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

Islam Hany Gamaleddin, Jose M.Trigo, Aliou B. Gueye, Alexander Zvonok, Alexandros Makriyannis, Steven R. Goldberg and Bernard Le Foll

Frontiers in Psychiatry, 2015, Vol 6, Article 41, 1-12.

doi : 10.3389/fpsyt.2015.00041

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.

Keywords : cannabinoid system, nicotine, addiction, endogenous cannabinoids

 

INTRODUCTION

Among addictive substances, nicotine use is one of the most prevalent worldwide. The World Health Organization (WHO) estimates that nearly six million tobacco smokers will die every year as a consequence of their tobacco use (1). Therefore, tobacco smoking represents the largest preventable cause of death in the world. Nicotine exerts its effects on the main neurotransmitter systems, such as acetylcholine, dopamine, noradrenaline, serotonin, opioid, glutamate, and gamma-aminobutyric acid (GABA) systems (2–7). There is also mounting evidence supporting the existence of a significant role of the endocannabinoid system in mediating the reinforcing and other addiction-related effects of nicotine. The close overlap of cannabinoid and nicotinic acetylcholine receptors (nAChRs) in certain brain areas such as the midbrain, known to mediate the reinforcing properties of nicotine, but also the hippocampus and the amygdala that are involved in nicotine-associated memory certainly facilitates the interaction between both systems (8–10). There is also evidence of the existence of modulatory interactions between endocannabinoid and cholinergic signaling systems (11–13). Behavioral experiments have shown specific functional interactions between nicotine and the endocannabinoid system that could be mediated by brain structures involved in motivation (14).

The cannabinoid systemincludes the cannabinoidCB1 andCB2 receptors, endogenous cannabinoids, and the processes responsible for their biosynthesis, cellular uptake,andmetabolism (15–18). Endocannabinoids are synthesized on-demand and can activate cannabinoid CB1 and/or CB2 receptors (19, 20). CB1 receptors are believed to be the main mediators of the psychoactive properties of delta 9-tetrahydrocannabinol (THC), which is the main psychoactive component of cannabis (21). CB1 receptors are among the most abundant G-protein-coupled receptors in the central nervous system (CNS) (22). Cannabinoids modify the synaptic efficacy of central neuronal circuits involved in reward and other processes by acting at CB1 receptors located pre-synaptically (23).

Although CB2 receptor protein can be detected in the brainstem neurons using western blotting and immunohistochemistry (24), yet, levels of expression of brain CB2 receptors are much lower than those of CB1 receptors (25, 26). CB2 receptor mRNAs were detected in certain regions of the rat brain such as, the cerebellum, cortex, and brainstemusing reverse transcription polymerase chain reaction (RT-PCR) (24). In contrast to the predominant pre-synapticlocalizationofCB1 receptors in the brain, immuno re- activity studies suggest a more likely post-synaptic localization of CB2 receptors(25, 26).

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