Role of the endocannabinoid system in drug addiction

Abstract

Drug addiction is a chronic relapsing disorder that produces a dramaticglobal health burden worldwide. Not effective treatment of drug addiction is currently available probably due to the difficulties to find an appropriate target to manage this complex disease raising the needs for further identification of novel therapeutic approaches. The endocannabinoid system has been found to play a crucial role in the neurobiological substrate underlying drug addiction. Endocannabinoids and cannabinoid receptors are widely expressed in the main areas of the mesocorticolimbic system that participate in the initiation and maintenance of drug consumption and in the development of compulsion and loss of behavioral control occurring during drug addiction. The identification of the important role played by CB1 cannabinoid receptors in drug addiction encouraged the possible used of an early commercialized CB1 receptor antagonist for treating drug addiction. However, the incidence of serious psychiatric adverse events leaded to the sudden withdrawal from the market of this CB1 antagonist and all the research programs developed by pharmaceutical companies to obtain new CB1 antagonists were stopped. Currently, new research strategies are under development to target the endocannabinoid system for drug addiction avoiding these side effects, which include allosteric negative modulators of CB1 receptors and compounds targeting CB2 receptors. Recent studies showing the potential role of CB2 receptors in the addictive properties of different drugs of abuse have open a promising research opportunity to develop novel possible therapeutic approaches.

Gender differences in the effects of cannabidiol on ethanol binge drinking in mice

“…Furthermore, OPRM1 modulates dopamine transmission within the cortico‐mesolimbic system . Besides, CB 1 r plays an essential role in alcohol addiction, being involved in different processes such as decision‐making, alcohol withdrawal, and relapse . Thus, the results obtained here agree with previous reports showing an upregulation of TH gene expression in the VTA under acute or chronic alcohol administration and highlight the role of OPRM1 mediating the rewarding properties of ethanol .…”

β‐Caryophyllene, a dietary terpenoid, inhibits nicotine taking and nicotine seeking in rodents

“…The second important finding in this study is the involvement of CB 2 receptors in nicotine self‐administration in mice. An exciting body of literature provides compelling evidence that the eCB system interacts with brain reward circuits and is implicated in drug reward and addiction (Jordan & Xi, ; Manzanares et al, ). As CB 1 receptors are highly expressed in the brain, early studies focused on the involvement of these receptors in drug reward, including nicotine reward and relapse.…”

“…Recent studies indicate that, in addition to CB 1 receptors, the CB 2 receptors are also involved in drug reward, including nicotine reward and dependence (Jordan & Xi, ; Manzanares et al, ). In the present study, we found that CB2‐KO mice displayed significantly lower nicotine self‐administration than their WT littermates (Figure ).…”

“…In recent years, the CB 2 receptors have become a new target in medication development for the treatment of substance use disorders as this receptor has been identified on midbrain dopaminergic neurons and implicated in drug reward and addiction (Jordan & Xi, ; Liu et al, ; Manzanares et al, ). In support of this premise are the findings that, in CB2‐KO mice, there was attenuation of nicotine‐induced conditioned place preference (CPP; Canseco‐Alba et al, ; Ignatowska‐Jankowska, Muldoon, Lichtman, & Damaj, ; Navarrete et al, ), nicotine self‐administration (Navarrete et al, ), and nicotine withdrawal symptoms (Navarrete et al, , but see Ignatowska‐Jankowska et al, ), suggesting the involvement of CB 2 receptors in nicotine reward and dependence.…”

Protective role of neuronal and lymphoid cannabinoid CB2 receptors in neuropathic pain

“…CB2r, the main cannabinoid receptors in peripheral immune cells (Fernández-Ruiz et al, 2007; Schmöle et al, 2015a), are found in monocytes, macrophages and lymphocytes, and their expression increases in conditions of active inflammation (Schmöle et al, 2015b; Shang and Tang, 2017). The presence of CB2r in the nervous system was thought to be restricted to microglia and limited to pathological conditions or intense neuronal activity (Manzanares et al, 2018). However, recent studies using electrophysiological approaches and tissue-specific genetic deletion revealed functional CB2r also in neurons, where they modulate dopamine-related behaviors (Zhang et al, 2014) and basic neurotransmission (Quraishi and Paladini, 2016; Stempel et al, 2016).…”