilocarpine-induced potentiation of THC discrimination, suggesting that nicotine potentiation is, at least in part, mediated by release of endogenous cannabinoids in the brain. In addition, when metabolic degradation of the endogenous cannabinoid anandamide was blocked by the fatty acid amide hydrolase inhibitor cyclohexyl carbamic acid 3′-carbamoylbiphenil-3-yl-ester (URB-597; 0.3 mg/kg i.p.) nicotine, but not pilocarpine, produced significant THC-like discriminative effects that were antagonized by rimonabant. Our results suggest that nicotinic and muscarinic cholinergic receptors modulate the discriminative effects of THC by fundamentally different mechanisms. Nicotinic, but not muscarinic, modulation of THC discrimination involves elevations in endogenous levels of anandamide.

The endocannabinoid system: a new molecular target for the treatment of tobacco addiction

Tobacco addiction is one of the leading preventable causes of mortality in the world and nicotine appears to be the main critical psychoactive component in establishing and maintaining tobacco dependence. Several lines of evidence suggest that the rewarding effects of nicotine, which underlie its abuse potential, can be modulated by manipulating the endocannabinoid system. For example, pharmacological blockade or genetic deletion of cannabinoid CB(1) receptors reduces or eliminates many behavioral and neurochemical effects of nicotine that are related to its addictive potential. This review will focus on the recently published literature about the role of the endocannabinoid system in nicotine addiction and on the endocannabinoid system as a novel molecular target for the discovery of medications for tobacco dependence.

The role of the endocannabinoid system in eating disorders: neurochemical and behavioural preclinical evidence.

The endocannabinoid system has long been known as a modulator of several physiological functions, among which the homeostatic and hedonic aspects of eating. CB1 receptors are widely expressed in brain regions that control food intake, reward and energy balance. Animal and human studies indicate that CB1 receptor agonists possess orexigenic effects enhancing appetite and increasing the rewarding value of food. Conversely, CB1 antagonists have been shown to inhibit the intake of food. Eating disorders include a range of chronic and disabling related pathological illnesses that are characterized by aberrant patterns of feeding behaviour and weight regulation, and by abnormal attitudes and perceptions toward body shape image. The psychological and biological factors underlying eating disorders are complex and not yet completely understood. However in the last decades, converging evidence have led to hypothesise a link between defects in the endocannabinoid system and eating disorders, including obesity. Here we review the neurochemical and behavioural preclinical evidence supporting the role of the endocannabinoid system in eating disorders to offer the reader an update regarding the state of the art. Despite the recent withdrawal from the market of rimonabant for treating obesity and overweight individuals with metabolic complications due to its psychiatric side effects, preclinical findings support the rationale for the clinical development of drug which modulate the endocannabinoid system in the treatment of eating disorders.

Pharmacological modulation of the endocannabinoid signalling alters binge‐type eating behaviour in female rats

Binge eating disorder (BED) is characterized by excessive food intake during short periods of time. Recent evidence suggests that alterations in the endocannabinoid signalling could be involved in the pathophysiology of BED. In this study, we investigated whether pharmacological manipulation of endocannabinoid transmission may be effective in modulating the aberrant eating behaviour present in a validated rat model of BED.