Distinct functions of endogenous cannabinoid system in alcohol abuse disorders

Basavarajappa, Balapal S.; Joshi, Vikram; Shivakumar, Madhu; Subbanna, Shivakumar

doi:10.1111/bph.14780

Cited by 29 publications

(29 citation statements)

References 153 publications

(224 reference statements)

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“…Increased alcohol preference and reduced sensitivity to the effects of alcohol are believed to be mediated, at least in part, through the cannabinoid 1 (CB1) receptor, with the majority of preclinical studies, suggesting that CB1 stimulation increases alcohol consumption, while CB1 receptor antagonism/inverse agonism decreases alcohol intake (Cippitelli et al, 2005; Colombo et al, 2002; Hansson et al, 2007; Linsenbardt and Boehm, 2009; Malinen and Hyytiä, 2008). It has therefore been proposed that reduced FAAH activity, resulting in increased anandamide, may influence alcohol intake via a CB1 receptor‐mediated mechanism (Basavarajappa et al, 2019).…”

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confidence: 99%

Association of the Fatty Acid Amide Hydrolase C385A Polymorphism With Alcohol Use Severity and Coping Motives in Heavy‐Drinking Youth

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Wardell

Tyndale

et al. 2021

Alcoholism Clin & Exp Res

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Background Reduced function of fatty acid amide hydrolase, the catabolic enzyme for the endocannabinoid anandamide, can be inherited through a functional genetic polymorphism (FAAH rs324420, C385A, P129T). The minor (A) allele has been associated with reduced FAAH enzyme activity and increased risk for substance use disorders in adults. Whether this inherited difference in endocannabinoid metabolism relates to alcohol use disorder etiology and patterns of alcohol use in youth is unknown. Methods To examine this question, heavy‐drinking youth (n = 302; mean age = 19.74 ± 1.18) were genotyped for FAAH C385A. All subjects completed a comprehensive interview assessing alcohol use patterns including the Timeline Follow‐back Method, Alcohol Use Disorders Identification Test (AUDIT), and Drinking Motives Questionnaire. Analyses of Covariance (ANCOVAs) were conducted to assess differences in drinking patterns and drinking motives between genotype groups, and mediation analyses investigated whether drinking motives accounted for indirect associations of genotype with alcohol use severity. Results Youth with the FAAH minor allele (AC or AA genotype) reported significantly more drinking days (p = 0.045), significantly more frequent heavy episodic drinking (p = 0.003), and significantly higher alcohol‐related problems and consumption patterns (AUDIT score p = 0.045, AUDIT‐C score p = 0.02). Mediation analyses showed that the association of FAAH C385A with drinking outcomes was mediated by coping motives. Conclusions These findings extend previous studies by suggesting that reduced endocannabinoid metabolism may be related to heavier use of alcohol in youth, prior to the onset of chronic drinking problems. Furthermore, differences in negative reinforcement‐related drinking could account in part for this association.

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confidence: 99%

Association of the Fatty Acid Amide Hydrolase C385A Polymorphism With Alcohol Use Severity and Coping Motives in Heavy‐Drinking Youth

Best

Wardell

Tyndale

et al. 2021

Alcoholism Clin & Exp Res

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“…In the present review, we will give updated progress that has been made in studying the role of GPCRs in alcohol actions using transgenic mouse models and in particular knockout animals. We decided to discuss below only 1) GPCRs that have recognized a role in drug use disorders and that represent key neurotransmitter systems (DA, serotonin, glutamate, and γ-aminobutyric acid (GABA) receptors) and 2), based on our current knowledge, GPCRs that constitute current therapeutic or emerging targets for the treatment of AUD (opioid [36], endocannabinoid [37], ghrelin receptor [215], corticotropin-releasing factor (CRF) [38], melanocortin receptors [39], and orphan GPCRs). However, we have also broadly catalogued reports that addressed GPCR function in alcohol drinking using knockout mice (see Table 1) which will enhance the system-wide view of GPCR genes role in alcohol actions.…”

Section: Gpcrs and Alcohol-related Behaviors: Studies In Mutant Knockmentioning

confidence: 99%

“…Owing to its key role in neurotransmission, synaptic plasticity, and addiction-related behaviors, the endocannabinoid system has emerged as a reasonable target for the treatment of alcohol abuse [169,171,175]. This possibility has been further strengthened by human studies indicating that genetic polymorphisms including SNPs (e.g., rs1049353 and rs2023239) within the CNR1 gene encoding CB1R were associated with several features of AUD [37,176,177]. Thus, the development of endocannabinoid-based compounds and the generation of CB1R and CB2R mutant mice have understandably spurred scientists to preclinical and clinical initiatives [37,175,[178][179][180][181].…”

Section: Endocannabinoid Receptorsmentioning

confidence: 99%

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GPCR and Alcohol-Related Behaviors in Genetically Modified Mice

et al. 2020

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G protein-coupled receptors (GPCRs) constitute the largest class of cell surface signaling receptors and regulate major neurobiological processes. Accordingly, GPCRs represent primary targets for the treatment of brain disorders. Several human genetic polymorphisms affecting GPCRs have been associated to different components of alcohol use disorder (AUD). Moreover, GPCRs have been reported to contribute to several features of alcohol-related behaviors in animal models. Besides traditional pharmacological tools, genetic-based approaches mostly aimed at deleting GPCR genes provided substantial information on how key GPCRs drive alcohol-related behaviors. In this review, we summarize the alcohol phenotypes that ensue from genetic manipulation, in particular gene deletion, of key GPCRs in rodents. We focused on GPCRs that belong to fundamental neuronal systems that have been shown as potential targets for the development of AUD treatment. Data are reviewed with particular emphasis on alcohol reward, seeking, and consumption which are behaviors that capture essential aspects of AUD. Literature survey indicates that in most cases, there is still a gap in defining the intracellular transducers and the functional crosstalk of GPCRs as well as the neuronal populations in which their signaling regulates alcohol actions. Further, the implication of only a few orphan GPCRs has been so far investigated in animal models. Combining advanced pharmacological technologies with more specific genetically modified animals and behavioral preclinical models is likely necessary to deepen our understanding in how GPCR signaling contributes to AUD and for drug discovery.

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“…CB 2 receptors are expressed sparsely in microglia, macrophages, and some neurons in the central nervous system, but are more ubiquitous in the peripheral nervous system (Roche and Finn, 2010). There is evidence that alcohol acts to reduce endogenous cannabinoid levels through a CB 2 receptor–mediated pathway and that this mechanism is important in alcohol use disorders (Basavarajappa et al, 2019; Martín‐Sánchez et al, 2019). CB 1 receptors are expressed in both inhibitory and excitatory neurons, at perinatal timepoints in the rodent cortex, basal forebrain, and telencephalon (Scheyer et al, 2019).…”

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confidence: 99%

A Systematic Review of the Effects of Perinatal Alcohol Exposure and Perinatal Marijuana Exposure on Adult Neurogenesis in the Dentate Gyrus

Reid

Lysenko‐Martin

Snowden

et al. 2020

Alcoholism Clin & Exp Res

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Background: Marijuana and alcohol are both substances that, when used during pregnancy, may have profound effects on the developing fetus. There is evidence to suggest that both drugs have the capacity to affect working memory, one function of the hippocampal formation; however, there is a paucity of data on how perinatal exposure to alcohol or cannabis impacts the process of adult neurogenesis.Methods: This systematic review examines immunohistochemical data from adult rat and mouse models that assess perinatal alcohol or perinatal marijuana exposure. A comprehensive list of search terms was designed and used to search 3 separate databases. All results were imported to Mendeley and screened by 2 authors. Consensus was reached on a set of final papers that met the inclusion criteria, and their results were summarized.Results: Twelve papers were identified as relevant, 10 of which pertained to the effects of perinatal alcohol on the adult hippocampus, and 2 pertained to the effects of perinatal marijuana on the adult hippocampus. Cellular proliferation in the dentate gyrus was not affected in adult rats and mice exposed to alcohol perinatally. In general, perinatal alcohol exposure did not have a significant and reliable effect on the maturation and survival of adult born granule neurons in the dentate gyrus. In contrast, interneuron numbers appear to be reduced in the dentate gyrus of adult rats and mice exposed perinatally to alcohol. Perinatal marijuana exposure was also found to reduce inhibitory interneuron numbers in the dentate gyrus.Conclusions: Perinatal alcohol exposure and perinatal marijuana exposure both act on inhibitory interneurons in the hippocampal formation of adult rats. These findings suggest simultaneous perinatal alcohol and marijuana exposure (SAM) may have a dramatic impact on inhibitory processes in the dentate gyrus.

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Distinct functions of endogenous cannabinoid system in alcohol abuse disorders

Cited by 29 publications

References 153 publications

Association of the Fatty Acid Amide Hydrolase C385A Polymorphism With Alcohol Use Severity and Coping Motives in Heavy‐Drinking Youth

Association of the Fatty Acid Amide Hydrolase C385A Polymorphism With Alcohol Use Severity and Coping Motives in Heavy‐Drinking Youth

GPCR and Alcohol-Related Behaviors in Genetically Modified Mice

A Systematic Review of the Effects of Perinatal Alcohol Exposure and Perinatal Marijuana Exposure on Adult Neurogenesis in the Dentate Gyrus

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