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+�:Neuroinflammation as a possible link between cannabinoids and addiction
Rodrigues LCM1, Gobira PH2, de Oliveira AC2, Peli��o R1, Teixeira AL 3,4, Moreira FA2 and Campos AC 3,4*.
1 Department of Physiological Sciences�, Health Science Center (CCS) ,  Universidade Federal do Esp�rito Santo.
2  Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais
3 Group of Neuroimmunology, Laboratory of Immunopharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
4 Infectious Diseases and Tropical Medicine Program, Medical School, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.�

* Corresponding author:
Alline Cristina de Campos Ph.D.
Laboratory of Immunopharmacology, Institute of Biological Sciences and School of Medicine, Federal University of Minas Gerais. �6627, Ant�nio Carlos avenue, Pampulha, zip code: 31270-901, Belo Horizonte, Brazil. e-mail: allinecampos@hotmail.com Abstract
Substance dependence disorder is a chronically relapsing disorder characterized by neurobiological changes leading to loss of control in restricting a substance intake, compulsion and withdrawal syndrome. In the last past years, (endo)cannabinoids have been raised as a possible target in the etiology of drug addiction. In this context, several studies suggested that cannabinoid receptors (CB1 and CB2) might be involved in ethanol and cocaine addiction. On the other hand, although the exact mechanisms of the genesis of addiction remain poorly understood, it is possible that neuroinflammation might play a role in the pathophysiology of this condition. Several pieces of evidences suggested that psychostimulants drugs induce microglia activation and the expression of inflammatory mediators, such as cytokines (IL-1�, TNF-�, IFN-�), transcription factors (NF�b) and microglial cells activation. Also, studies demonstrated that (endo)cannabinoids act as immunomodulators by inhibiting cytokines production and microglial cell activation. Thus, in the present review, we explore the possible role of neuroinflammation on the neuroprotective and behavioral effects of cannabinoids on drug addiction. 
keywords: Cannabinoids, neuroinflammation, addiction, alcohol, cocaine
Cannabinoids and addiction
The Diagnostic and Statistical Manual of Mental Disorders in its fourth edition (DSM-IV) defines substance dependence as a chronically relapsing disorder characterized by neurobiological changes leading to loss of control in restricting a substance intake, compulsion and negative emotional states induced by motivational withdrawal syndrome when the drug take is prevented [1, 2].
Marijuana (Cannabis sativa) is the most widely used illicit drug in worldwide. The 2006 Annual report on Drug Abuse estimates that 4% of the adult world�s population consume Cannabis regularly [3]. Cannabis can induce transient psychotic symptoms in healthy individuals [4, 5] and possibly increase the risk of psychotic disorders, such as schizophrenia, in a dose dependent manner [6]. Although its primary psychoactive ingredient, �9-tetrahydrocannabinol (THC), is largely responsible for the subjective effects of Cannabis sativa, other phyto- and synthetic-cannabinoids may also induce psychotomimetic effects [7].
The very first hypothesis on the mechanism involving subjective effects of THC was based on the ability of this substance in perturbing membrane permeability of neural cells [8]. In the late 80�s, however, a specific receptor for cannabinoids was proposed [9] and later cloned  and termed cannabinoid CB1 receptor [10] the major pharmacological target responsible for cannabinoid effects, including the subjective effects related to THC-abuse [6, 11]. Afterwards, endogenous ligands for the CB1 receptor (termed endocannabinoids) have been identified, from which the most extensively studied are the arachidonic acid derivates arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol (2-AG), which have their activity terminated by the enzymes fatty acid amide hydrolase and monoacylglicerol lipase, respectively [12]. A second cannabinoid receptor (CB2) has also been characterized, which was initially proposed to be absent in the central neurons, although later research has been changing this notion [13].
Accumulating evidence has implicated the brain endocannabinoid signaling in the etiology of drug addiction [14] and several studies support the view that endocannabinoid system represents a new candidate for the control of drug rewarding properties [15], since there is a dense CB1 receptor expression in brain regions involved in the motivational and addictive properties of abused drugs, including the ventral tegmental area, nucleus accumbens and prefrontal cortex [16]. The endocannabinoids anandamide and 2-AG [12], as well as the enzymes responsible for their catabolism [17], are expressed in dopaminergic neurons. CB1 receptors are abundant in the brain reward circuitry and participate in the addictive properties induced by different drugs of abuse ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "The cannabinoid receptor type 1 (CB1) displays unusual properties, including the dual capacity to inhibit or stimulate adenylate cyclase and a brain density considerably higher than the majority of G protein-coupled receptors. Together with overlapping expression patterns of dopamine and serotonin receptors this suggests a potential of CB1 to modulate the function of the dopamine and serotonin system. Indeed, pharmacological studies provide evidence for cross-talks between CB1 and receptors of these neurotransmitter systems. In trying to obtain further insights into possible functional and/or structural interactions between CB1 and the dopamine receptors and the serotonin receptors, we performed double-label in situ hybridization at the cellular level on mouse forebrain sections by combining a digoxigenin-labelled riboprobe for CB1 with 35S-labelled riboprobes for dopamine receptors D1 and D2, and for serotonin receptors 5-HT1B and 5-HT3, respectively. As a general rule, we found that CB1 colocalizes with D1, D2 and 5-HT1B only in low-CB1-expressing cells which are principal projecting neurons, whereas CB1 coexpression with 5-HT3 was also observed in high-CB1-expressing cells which are considered to be mostly GABAergic. In striatum and olfactory tubercle, CB1 is coexpressed to a high extent with D1, D2 and 5-HT1B. Throughout the hippocampal formation, CB1 is coexpressed with D2, 5-HT1B and 5-HT3. In the neocortex, coexpression was detected only with 5-HT1B and 5-HT3. In summary a distinct pattern is emerging for the cannabinoid system with regard to its colocalization with dopamine and serotonin receptors and, therefore, it is likely that different mechanisms underlie its cross-talk with these neurotransmitter systems.", "author" : [ { "dropping-particle" : "", "family" : "Hermann", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marsicano", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lutz", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neuroscience", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2002", "1" ] ] }, "page" : "451-60", "title" : "Coexpression of the cannabinoid receptor type 1 with dopamine and serotonin receptors in distinct neuronal subpopulations of the adult mouse forebrain.", "type" : "article-journal", "volume" : "109" }, "uris" : [ "http://www.mendeley.com/documents/?uuid=5296fcc6-7159-4faf-9c83-0fec8093bfc4" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Hermann, Marsicano, & Lutz, 2002)" }, "properties" : { "noteIndex" : 0 }, "schema" : "https://github.com/citation-style-language/schema/raw/master/csl-citation.json" }[18]. In vivo microdialysis experiments have shown that CB1 receptor activation increases dopamine release in nucleus accumbens [19]. The second cannabinoid receptor, CB2, which is believe to control neuroinflammatory mechanisms, has been also found expressed in neurons in striatum and midbrain, areas related to reward and addiction [13]. Moreover, endocannabinoids can be released following depolarization in neurons in brain areas related to reward circuitry [15].
Notwithstanding the abuse potential of cannabinoids, it has been difficult to establish sensitive paradigms to evaluate their reward properties. Contrasting to other drugs, cannabinoids produce false negative results in some behavioral methods for investigation of abused drugs [7]. For instance, some investigations failed to establish cannabinoid intravenous self-administration in non-human primates [20]. More recently, however, a new reliable method was developed to induce self-administration of the phytocannabinoid (9-THC [21] and the endocannabinoids anandamide or 2-AG by monkeys [22, 23]. These effects were prevented by pretreatment with rimonabant, showing involvement of CB1 receptor in reward. Intravenous anandamide administration increases extracellular dopamine levels in nucleus accumbens of rats in a CB1 receptor-dependent manner [24], contributing to the reinforcing effects of exogenous anandamide. 
The abuse liability of drugs that inhibit endocannabinoid-hydrolysis have also been investigated. Mice given daily injections of FAAH inhibitors, URB597 or PF-3845, for 6 days and challenged with the CB1 antagonist SR141716A displayed no withdrawal symptoms ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1208/s12248-009-9110-7", "abstract" : "Abstinence symptoms in cannabis-dependent individuals are believed to contribute to the maintenance of regular marijuana use. However, there are currently no medications approved by the FDA to treat cannabis-related disorders. The only treatment currently shown consistently to alleviate cannabinoid withdrawal in both animals and humans is substitution therapy using the psychoactive constituent of marijuana, Delta(9)-tetrahydrocannabinol (THC). However, new genetic and pharmacological tools are available to increase endocannabinoid levels by targeting fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), the enzymes responsible for the degradation of the endogenous cannabinoid ligands anandamide and 2-arachidonoylglycerol, respectively. In the present study, we investigated whether increasing endogenous cannabinoids levels, through the use of FAAH (-/-) mice as well as the FAAH inhibitor URB597 or the MAGL inhibitor JZL184, would reduce the intensity of withdrawal signs precipitated by the CB(1) receptor antagonist rimonabant in THC-dependent mice. Strikingly, acute administration of either URB597 or JZL184 significantly attenuated rimonabant-precipitated withdrawal signs in THC-dependent mice. In contrast, FAAH (-/-) mice showed identical withdrawal responses as wild-type mice under a variety of conditions, suggesting that the absence of this enzyme across the development of dependence and during rimonabant challenge does not affect withdrawal responses. Of importance, subchronic administration of URB597 did not lead to cannabinoid dependence and neither URB597 nor JZL184 impaired rotarod motor coordination. These results support the concept of targeting endocannabinoid metabolizing enzymes as a promising treatment for cannabis withdrawal.", "author" : [ { "dropping-particle" : "", "family" : "Schlosburg", "given" : "Joel E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Carlson", "given" : "Brittany L A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ramesh", "given" : "Divya", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Abdullah", "given" : "Rehab A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Long", "given" : "Jonathan Z", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cravatt", "given" : "Benjamin F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lichtman", "given" : "Aron H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The AAPS journal", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2009", "6" ] ] }, "page" : "342-52", "title" : "Inhibitors of endocannabinoid-metabolizing enzymes reduce precipitated withdrawal responses in THC-dependent mice.", "type" : "article-journal", "volume" : "11" }, "uris" : [ "http://www.mendeley.com/documents/?uuid=4b05553d-9445-4aa2-98f6-e60b0891d0a9" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Schlosburg et al., 2009)" }, "properties" : { "noteIndex" : 0 }, "schema" : "https://github.com/citation-style-language/schema/raw/master/csl-citation.json" }(Schlosburg et al., 2009). However, treatment for 6 days with high doses of selective monoacylglycerol lipase inhibitor JZL184 resulted in significant reduction in CB1 function and expression, in addiction to significant SR141716A-induced somatic withdrawal symptoms [25]ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nn.2616", "abstract" : "Prolonged exposure to drugs of abuse, such as cannabinoids and opioids, leads to pharmacological tolerance and receptor desensitization in the nervous system. We found that a similar form of functional antagonism was produced by sustained inactivation of monoacylglycerol lipase (MAGL), the principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol. After repeated administration, the MAGL inhibitor JZL184 lost its analgesic activity and produced cross-tolerance to cannabinoid receptor (CB1) agonists in mice, effects that were phenocopied by genetic disruption of Mgll (encoding MAGL). Chronic MAGL blockade also caused physical dependence, impaired endocannabinoid-dependent synaptic plasticity and desensitized brain CB1 receptors. These data contrast with blockade of fatty acid amide hydrolase, an enzyme that degrades the other major endocannabinoid anandamide, which produced sustained analgesia without impairing CB1 receptors. 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These findings suggest that inhibitor of endocannabinoid-hydrolysis may present a lower abuse liability, as compared to direct CB1 agonists [14, 15, 26].
In addition to the obvious role of the endocannabinoid system in cannabinoid abuse, this system may also been involved in the effect of other drugs, from which alcohol and cocaine are discussed below. 
Cannabinoids and Alcohol
 	The endocannabinoid system may play a role on addictive properties in different drugs of abuse. Alcohol (or ethanol) is a widely abused substance which is associated to diverse social problems. A growing body of biochemical and pharmacological evidences have established a role for the endocannabinoid system in the neurobiology of alcohol [27]. Rats exposed chronically to alcohol had an increase in anandamide content in the limbic forebrain, a key area for the reinforcement of psychoactive drugs [28]. FAAH knockout mice displays increased preference for alcohol and consume more ethanol than the wild type mice [29]. In this context, it seems that CB1 receptor might be involved in ethanol addiction. Acute exposition to a CB1 receptor agonist increased motivation for drinking beer [30]. In agreement with this finding, studies have shown that genetic deletion of CB1 receptor results in reduced alcohol consumption in rodents; e.g. CB1 receptor knockout mice exhibit reduced voluntary alcohol consumption and does not release dopamine in nucleus accumbens after alcohol consumption [31]. Further, there is a reduction in ethanol self-administration and ethanol conditioned place preference in mice lacking CB1 receptor ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.bbr.2005.06.021", "abstract" : "Cannabinoids are postulated to play a role in modulating the reinforcing effects of abused drugs, including alcohol. Experiment 1 examined alcohol self-administration in cannabinoid CB1 receptor knockout (KO), heterozygous (HT) and wild type (WT) mice in a two-bottle choice paradigm. Mice were trained in a limited 8 h access/day to 10% (v/v) EtOH (EtOH) versus water. After baseline drinking levels (% EtOH preference and total EtOH intake (g/kg)), results indicated that the CB1 knockout mice displayed significantly lower baseline EtOH consumption compared to wild type mice. Subsequently, treatment with SR141716A (5mg/kg) significantly attenuated EtOH intake in the WT and HT mice but had little effect on the knockout mice. Experiment 2 examined the CB1 WT and CB1 KO strains in a conditioned place preference (CPP) procedure between saline and 2g/kg EtOH. The CB1 WT mice spent significantly more time in the EtOH-paired versus saline-paired chambers, whereas no significant preference was observed in the CB1 KO mice. Finally, we observed that CB1 KO mice were significantly lighter than WT and HT and that SR141716A did not significantly alter body weight. These results demonstrate that the cannabinoid CB1 receptor is an essential component of the molecular pathways underlying the reinforcing effects of alcohol. Thus, medications targeting the CB1 receptors may be beneficial for the treatment of alcoholism.", "author" : [ { "dropping-particle" : "", "family" : "Thanos", "given" : "Panayotis K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dimitrakakis", "given" : "Elias S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rice", "given" : "Onarae", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gifford", "given" : "Andrew", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Volkow", "given" : "Nora D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Behavioural brain research", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2005", "11", "7" ] ] }, "page" : "206-13", "title" : "Ethanol self-administration and ethanol conditioned place preference are reduced in mice lacking cannabinoid CB1 receptors.", "type" : "article-journal", "volume" : "164" }, "uris" : [ "http://www.mendeley.com/documents/?uuid=4c0c9a66-fd9c-4bc4-8d63-6d060e259273" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Thanos, Dimitrakakis, Rice, Gifford, & Volkow, 2005)" }, "properties" : { "noteIndex" : 0 }, "schema" : "https://github.com/citation-style-language/schema/raw/master/csl-citation.json" }[32]. 
Preclinical evidence indicates that the CB1 antagonist, Rimonabant, is able to suppress alcohol-related behaviors, like alcohol drinking and seeking behavior, and alcohol self-administration in rats and mice [27, 33, 34]. On the other hand, clinical studies revealed controversial data. In one study, the subjects were treated with Rimonabant (20 mg/day for 12 weeks) and no significant benefits were observed, although a delayed time do have the first drink and to relapse ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1097/JCP.0b013e318172b8bc", "abstract" : "Multiple lines of evidence suggest that the endocannabinoid system is implicated in the development of alcohol dependence. In addition, in animal models, the cannabinoid receptor 1 blocker rimonabant was found to decrease alcohol consumption, possibly by indirect modulation of dopaminergic neurotransmission. This was a 12-week double-blind, placebo-controlled, proof-of-concept study to assess the possible efficacy of the cannabinoid receptor 1 antagonist rimonabant 20 mg/d (2 x 10 mg) in the prevention of relapse to alcohol in recently detoxified alcohol-dependent patients. A total of 260 patients were included, 258 were exposed to medication, and 208 (80.6%) were men. Patients had an alcohol history of 15 years on average. More patients in the rimonabant group (94/131 [71.8%]) completed treatment compared with the placebo group (79/127 [62.2%]). Although there was a modest effect of rimonabant with respect to relapse rate, there were no statistically significant differences between treatment groups. Approximately 41.5% of the rimonabant group had relapsed to drinking at the end of the study compared with 47.7% of the placebo group (obtained from Kaplan-Meier-curve). Differences were more marked but not statistically significant in patients who relapsed to heavy drinking: 27.7% versus 35.6%, respectively. Safety and tolerance of the drug were good. Similar rates of adverse events were reported between the 2 groups; less patients experienced serious events or discontinued the treatment with rimonabant compared with placebo. Rates of depression-related events were low (3.8% with rimonabant compared with 1.6% with placebo). Patients on rimonabant lost weight (Mean, -1.7 kg) compared with baseline, whereas there was no such change in the placebo group. Weight loss was more pronounced in patients with a higher body mass index. In addition, there was a significant decrease in leptin levels in the rimonabant group compared with baseline. Lack of efficacy in this study may be explained by a very high response rate in the placebo group and a relatively short treatment duration. Taking the substantial numbers of animal studies suggesting a possible role of CB1 antagonists for the treatment of alcohol dependence into account, it seems worthwhile to further test cannabinoid blockers in the treatment of alcoholism.", "author" : [ { "dropping-particle" : "", "family" : "Soyka", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koller", "given" : "Gabriele", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schmidt", "given" : "Peggy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lesch", "given" : "Otto-Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leweke", "given" : "Markus", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fehr", "given" : "Christoph", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gann", "given" : "Horst", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mann", "given" : "Karl F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of clinical psychopharmacology", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2008", "6" ] ] }, "page" : "317-24", "title" : "Cannabinoid receptor 1 blocker rimonabant (SR 141716) for treatment of alcohol dependence: results from a placebo-controlled, double-blind trial.", "type" : "article-journal", "volume" : "28" }, "uris" : [ "http://www.mendeley.com/documents/?uuid=b2529f4e-6400-4a74-9802-1324df8f8af6" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Soyka et al., 2008)" }, "properties" : { "noteIndex" : 0 }, "schema" : "https://github.com/citation-style-language/schema/raw/master/csl-citation.json" }(Soyka et al., 2008). Another study showed that Rimonabant in the same treatment regimen did not change alcohol self-administration or endocrine measures during a laboratory session in nontreatment-seeking heavy alcohol drinkers ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1007/s00213-009-1704-3", "abstract" : "There is an extensive literature showing that the CB(1) cannabinoid receptor antagonist rimonabant (SR141716) decreases alcohol consumption in animals, but little is known about its effects in human alcohol drinkers.", "author" : [ { "dropping-particle" : "", "family" : "George", "given" : "David Ted", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Herion", "given" : "David W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jones", "given" : "Cheryl L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Phillips", "given" : "Monte J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hersh", "given" : "Jacqueline", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hill", "given" : "Debra", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Heilig", "given" : "Markus", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ramchandani", "given" : "Vijay A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Geyer", "given" : "Christopher", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Spero", "given" : "David E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Singley", "given" : "Erick D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "O'Malley", "given" : "Stephanie S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bishai", "given" : "Raafat", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rawlings", "given" : "Robert R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kunos", "given" : "George", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Psychopharmacology", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2010", "1" ] ] }, "page" : "37-44", "title" : "Rimonabant (SR141716) has no effect on alcohol self-administration or endocrine measures in nontreatment-seeking heavy alcohol drinkers.", "type" : "article-journal", "volume" : "208" }, "uris" : [ "http://www.mendeley.com/documents/?uuid=38447912-2b24-4221-a38e-e0525d6d16f2" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(George et al., 2010)" }, "properties" : { "noteIndex" : 0 }, "schema" : "https://github.com/citation-style-language/schema/raw/master/csl-citation.json" }[35]. However, due to adverse psychiatric effects of Rimonabant, all clinical trials were discontinued.
As an alternative, CB2 receptor has also emerged as a potential target for alcohol abuse. CB2 receptor activation enhances alcohol intake in stressed mice, whereas a CB2 antagonist may induce the opposite [13]. On the other hand, a more recent work has suggest the opposite, showing that deletion of the CB2 receptor gene increased preference for and vulnerability to ethanol consumption [36].
Therefore, although the picture is not entirely clear, the endocannabinoid system may favour or counteract neural changes mediating alcohol abuse, depending on a predominant activity through CB1 or CB2 receptors.
Cannabinoids and cocaine
Several studies suggest the involvement of the endocannabinoid system in behaviors related to cocaine addiction [37, 38]. Both CB1 and CB2 receptors are expressed in glutamatergic and GABAergic interneurons present in the reward circuitry of the mesolimbic system, modulating dopaminergic neurons responsible for most effects of cocaine [15, 39-41]. 
An important animal model currently used to study addictive behavior of cocaine is the behavioral sensitization [42]. This test is characterized by a progressively increase in a particular response, such as locomotion, after repeated exposure to a drug [42]. Motor sensitization to cocaine is impaired in CB1-deficient mice or after pharmacological blockade of these receptors [43, 44]. Furthermore, the genetic ablation of CB1 receptors promotes a decrease in this cocaine self-administration [45]. Treatment with the antagonists impaired self-administration behavior and inhibited cocaine-enhanced brain stimulation reward [45, 46].  The stress-induced reinstatement of cocaine seeking was also prevented by blockade of CB1 receptor [47]. Reductions in CB1 receptor expression and signaling in the prefrontal cortex from human cocaine addicts and animal rodents have also been reported [28, 48].
In addition to CB1, evidence has emerged suggested that CB2 receptors may also modulate processes related to cocaine addition, even though this topic has remained controversial. Recent studies showed a decreased in cocaine motor sensitization and self-administration in mice overexpressing cannabinoid CB�  receptors, suggesting that this receptor are involved in cocaine-evoked behaviors [48, 49].
Beside changes in CB1 and CB2 receptors expression, acute and chronic administration of cocaine also can promote alterations in levels of anandamide and 2-AG  ADDIN EN.CITE  ADDIN EN.CITE.DATA [50-52]. These data suggest that somehow the cannabinoid system attempts to modulate the changes induced by cocaine. However, pharmacological interventions that culminate with increase of endocannabinoids levels, such treatment with hydrolysis inhibitors, have yielded controversial responses. Inhibition of MGL or FAAH, for example, did not altered sensitization behavior to cocaine, in addition, the blockade of FAAH not affect self-administration [53, 54]. On the other hand, inhibition of anandamide hydrolysis prevented reinstatement of cocaine-seeking [54]. 
Although these data point to the importance of the endocannabinoid system in behavioural responses related to cocaine addiction, further studies are required to support the notion that this could be an avenue for developing new treatments. Blocking CB1 or activating CB2 are potential strategies for developing new treatments.
Neuroinflammation and addiction: role of (endo)cannabinoids
Although the exact mechanisms of the genesis of addiction are not well understood, it is possible that neuroinflammation might play a role in the pathophysiology of this condition. In fact, a wide range of literature has shown that psychostimulants induce microglia activation and the expression of different cytokines, such as tumor necrosis factor (TNF)( and interleukins (IL), and nitric oxide in animal models, although this could also be present in humans [55]. Moreover, these cytokines could, per se, facilitate addiction development. For example, IL-1( increases the mRNA expression and activity of serotonin transporter in human JAR choriocarcinoma cells [56]. This increased activity of serotonin transporters could enhance the effect of psychostimulants that target these transporters. 
Five-day intraperitoneal (i.p.) injections of IL-2 in male BALB/c mice enhances the sensitivity of animals to a selective dopamine uptake inhibitor administered five weeks after the treatment with the cytokine [57]. These long-lasting changes induced by IL-2 might be important for the CNS abnormalities induced by addictive drugs. Similar to the long-lasting effect observed with IL-2 treatment, five-day treatment with IL-6 increased the sensitivity to the locomotor-stimulating effects of a amphetamine administered 14 days after the last i.p. administration of IL-6 [58]. Moreover, in a protocol of drug discrimination behavioral effect using d-amphetamine, IL-2 and interferon (IFN)-( potentiated the response induced by the psychostimulant drug [59, 60]. On the contrary, TNF( might play a different role in addiction. It has been shown that methamphetamine increases the expression of this cytokine, which could, in turn, attenuate the rewarding effects and discriminative stimulus effects of this psychostimulant in rats [61, 62].
Besides the effects of cytokines in drug dependence, psychostimulants may also increase the activation of transcription factors. For instance, methamphetamine increases the activation of nuclear factor kappa B (NF(B) and activator protein 1 (AP-1) in endothelial cells [63]. The activation of these transcription factors induces the expression of different inflammatory mediators, which might be important for the development of the drug dependence.
Considering that microglia is an important source of inflammatory mediators in the central nervous system, these cells might be strictly associated with the addiction-related processes. Importantly, it has been hypothesized that, during the period of early recovery from addiction, primed microglial cells could release inflammatory mediators induced by different stressors, inducing sickness behavior syndrome-like, what could function as a first step for relapse behavior [55]. Microglia activation and the production of inflammatory mediators might also play an important role in the plasticity that accompanies the development and maintenance of drug abuse [64-66]. However, this is not currently clear and deserves further investigation.
Therefore, in this context, it could be assumed that (endo)cannabinoids could module addiction through its effects in microglia activation and in the production of inflammatory mediators. Importantly, different papers have demonstrated the presence of both CB1 and CB2 receptors on immune cells [67], and that cannabinoids reduced the binding of the respective transcription factors to CRE and �B in such cells [68]. Cannabinoids may act as immunomodulators by inhibiting cytokines and chemokines production, cell proliferation and expansion of regulatory T cells, as well as inducing apoptosis in these cells [69, 70]. 
On the other hand, AEA and 2AG degradation increased the production of prostaglandins in activated glial cells [71, 72]. This effect might be due to the hydrolyzation of AEA and 2 AG to arachidonic acid, leading to enhanced levels of substrate for the formation of prostaglandins [72]. The apparent contradictory proinflammatory effect of endocannabinoids seems to be mediated by a CB1/CB2 receptor independent mechanism and is prevented by endocannabinoids hydrolysis inhibitors (FAAH and MAGL inhibitors) [71, 72]. Also, it is important to stress that the enhanced levels of prostaglandins in the brain should not be interpreted as a mere pro-inflammatory signal, since these mediators also possess anti-inflammatory effects [73]  
In a viral model of multiple sclerosis, the treatment with WIN55,212-2, a CB1/CB2 receptor agonist, reduced mRNA expression for the proinflammatory cytokines TNF-�, IL-1�, IL-6 and IFN-� in the central nervous system [74]. The pharmacological inhibition of anandamide hydrolysis reduces microglial activation, nitric oxide levels and the production of several inflammatory mediators such as TNF-�, IL-6, IL-1�, IL-12 probably due the activation of CB2 receptors [75-77].  
It has been proposed that chronic activation of microglia plays a major role in disorders characterized by nervous tissue inflammation [78]. CB1 is expressed constitutively in microglial cells while CB2 is expressed in microglial cells during the activation state [77, 79]. However, although a role for CB1 receptor has been suggested to modulate inflammation [80, 81], CB2 is predominantly expressed in the immune system and might be a key mediator of cannabinoid regulation of immune functions, including microglia activation [82-84]. 
As previously mentioned, microglia cells have also been implicated on drug addiction. Primed microglial cells could release inflammatory mediators and in the maintenance of drug abuse [64-66]. Because mainly CB2 receptors activation may interfere on microglia activation via anti-neuroinflammatory mechanism, it is reasonable to suggest that cannabinoids effects on drug abuse might be mediated by neuroinflammatory mechanism via microglial cells. Although a recent study was not carried out to investigate this issue, it was shown that CB2 receptor stimulation reduced morphine-induced production of inflammatory mediators by activated microglia [85].
PLEASE INSERT FIGURE 1 ABOUT HERE
Perspectives and conclusions
The present paper reviewed the possible role of neuroinflammation on the mechanism of cannabinoids on drug addiction. Here we explored the hypothesis that a disruption in cannabinoid signaling during drug addiction process would involve microglial activation and neuroinflammation (Figure 1).
Several pieces of evidences suggested that psychostimulants drugs induce microglia activation and the expression of inflammatory mediators, such as cytokines and transcription factors. (endo)cannabinoids may act as immunomodulators by inhibiting cytokines production and microglial cell activation. This later mechanism seems to be of particular importance since CB2 receptors located in activated microglia cells might play a major role on neuroinflammatory processes related to addiction. Additional studies however, designed to test this hypothesis, are needed in order to elucidate the contribution of neuroinflammation on the behavioral and neuroprotective effects of cannabinoids on drug addiction. 
Conflict of interest statement
Authors do not declare any conflict of interest.
Acknowledgements
We thank Radael J�nior for his technical support on design and graphic art.  This work was supported by grants from CNPq, CAPES, FAPES (Programa Primeiros Projetos (PPP) number 53630408/2011) and FAPEMIG (Programa Primeiros Projetos (PPP), number CBB-APQ-04389-10; Programa de Apoio a Nucleos Emergentes de Pesquisa (PRONEM), number CBB-APQ-04625-10) and Pro-Reitoria de Pesquisa da UFMG (PRPq), Brazil. FAM and ALT are a recipient of productivity research fellowship (level 2 and 1C respectively) from CNPq. ACC is a recipient of CNPq fellowship. 

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���z�����a�%��������c������������D�E�F�GbH�H�IK�K�L7M����������������������������	7$8$H$gdm=ed�f�����������F�L�����������������������D�D�D�E�Ҿ����Ҿҫ����n�nW�UW�>,hm=eh�9NCJOJQJaJmH	nHsH	tHU,hm=eh�Z�CJOJQJaJmH	nHsH	tH,hm=eh~E�CJOJQJaJmH	nHsH	tH$hFh�<CJOJQJaJnHtH$hFhOg�CJOJQJaJnHtH$hFh~E�CJOJQJaJnHtH&h�<CJOJQJaJmH	nHsH	tH,hm=ehR:CJOJQJaJmH	nHsH	tH,hm=ehOg�CJOJQJaJmH	nHsH	tH] Shi, J., Johansson, J., Woodling, N. S., Wang, Q., Montine, T. J. and Andreasson, K. (2010) The prostaglandin E2 E-prostanoid 4 receptor exerts anti-inflammatory effects in brain innate immunity. J Immunol. 184 12: 7207-7218.
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Figure1- Role of microglial CB2 receptor in the possible mechanism linking neuroinflammation, (endo)cannabinoids and addiction. 








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