Role of the Cannabinoid System in Modulating the Reinforcing and Relapse Related Properties of Nicotine in Rats

There are several lines of evidence supporting the existence of a pivotal role of the cannabinoid system in mediating the reinforcing effects of nicotine. Characterization of the crosstalk between nicotine addiction and the cannabinoid system may have significant implications for our understanding of the neurobiological mechanisms underlying nicotine dependence. Objectives: The current series of experiments, we investigated the effects of activating CB1 receptors, modulating CB2 receptors as well as elevating levels of the endogenous cannabinoid ligand anandamide on nicotine taking and reinstatement of nicotine seeking behaviour. METHODS: In the first series of experiments, we investigated the effects of pretreatment with the CB receptor agonist WIN 55, 212-2 (0.1-1mg/kg), on nicotine self-administration and on the reinstatement of nicotine seeking behaviour. In the next series of experiments, we used a selective CB1 inverse agonist rimonabant (0.3mg/kg) and CB2 antagonist AM630 (5mg/kg) to delineate wether the effects obsereved with WIN 55, 212-2 are CB1 or CB2 meidated. Moreover, we investigated the effect of selective CB2 receptor activation (AM1241 1-10 mg/kg) and inhibition (AM630 1.25-5 mg/kg) on nicotine self-administration under fixed ratio (FR) and progressive (PR) schedules of reinforcement and on reinstatement of nicotine seeking induced by nicotine associated cues and nicotine priming. Finally, the effects of activation of CB receptors through administration of anandamide reuptake inhibitor VDM11 (1-10 mg/kg) on nicotine self-administration and on reinstatement of nicotine seeking were investigated. RESULTS: WIN 55,212-2 enhanced the break points for nicotine self-administration under a PR schedule of reinforcement, reinstated nicotine seeking behaviour and enhanced cue induced reinstatement of nicotine seeking. Neither activation nor blockade of CB2 receptors affected the responding of the animals for nicotine self-administration under FR or PR schedules of reinforcement or for reinstatement of nicotine seeking induced by nicotine associated cues and priming. Pretreatment with VDM11 dose dependently attenuated the reinstatement of nicotine seeking behaviour induced by nicotine associated cues and priming without affecting stable nicotine self administration. CONCLUSION: CB1 but not CB2 receptors appear to play a pivotal role in modulating the reinforcing effects of nicotine. Inhibition of anandamide reuptake could be a potentially useful tool in modulating relapse to smokingPh

Role of the endogenous cannabinoid system in nicotine addiction: novel insights

Several lines of evidence have shown that the endogenous cannabinoids are implicated in several neuropsychiatric diseases. Notably, preclinical and human clinical studies have shown a pivotal role of the cannabinoid system in nicotine addiction. The CB1 receptor inverse agonist/antagonist rimonabant (also known as SR141716) was effective to decrease nicotine-taking and nicotine-seeking in rodents, as well as the elevation of dopamine induced by nicotine in brain reward area. Rimonabant has been shown to improve the ability of smokers to quit smoking in randomized clinical trials. However, rimonabant was removed from the market due to increased risk of psychiatric side effects observed in humans. Recently, other components of the endogenous cannabinoid system have been explored. Here, we present the recent advances on the understanding of the role of the different components of the cannabinoid system on nicotine’s effects. Those recent findings suggest possible alternative ways of modulating the cannabinoid system that could have implication for nicotine dependence treatment

Attenuation of cue-induced reinstatement of nicotine seeking by URB597 through cannabinoid CB1 receptor in rats

International audienceRationale: The endocannabinoid system is composed of endocannabinoids (such as anandamide), their target receptors (CB1 and CB2 receptors, CB1Rs and CB2Rs), the enzymes that degrade them (fatty-acid-amide-hydrolase (FAAH) for anandamide), and an endocannabinoid transporter. FAAH inhibition has been recently identified as having a critical involvement in behaviors related to nicotine addiction and has been shown to reduce the effect of nicotine on the mesolimbic dopaminergic system via CB1R and peroxisome proliferator-activated receptor alpha (PPARα). Thus, inhibition of FAAH may represent a novel strategy for smoking cessation, but its mechanism of action on relapse to nicotine seeking is still unknown.Objective: The study aims to explore the mechanism of action of the inhibitor of FAAH activity, URB597, on relapse to nicotine seeking by evaluating the effect of the CB1R, CB2R, and PPARα antagonists on the attenuating effect of URB597 on cue-induced reinstatement of nicotine seeking in rats.Results: URB597 reduced cue-induced reinstatement of nicotine seeking, an effect that was reversed by the CB1R antagonist rimonabant, but not by the CB2R or PPARα antagonists AM630 and MK886, respectively.Conclusions: These results indicate that URB597 reduces cue-induced reinstatement in rats through a CB1 receptor-dependent mechanism, and not via CB2R or PPARα. Since FAAH inhibition represent a novel and promising strategy for tobacco smoking cessation, dissecting how it produces its action may lead to a better understanding of the neurobiological mechanisms underlying nicotine addiction

Effects of a selective cannabinoid CB2 agonist and antagonist on intravenous nicotine self administration and reinstatement of nicotine seeking.

Over the last decade there have been significant advances in the discovery and understanding of the cannabinoid system along with the development of pharmacologic tools that modulate its function. Characterization of the crosstalk between nicotine addiction and the cannabinoid system may have significant implications on our understanding of the neurobiological mechanisms underlying nicotine dependence. Two types of cannabinoid receptors (CB1 and CB2) have been identified. CB1 receptors are expressed in the brain and modulate drug taking and drug seeking for various drugs of abuse, including nicotine. CB2 receptors have been recently identified in the brain and have been proposed to play a functional role in mental disorders and drug addiction. Our objective was to explore the role of CB2 receptors on intravenous nicotine self administration under two schedules of reinforcement (fixed and progressive ratio) and on nicotine seeking induced by nicotine priming or by nicotine associated cues. For this, we evaluated the effects of various doses of the selective CB2 antagonist AM630 (1.25 to 5 mg/kg) and CB2 agonist AM1241 (1 to 10 mg/kg) on these behavioral responses in rats. Different groups of male Long Evans rats were trained to lever press for nicotine at a unit dose of 30 µg/kg/infusion. Subsequently, animals were randomized using a Latin-square design and injected with either AM1241 or AM630 using a counterbalanced within subject design. Administration of the CB2 ligands did not affect either nicotine-taking nicotine-seeking behavior. Our results do not support the involvement of CB2 receptors in nicotine-taking or nicotine-seeking behavior

Effect of AM630 on nicotine self administration under FR5 and PR schedules of reinforcement.

<p><b>A</b>. Effects of pretreatment with AM630 (1.25, 2.5 and 5 mg/kg, IP, H 30) on nicotine (30 µg/kg/infusion) self administration under the FR5 schedule. Data are expressed as means (±SEM) of the number of nicotine infusions obtained during the 60-min session. AM630 did not affect responding vs. vehicle (0 mg/kg) pretreatment (N = 12); P = 0.67. <b>B</b>. Effects of pretreatment with AM630 (5 mg/kg, IP) on nicotine (30 ug/kg/infusion) self administration under PR schedule. <b>A</b>, Data are expressed as means (±SEM) of the number of nicotine infusions obtained during the 4-hr sessions. AM630 did not affect break point P>0.05 vs. vehicle (0 mg/kg) pretreatment. (N = 7) P = 0.73.</p

Effects of AM630 on reinstatement of nicotine-seeking behavior induced by presentation of nicotine associated cues and by Nicotine priming.

<p><b>A</b>. Effects of pretreatment with AM630 (1.25, 2.5 and 5 mg/kg, IP H 30 min) on cue-induced reinstatement of nicotine-seeking behavior. A significant reinstatement of nicotine-seeking behavior was produced by presentation of nicotine-associated cues alone (* P<0.001). ANOVA showed that pretreatment with AM630 (1.25, 2.5 and 5 mg/kg, IP, H 30 min) did not modify cue induced reinstatement of nicotine-seeking behavior compared to vehicle (0 mg/kg) pretreatment (P>0.05). Data are expressed as means (±SEM) of the number of active and inactive lever presses during extinction (Ext); vehicle (0 mg/kg) pre-treatment and after pretreatment with AM630 (1.25, 2.5 and 5 mg). <b>B</b>. A significant reinstatement of nicotine-seeking was also produced by pretreatment with nicotine (0.15 mg/kg) (* P<0.001). ANOVA showed that AM630 (1.25, 2.5, 5 mg/kg, IP, H 30 min) did not modify reinstatement of nicotine-seeking behavior induced by a priming injection of 0.15 mg/kg nicotine administered 1 min before the session (P>0.05). Data are expressed as means (±SEM) of the number of active and inactive lever presses during extinction (Ext); vehicle (0 mg/kg) pre-treatment and after pretreatment with AM630 (1.25, 2.5 and 5 mg).</p

Knowledge, attitudes and use of anabolic-androgenic steroids among male gym users: A community based survey in Riyadh, Saudi Arabia

Recreational use of anabolic-androgenic steroids (AAS) is a growing worldwide public health concern. However, studies assessing the level of awareness and knowledge of its effects on health are fairly limited, especially in developing countries, including Saudi Arabia. This community-based cross-sectional study was conducted to assess knowledge, attitudes and practices among male gym members toward AAS in Riyadh (Saudi Arabia) from March to October 2016. Twenty gyms were randomly selected from four different geographical regions (clusters) within Riyadh. In total, 482 participants responded to the self-administered anonymous questionnaire, which covered socio-demographic data, data assessing knowledge, attitude and behavior related to AAS use. The mean (±standard deviation) age of study participants was 27.2 (±6.9) years. Among these, 29.3% of participants reported having used AAS, while the majority (53.5%) reported hearing of AAS use, mostly through friends. Most study participants reported awareness of the effects of AAS on muscle mass, body weight and muscles strength (53.2%, 51.1% and 45.5%, respectively). In contrast, a higher proportion of study participants were unaware of the side-effects of AAS use. A high proportion of study participants (43.2%) reported that they had been offered AAS and 68.7% believed that AAS are easily accessible. Most of the gym users (90.1%) reported never having used any narcotics or psychoactive drugs. Regression analysis revealed that use of anabolic-androgenic steroids is significantly associated with “weight lifting practice” OR [95%CI] = 1.9[1.02 − 3.61], P = 0.044; “using supplementary vitamins, OR [95%CI] = 7.8[4.05 − 15.03], P < 0.0001, knowing anyone using anabolic-androgenic steroids’ OR [95%CI] = 7.5[3.78 − 14.10], P < 0.0001, and someone advised Gym users to take anabolic-androgenic steroids” OR [95%CI] = 2.26[1.23 − 4.14], P < 0.008. Our findings suggest that the level of awareness regarding the possible side-effects of AAS is fairly limited. Thus, efforts directed toward educating the public and limiting access to AAS as well as health policy reforms are crucial to reduce future negative implications of AAS use. Keywords: Androgenic anabolic steroids, Steroids, Drug abuse, Steroid abuse, Gym users, Addiction, Substance abuse, Saudi Arabi

Effects of AM1241 on nicotine self-administration under FR5 and PR schedules of reinforcement.

<p><b>A</b>. Effects of pretreatment with AM1241 (1, 3 and 10 mg/kg, IP H 30) on nicotine (30 µg/kg/infusion) self-administration under the FR5 schedule. Data are expressed as means (±SEM) of the number of nicotine infusions obtained during the 60-min session. All doses of AM1241 did not affect responding vs. vehicle (0 mg/kg) pretreatment (N = 10); P = 0.35. <b>B</b>. Effects of pretreatment with AM1241 (1, 3 and 10 mg/kg) on nicotine (30 ug/kg/infusion) self- administration under PR schedule. <b>A</b>, Data are expressed as means (±SEM) of the number of nicotine infusions obtained during the 4-hr sessions. AM1241 did not affect break point P>0.05 compared to vehicle (0 mg/kg) pretreatment. (N = 8) P = 0.89.</p

Pattern of respondinng during acquisition and extinction phases.

<p>A. Acquisition of nicotine self-administration (30 µg/kg/infusion). The total number of active (•) and inactive(▪) lever presses (means ± SEM) received in each session (during time in and time out periods) under the different schedules of reinforcement (FR- 1, FR-2, FR-5,). B. Number of nicotine infusions (means ± SEM) earned during acquisition phase in the same group of animals represented as <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029900#pone-0029900-g001" target="_blank">fig. 1A</a>. C. The number of active (•) and inactive(▪) lever presses (means ± SEM) received in each extinction session in the same group of animals represented in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029900#pone-0029900-g001" target="_blank">figures 1A & 1B</a>.</p