Immune System: a Possible Nexus Between Cannabinoids and Psychosis

YBRBI 2305 No. of Pages 14, Model 5G 11 February 2014

Brain, Behavior, and Immunity xxx (2014) xxx–xxx 1 Contents lists available at ScienceDirect

Brain, Behavior, and Immunity

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3 Immune system: A possible nexus between cannabinoids and psychosis

a,b,c,⇑,1 a,1 a,b,c 6 Q1 Paula Suárez-Pinilla , José López-Gil , Benedicto Crespo-Facorro

7 a University Hospital Marqués de Valdecilla, Department of Psychiatry, School of Medicine, University of Cantabria, Santander, Spain 8 b CIBERSAM, Biomedical Research Network on Mental Health Area, Madrid, Spain 9 c IFIMAV, Valdecilla Biomedical Research Institute, Santander, Spain

1011 article info abstract 2913 14 Article history: Background: Endocannabinoid system is involved in the regulation of the brain-immune axis. Cannabis 30 15 Received 28 October 2013 consumption is related with the development, course, and severity of psychosis. The epidemiological evi- 31 16 Received in revised form 29 January 2014 dence for increased occurrence of immunological alterations in patients with psychosis has not been suf- 32 17 Accepted 29 January 2014 ficiently addressed. The aim of this review is to establish whether there is any scientific evidence of the 33 18 Available online xxxx influence of cannabinoids on aspects of immunity that affect susceptibility to psychotic disorder induc- 34 tion. 35 19 Keywords: Methods: A comprehensive search of PubMed/MEDLINE, EMBASE and ISI Web of Knowledge was per- 36 20 D9THC formed using combinations of key terms distributed into three blocks: ‘‘immune’’, ‘‘cannabinoid’’, and 37 21 First-episode psychosis 22 Immunology ‘‘endocannabinoid receptor’’. Studies were considered to be eligible for the review if they were original 38 23 Endocannabinoid system articles, they reported a quantitative or qualitative relation between cannabinoid ligands, their receptors, 39 24 Schizophrenia and immune system, and they were carried out in vitro or in mammals, included humans. All the infor- 40 25 Cytokines mation was systematically extracted and evaluated. 41 26 Microglia Results: We identified 122 articles from 446 references. Overall, endocannabinoids enhanced immune 42 27 Infection response, whereas exogenous cannabinoids had immunosuppressant effects. A general change in the 43 28 immune response from Th1 to Th2 was also demonstrated for cannabinoid action. Endogenous and syn- 44 thetic cannabinoids also modulated microglia function and neurotransmitter secretion. 45 Conclusion: The actions of cannabinoids through the immune system are quite regular and predictable in 46 the peripheral but remain fuzzy in the central nervous system. Despite this uncertainty, it may be 47 hypothesized that exposure to exocannabinoids, in particular during adolescence might prompt immu- 48 nological dysfunctions that potentially cause a latent vulnerability to psychosis. Further investigations 49 are warranted to clarify the relationship between the immunological effects of cannabis and psychosis. 50 Ó 2014 Published by Elsevier Inc. 51 52

53 54 55 1. Introduction cannabidiol receptor (GPR18), the G protein coupled receptor 55 64 (GPR55), PPARs, and the vanilloid TRPV1 receptor (Onaivi et al., 65 56 1.1. Endocannabinoid system and ligands 2012). Cannabinoids are ligands for the endocannabinoid recep- 66 tors, that activate the endocannabinoid system (Onaivi, 2009). 67 57 The involvement of the endocannabinoid system in nervous Endocannabinoids, such as anandamide (AE) and 2-arachidonyl- 68 58 system health and disease is currently a topic of interest. The endo- glycerol (2-AG), are generated and released on demand, and their 69 59 cannabinoid system has a pivotal role in the modulation of neuro- synthesis is modulated by intracellular calcium concentrations 70 60 genesis, synaptic plasticity, and neuroprotection (Skaper and Di (Piomelli, 2003). Delta-9-tetrahydrocannabinol (D9THC), the main 71 61 Marzo, 2012). There are two well-characterized cannabinoid psychoactive substance in Cannabis sativa, acts as an exogenous 72 62 receptors, CB1-R and CB2-R, which are part of the endocannabinoid agonist of the endocannabinoid system and may alter endocannab- 73 63 system, together with other candidates: the putative abnormal inoid signaling (Leweke et al., 2007). 74 Cannabinoid receptors are abundantly distributed in the brain 75 and peripheral tissues. They are G-protein-coupled receptors that, 76 ⇑ Corresponding author. Address: Unidad de Investigación Psiquiatría, Hospital when activated, inhibit intracellular cyclic AMP concentration and 77 Universitario Marqués de Valdecilla, Avda. Valdecilla, SN, 39008 Santander, Spain. activates mitogen-activated protein kinases (MAPKs) (Childers 78 Tel.: +34 942 203826. et al., 1993). CB1 receptors are localized in the central nervous sys- 79 E-mail address: p.suarez.pinilla@gmail.com (P. Suárez-Pinilla). tem (CNS), mainly in glutamate and gamma-aminobutyric acid 80 1 These authors have equally contributed to this work.

http://dx.doi.org/10.1016/j.bbi.2014.01.018 0889-1591/Ó 2014 Published by Elsevier Inc.

Please cite this article in press as: Suárez-Pinilla, P., et al. Immune system: A possible nexus between cannabinoids and psychosis. Brain Behav. Immun. (2014), http://dx.doi.org/10.1016/j.bbi.2014.01.018 YBRBI 2305 No. of Pages 14, Model 5G 11 February 2014

2 P. Suárez-Pinilla et al. / Brain, Behavior, and Immunity xxx (2014) xxx–xxx

81 (GABA) terminations (Devane et al., 1992; Chevaleyre et al., 2006), illness supporting this fact are peripheral inflammation, increased 143 82 but they are also present in the periphery of the nervous system intracellular components of the main proinflammatory pathway, 144 83 (Pertwee, 1999). CB2-Rs have a similar structure and are predom- alterations in the classical complement and lectin pathways, glial 145 84 inantly expressed in the spleen and immune cells (Graham et al., cell dysfunction, and interleukin imbalance (McKernan et al., 146 85 2009). Although the proportion of CB2-Rs in the CNS is lower than 2011; Chew et al., 2013; Mayilyan et al., 2008; Garcia-Bueno 147 86 that of CB1-Rs, their presence in brain cells has been demonstrated et al., 2013). Some of these alterations remain after antipsychotic 148 87 (Onaivi et al., 2012). Alterations in the endocannabinoid system treatment (Miller et al., 2011).On the other hand, increased levels 149 88 have been associated with vulnerability to several neuropsychiat- of AE in the serum are associated with clinical improvement in pa- 150 89 ric disorders such as schizophrenia (Bioque et al., 2013; Ishiguro tients with schizophrenia (Leweke et al., 2012). 151 90 et al., 2010). Dysregulations in receptor expression (Eggan et al., Brain inflammation in early life has been proposed to play an 152 91 2008) and alterations in the release of neurotransmitters, such as important role in the development of psychosis-related disorders 153 92 dopamine (Muller-Vahl and Emrich, 2008) and glutamate (Vicen- in adulthood. Animal studies suggest that neonatal inflammation 154 93 te-Sanchez et al., 2013), among others, may be involved. may have a long lasting impact on glutamate (Auclair et al., 155 2000), dopamine (Vuillermot et al., 2010), endocannabinoids 156 94 1.2. Genetic and environmental factors of schizophrenia (Fride, 2004), and their receptors in specific brain areas involved 157 in the pathophysiology of the illness (Zavitsanou et al., 2013). 158 95 Schizophrenia is a serious mental disorder characterized by a Microglia activation seems to be particularly relevant in schizo- 159 96 disintegration of thinking processes and emotional responsiveness, phrenia (Busse et al., 2012). Therefore, during critical phases for 160 97 predominantly defined by signs of psychosis. The pathogenesis is a cerebral development such as adolescence, strong stimulation by 161 98 multifactorial process resulting from the interplay between genetic psychoactive components such as D9THC might lead to lasting 162 99 predisposition and environmental exposure (van Os and Kapur, neurobiological changes that can also affect adult brain functions 163 100 2010). The predominant role of genetic factors in the etiology of and behaviors (Realini et al., 2009). Thus, microglia activation over 164 101 schizophrenia has previously been defined by classical studies of a prolonged period of time can alter the synaptic architecture and 165 102 twins (Cannon et al., 1998), where the estimated concordance rates function (Hickie et al., 2009). 166 103 are 30–40% in monozygotic siblings (Kringlen, 2000). Recently, a In summary, the endocannabinoid system seems to play an 167 104 significant differential expression in several genes of schizophrenia important role in regulating various aspects of neuropsychological 168 105 patients compared to healthy controls has been found. Some of and psycho-behavioral, as well as immunological, functions. Endo- 169 106 these genes are connected with biological pathways related to pro- cannabinoids are being used as biomarkers of several mental ill- 170 107 tein processing and the maturation, the innate immune response, nesses (Leweke et al., 2012). Thus, the endocannabinoid system 171 108 acute inflammatory response, and response to wounding (Sainz represents a novel therapeutic target for stress-related neuroin- 172 109 et al., 2013). Genome-wide association studies (GWAS) of copy flammatory and psychiatric disorders. 173 110 number of variations (CNV) associated with schizophrenia also In light of these findings, it can be suggested that cannabinoids 174 111 implicate a major histocompatibility complex (MHC) region that such as D9THC might produce psychotic symptomatology in 175 112 is consistent with an immune component to schizophrenia schizophrenia susceptible individuals by altering immune pro- 176 113 (Stefansson et al., 2009). cesses. The aim of the present review is to establish whether there 177 114 On the other hand, there is evidence of some environmental is any scientific evidence of the influence of cannabinoids on as- 178 115 factors and putative antecedents that may supplement the pects of immunity that affect susceptibility to disease induction. 179 116 contribution of genetic factors in the development of psychosis. 117 The strongest evidence among putative antecedents was identified 2. Materials and methods 180 118 for motor dysfunction and low intellectual coefficient (IQ) 119 (Matheson et al., 2011). Cannabis use, urbanicity, minority status 2.1. Comprehensive literature search 181 120 or discrimination, prenatal factors, and environmental trauma in 121 childhood or early adolescence are some of the non-genetic factors We systematically reviewed the literature to identify journal 182 122 related to the disorder (van Os et al., 2005). Infection of Toxoplasma articles reporting on the endocannabinoid and immune system 183 123 gondii and elderly fatherhood are also risk factors (Torrey et al., and psychosis. An electronic database search was conducted, 184 124 2012). including PubMed/MEDLINE, EMBASE, and ISI Web of Knowledge, 185 using combinations of key terms distributed into three blocks: 186 125 1.3. Inflammatory hypothesis of schizophrenia ‘‘immune’’, ‘‘cannabinoid’’, and ‘‘endocannabinoid receptor.’’ The 187 reference lists from previous reviews and retrieved articles were 188 126 The alteration of the expression of genes involved in the also hand-searched for additional studies. 189 127 immune and inflammatory response seems to provide further 128 support for the neurodevelopmental model of schizophrenia, 129 which suggests a dimensional rather than categorical concept of 2.2. Eligibility 190 130 psychosis (Sainz et al., 2013; Rapoport et al., 2005; Ayalew et al., 131 2012). The ‘‘double hit’’ theory of the pathogenesis of schizophre- The literature review was limited to English and Spanish lan- 191 132 nia proposes that the illness may involve an early exposure to guage articles published during the last 10 years up to December 192 133 any adverse factor that produces a latent immune vulnerability, 2013. Studies were considered to be eligible for the review if they 193 134 and when this vulnerability is manifested, individuals become met the following criteria: (1) original articles, such as clinical 194 135 more susceptible to infections and immune dysfunctions that con- trials, journal articles, comparative, or multicenter studies; (2) 195 136 Q2 tribute to schizophrenia (Kinney et al., 2010). Thus, it has been studies reporting a quantitative or qualitative relation between 196 137 shown that infection during pregnancy and the exposure to can- (i) cannabinoid ligands, (ii) their receptors, and (iii) actions on 197 138 nabinoids during adolescence might have a synergistic effect on the immune system for a specified period after exposure; (3) pro- 198 139 the integrity of the serotoninergic system (Dalton et al., 2012). spective or retrospective observational (analytical or descriptive, 199 140 Several authors have then suggested that increased inflamma- except case reports), experimental, or quasi-experimental studies; 200 141 tion is associated with schizophrenia (Kirkpatrick and Miller, and (4) studies carried out in vitro or in mammalian animals 201 142 2013). Further processes described during the early phases of the including humans (mammals because of the genetic similarities 202

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203 to humans and the fact that the sequence of early events in brain 204 development is particularly consistent across mammalian species) 205 (Finlay and Darlington, 1995). Studies were excluded for any of the 206 following reasons: (1) other designs, such as case-reports, series of 207 cases, literature reviews, and commentaries; (2) non-original 208 studies, including editorials, prefaces, brief communications, and 209 letters to the editor; reviews or meta-analyses; (3) no results 210 described for the immune system or no clear relation with immune 211 phenomena; and (4) studies conducted on invertebrates or 212 non-mammalian animals. 213 The search strategy and the abstracts retrieved from identiﬁed 214 articles were reviewed independently by two researchers (JLG, 215 PSP) to ensure adequate sampling and to determine the eligibility 216 for inclusion. Disagreements over articles, quality, and inclusion 217 criteria were addressed through discussions with co-authors.

218 2.3. Data collection and analysis

219 After classifying the articles included, each paper in the sample 220 was read in its entirety, and data elements were then extracted and 221 entered in a customized database. Data were extracted from the 222 source documents independently by two investigators (PSP, JLG). Fig. 1. Flow diagram selection of study process. 223 The information collected from each article included the following: 224 (1) authors; (2) publication year; (3) description of intervention; 225 (4) ethical approval; (5) study sample; (6) form of analysis comple- 226 tion/intention to treat; (7) endocannabinoid or exocannabinoid li- 2007) and that the exocannabinoids JWH-015 (selective CB2-R 259 9 227 gands; (8) cannabinoid receptors: CB1-Rs, CB2-R2, GPR55, GPR18, agonist), and D THC (CB1 and 2-R agonist) induced T cell apoptosis 260 228 TRPV1, and others; (9) agonist, inverse agonist, or antagonist ef- (Eisenstein et al., 2007; Lombard et al., 2011). In-vivo mouse 261 229 fect; and (10) main findings, manifestations over involved immune studies demonstrated immunosuppressant effects after exocanna- 262 230 cell lines, or immune targets. binoid administration (Singh et al., 2012; Jan et al., 2007; Alvaro- 263 231 A qualitative approach was chosen because the information Bartolome et al., 2010; Yang et al., 2013). However, information 264 232 necessary to calculate the result size using quantitative methods concerning the exact T cell phenotype was not addressed in the 265 233 is not available, which may limit the analysis to a small subset of original studies. 266 9 234 studies, and because the design of the experiments varies greatly Moreover, the exposure to exocannabinoids, such as D THC, 267 235 among studies included in such a sample, making it difficult to yielded a T cell reaction, with a biased response from Th1 to Th2 268 236 undertake adequate comparisons and implement proper statistical immunity in both in vitro (McKallip et al., 2005) and in vivo studies 269 237 analyses. (Newton et al., 2009, 2004). 270 9 238 To provide a better analysis, for heuristic reasons, the studies Concerning in vivo mouse studies, D THC administration re- 271 239 were compared and grouped into six categories regarding immune duced CD4+ T cells (Roth et al., 2005) and the T cell subpopulation 272 240 target: T cells, B cells and humoral immunity, other leukocytes, in the thymus (Lombard et al., 2011). There was also a suppressed 273 241 cytokines, immune tumor cells, and CNS cell types. expression of the inducible co-stimulator (ICOS) of T lymphocytes 274 (Lu et al., 2009). However, although synthetic cannabinoids inhibit 275 the activation of T cell effectors, exposure resulted in an increase in 276 242 3. Results the regulatory T cell subtype (Arevalo-Martin et al., 2012; Pandey 277 et al., 2011; Croxford et al., 2005; Hegde et al., 2008). Moreover, 278 243 3.1. Study selection influenza infection caused a major T cell activation and infiltration 279 in CB1 and CB2-R knock-out mice compared with wild-type mice 280 244 Electronic database searches yielded 446 references. Fig. 1 illus- (Buchweitz et al., 2007). Exogenous cannabinoid agonists, such as 281 245 trates the flow diagram of the study selection process. After exclu- WIN-55212-2 prevented the development of fibrosis in a mouse 282 246 sion, 122 studies were included in the global synthesis. model of systemic sclerosis (Servettaz et al., 2010), and the CB2- 283 R selective agonist JWH-133 inhibited the expression of adhesion 284 247 3.2. Characteristics of cannabinoid ligands and their receptors molecules in autoimmune mouse uveitis (Xu et al., 2007). An 285 attenuation of CD4+ and CD8+ T cells in the bronchoalveolar fluid 286 248 Table 1 provides an overview of the cannabinoid ligands and in wild-type mice was found after D9THC administration (Karmaus 287 249 receptors included in the systematic review. The 122 studies in- et al., 2011), and a CB1/CB2-R independent signaling mechanism 288 250 cluded a total of six potential endogenous cannabinoid ligands was suggested (Braun et al., 2011). Thus, both knock-out and 289 251 and 27 synthetic cannabinoid ligands, and the receptors: CB1-R, wild-type mice demonstrated inhibited T cell infiltration during 290 252 CB2-R, TRPV1, and GPR18. The immunological role of cannabinoid contact dermatitis induced by exposure to topical D9THC (Gaffal 291 253 ligands is described in the following sections and summarized in et al., 2013). The immunomodulator effect of cannabinoids is ab- 292 254 Table 2. sent in mice deficient for CB2-R (Buckley et al., 2000). These results 293 were assessed by specific measurement parameters in each study, 294 255 3.3. Cannabinoid effects on T cell immunity including the magnitude of the edema (Servettaz et al., 2010) 295 immunohistopathology (Buchweitz et al., 2007; Karmaus et al., 296 256 In most cases, studies yielded attenuated inflammatory 2011), and total cell count (Braun et al., 2011; Gaffal et al., 2013). 297 257 responses after exposure to exo and endocannabinoids. In-vitro Whit regard to in vitro studies, during cultured T cell activation, 298 258 studies found that AE inhibits T cells via CB2-R (Eisenstein et al., there was an induction of CB1-R and l-opioid receptors on the cell 299

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Table 1 3.4. Cannabinoid effects on B cell and humoral immunity 321 Summary of cannabinoid ligands of included articles in the systematic review.

Ligand Activity Selectivity Endocannabinoids, such as 2-AG, have been shown to preferen- 322 323 Endocannabinoids tially induce the chemotaxis of unstimulated naïve B cells (Tanik- Docosatetraenoylethanolamine Agonist CB1 awa et al., 2007), and exocannabinoids have been shown to 324 (DEA) induce the apoptosis of B lymphocytes (Lombard et al., 2011) via 325 Anandamide (AE) Agonist CB1- > CB2-R; TRPV1 CB2-R mechanisms, in in vivo mouse studies. 326 N-palmitoylethanolamide (N- Agonist CB1 and CB2-R Concerning in vivo studies, those conducted in humans 327 PEA) 2-arachidonylglycerol (2-AG) Agonist CB1 > CB2-R observed that exocannabinoid ingestion triggered a significant 328 N-arachidonyl-dopamine Agonist CB1-R and TRPV1 decrease in serum immunoglobulins (IgG and IgM) El-Gohary 329 (NADA) and Eid, 2004. Moreover, those studies carried out in mice found 330 N-arachidonyl glycine (NAGly) Agonist GPR18 that the use of CB2-R antagonists or CB2R knock-out mice showed 331 Synthetic cannabinoids fewer B cells in the marginal zone of lymph nodes compared to 332 D9 Tetrahydrocannabinol Agonist CB1 and CB2-R wild-type mice (Muppidi et al., 2011). There was a decrease in 333 (D9THC) 9 334 D8 Tetrahydrocannabinol Agonist CB1 and CB2-R the CD40L-induced IgM response following D THC administration ACPA Agonist CB1-R in wild-type mice but not in CB-R knock-out mice (Springs et al., 335 Cannabidiol (CBD) Agonist CB1, CB-2-R and 2008). Interestingly, immunized T-antigen mice demonstrated a 336 TRPV1 reduction in splenic B cells in both the knock-out and wild-type 337 b-carophyllene Agonist CB2-R mice, with similar levels of antigen-specific IgM and IgG (Basu 338 JWH-015 Agonist CB2-R JWH-133 Agonist CB2-R et al., 2013). Regarding in vitro studies with cultured lymphocytes, 339 CP55940 Agonist CB1 and CB2-R cannabinoids directly induced B cell antibody class switching from 340 R+Methanandamide Agonist CB1-R IgM to IgE through a mechanism involving CB2-R (Eisenstein et al., 341 1,8-naphthyridine Agonist CB2 > CB1-R 2007; Agudelo et al., 2008). 342 WIN55,212-2 Agonist CB1 and CB2-R 343 ACEA Agonist CB1-R Fig. 2 summarizes the effects of cannabinoids on T and B O-1966 Agonist CB2-R lymphocytes. 344 HU-308 Agonist CB2-R AM-1710 Agonist CB2-R 3.5. Cannabinoid effects on other leukocyte lines 345 AM-1241 Agonist CB2-R N-alkyl-amide Agonist CB2-R Gp1a Antagonist CB2-R Whit regard to the effects of cannabinoids on other leukocyte 346 Sch.336 Inverse agonist CB2-R lines, the results seem more disparate. Some authors explained 347 SR144528 Antagonist CB2-R that these discrepancies may be due to the quantity of ligands, 348 SR141716A Antagonist CB1-R resulting in different or even reversed effects (Croxford et al., 349 PF-095453 Antagonist CB1-R 350 CE-178253 Antagonist CB1-R 2005). In mice (Maestroni, 2004) and in cell culture studies (Maes- AM251 Antagonist CB1-R troni, 2004; Marazzi et al., 2011; Shiratsuchi et al., 2008), endocan- 351 AM630 Antagonist CB2-R nabinoids have been found to activate macrophages and dendritic 352 SB366791 Antagonist TRPV1 cells. However, it has been noted that the fetal bovine serum used 353 Noni (Morinda citrifolia) Selective agonist and CB2-R agonism, CB1-R in laboratories may contain levels of endocannabinoids that could 354 antagonist antagonism alter the results for different cell lines (Marazzi et al., 2011). 355 Abbreviations: ACEA, arachidonyl-2-chloroethylamide; ACPA, arachidonylcyclopro- Conversely, other studies have yielded different results. In in vivo 356 pylamide; CB-R, cannabinoid receptor; GPR18, putative abnormal cannabinoid studies conducted in humans with kidney disease, N-arachidonol- 357 receptor; Gp1a, N-(piperidin-1-y1)-1-(2,4-dichlorophenil)-1,4-dihydro-6-methylindeno [1,2-C] pyrazole-3-carboxamide; SCh.336, selective for the human can- yl-dopamine (NADA) induced mononuclear cell death via TRPV1 358 nabinoid CB2 receptor; TRPV1, transient receptor potential vanilloid receptor. (Saunders et al., 2009). In studies conducted in mice, AE reduced 359 major histocompatibility complex (MHC) II expression in dendritic 360 cells (Wacnik et al., 2008), whereas D9THC triggered the apoptosis 361 of dendritic cells (Do et al., 2004). With respect to the in vitro 362 300 surface, together with the constitutive expression of CB2-R (Kraus, administration of exocannabinoids, WIN 55,212-2 inhibited mac- 363 301 2012). Endo and exocannabinoids were able to inhibit mixed rophage differentiation (Paulsen et al., 2011) and D8THC induced 364 302 lymphocyte reactions in assays for graft reaction through CB2-R macrophage death (Yamaori et al., 2013). CBD (cannabidiol) also 365 303 mechanisms (Robinson et al., 2013), and they attenuated reduced macrophage activation in an ex-vivo mouse study (De Fil- 366 304 chemotaxis in activated T cells (Coopman et al., 2007; Ghosh ippis et al., 2011). 367 305 et al., 2006). Moreover, D9THC induced the mobilization of mye- In relation to neutrophil function, two in vivo studies conducted 368 306 loid-derived suppressor cells (MDSCs) from the bone marrow to in humans directly correlated serum endocannabinoid levels, via 369 307 the periphery, via TRPV1, CB1, and CB2 receptors (Hegde et al., CB2-R, with neutrophil activity, which was measured by hydrogen 370 308 2011, 2010). Therefore, when a high dose of WIN 55,212-2 was peroxide release (Kaufmann et al., 2008; Balenga et al., 2011). In an 371 309 used, splenic lymphocyte migration was inhibited (Tanikawa in vivo study conducted in rabbits, AE was also found to enhance 372 310 et al., 2011). A potential limitation of this in vitro study design is adhesion, phagocytosis, and the migration of neutrophils (Altinsoy 373 311 that the effect of the micromolar concentrations of cannabinoids et al., 2011). Therefore, in rodent studies, the CB2-R inverse agon- 374 312 may or may not be physiologically relevant. ism (Lunn et al., 2006), CB1-R antagonism (Caraceni et al., 2009), 375 313 Nevertheless, other studies have found different and sometimes and the lack of CB2-R (Tschop et al., 2009) resulted in the inhibition 376 314 contradictory results regarding cannabinoid action over T cells. of neutrophil migration and in the response to infection. Moreover, 377 315 Some in vivo mouse studies have shown that the absence or block- in vivo mouse studies obtained an abolition of neutrophil degran- 378 316 age of CB2-R by antagonists resulted in increased T cell apoptosis ulation through the interaction of endocannabinoids with CB2-R 379 317 and a deficiency in splenic CD4+ T cell memory (Avraham et al., and GPR55 (Balenga et al., 2011). There was also a decrease in 380 318 2012; Ziring et al., 2006). The absence of CB1-R also produced a the oxidative function of neutrophils as a result of the in vitro 381 319 decline in T cell infiltration during experimental skin fibrosis in administration of the synthetic cannabinoid CP-55940 through 382 320 an in vivo rodent study (Marquart et al., 2010). CB-R-independent mechanisms (Kraft et al., 2004). It should be 383

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Table 2 Cannabinoid ligands and their actions.

Target cells Actions Ligands Cannabinoid receptors References T-cell Increment receptors in T CB1-R; CB2-R Kraus (2012) cells Major T-cell activation CB1-R and CB2-R knock- Karmaus et al. (2011) out mice Immunosuppressant WIN 55, 212-2 CB1-R Yang et al. (2013) effects in T cells JWH-133 CB2-R Singh et al. (2012) D9THC CB1-R; CB2-R Lombard et al. (2011, 2005), Lu et al. (2009) and Roth et al. (2005) CBD CB1-R; CB2-R Jan et al. (2007) Inhibition SR144528 and CB2-R and CB1-R Eisenstein et al. (2007) immunosuppressant SR141716A effects in T cells Increment T-cell WIN 55, 212-2 CB1-R; CB2-R Arevalo-Martin et al. (2012) regulatory subtype D9THC CB1-R; CB2-R Pandey et al. (2011) and Hegde et al. (2008) Inhibition T-cell effectors WIN 55, 212-2 CB1-R; CB2-R Croxford et al. (2005) Inhibition mixed D9THC CB2-R Robinson et al. (2013) lymphocyte reaction Inhibition T-cell CP55940; AE CB1-R; CB2-R Ribeiro et al. (2013) infiltration AM-1241; JWH- CB2-R Ribeiro et al. (2013) 015 ACPA; CB1-R Ribeiro et al. (2013) Methanandamide ACEA CB1-R Ribeiro et al. (2013) and Marquart et al. (2010) D9THC CB1-R; CB2-R Gaffal et al. (2013) and Buchweitz et al. (2007) D9THC CB1-R and CB2-R knock- Braun et al. (2011) out mice; other receptors Inhibition of activated T- 2-AG; JWH-133 CB2-R Coopman et al. (2007) cell chemotaxis JWH-015; WIN CB2-R Ghosh et al. (2006) 55, 212-2 Mobilization of MDSC to D9THC CB1-R; CB2-R; TRPV1 Hegde et al. (2010, 2011) periphery Bias from Th1 to Th2 D9THC CB1-R; CB2-R Nagarkatti et al. (2010), Newton et al. (2009) and McKallip et al. (2005) Deficiency/ apoptosis of T CB2-R knock-out Avraham et al. (2012) and Ziring et al. (2006) cells B-cell and humoral ; Antibody concentration D9THC El-Gohary and Eid (2004) immunity ; Ig M CP55940 CB2-R Agudelo et al. (2008) Increment of unstimulated 2-AG CB2-R Tanikawa et al. (2007) B-cell chemotaxis Deficiency/ apoptosis of B WIN 55, 212-2; CB2-R Servettaz et al. (2010) cells JWH-133 D9THC CB2-R; CB1-R Lombard et al. (2007) ;B-cell in marginal node CB2-R knock-out mice Muppidi et al. (2011) Memory B-cell formation/ CB2-R Basu et al. (2013) maintenance in the spleen Macrophages/ Macrophage activation AE; 2-AG CB1-R; CB2-R Marazzi et al. (2011) microglia 2-AG CB2-R Shiratsuchi et al. (2008) Microglia reclutation AE GPR-18 McHugh et al. (2010) Macrophage WIN 55, 212-2 Paulsen et al. (2011) immunosuppression D9THC El-Gohary and Eid (2004) D8THC CB2-R Yamaori et al. (2013) N-PEA Other CB-Rs Franklin et al. (2003) Potentiation of microglia migration ; Microglia activation CBD CB2-R Mecha et al. (2013) JWH-015 CB2-R Merighi et al. (2012) O-1966 CB2-R Amenta et al. (2012) 2-AG CB2-R Walter et al. (2003) CBD; D9THC Torres et al. (2011) "Macrophage phagocytosis JWH-015 CB2-R Tolon et al. (2009) in brain ;MHC-II expression in CP55940 Gongora et al. (2004) microglia cells Other immune cell/ Neutrophil activation AE CB1-R Altinsoy et al. (2011) pathways/ 2-AG GPR55 Balenga et al. (2011) molecules 2-AG CB2-R Vannacci et al. (2004) AE Kaufmann et al. (2008) " COX-2 and WIN 55, 212-2 Other CB-Rs Mestre et al. (2005) prostaglandins in brain endothelial cells ; neutrophil migration SR141716A CB1-R Caraceni et al. (2009) Sch. 336 CB2-R Lunn et al. (2006) CB2-R knock-out Tschop et al. (2009) ; T-cell adhesion in SR141716A CB1-R Rossi et al. (2011) venules of brain

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Table 2 (continued)

Target cells Actions Ligands Cannabinoid receptors References Neutrophil D9THC El-Gohary and Eid (2004) immunosuppression WIN 55, 212-2 Paulsen et al. (2011) JWH-133 CB2-R Singh et al. (2012) PMN apoptosis NADA CB1-R; TRPV1 Saunders et al. (2009) D9THC CB1-R; CB2-R Do et al. (2004) No PMN modulation D9THC CB1-R; CB2-R Deusch et al. (2003) NK immunosuppression WIN 55, 212-2 CB2-R Paulsen et al. (2011) JWH-133 CB2-R Singh et al. (2012) D9THC CB2-R El-Gohary and Eid (2004) Mast cell inhibition JWH-133 CB2-R Singh et al. (2012) N-PEA CB2-R Skaper et al. (2013) and Esposito et al. (2011) AE CB2-R Cencioni et al. (2010) CBD De Filippis et al. (2011) ;proinflammatory D9THC CB1-R; CB2-R Gaffal et al. (2013) and Cabral and Marciano-Cabral (2004) cytokines 1,8-naphthyridine CB2-R Malfitano et al. (2013) CB1 and CB2-R knock- Karmaus et al. (2013) out mice AE; 2-AG CB1-R; CB2-R Dutra et al. (2012), Krishnan and Chatterjee (2012), Rettori et al. (2012), Mestre et al. (2005) and Rockwell and Kaminski (2004) B-carophyllene CB2-R Bento et al. (2011) SR144528 and CB2-R and CB1-R Lou et al. (2012, 2011) SR141716A CE-178258 CB1-R Mnich et al. (2010) Methanandamide CB1-R and CB2-R Borner et al. (2009) and JWH-015 N-alkylamide CB2-R Chicca et al. (2009) CBD CB1-R; CB2-R Kaplan et al. (2008) Morinda citrifolia CB2-R Palu et al. (2008) (Noni) WIN 55, 212-2 Downer et al. (2011) and Faubert Kaplan and Kaminski (2003) " IL4, IL10 B-carophyllene CB2-R Bento et al. (2011) N-alkylamide CB2-R Chicca et al. (2009) Morinda citrofila CB2-R Palu et al. (2008) (Noni) AE CB2-R Correa et al. (2010, 2009) CBD CB2-R Sacerdote et al. (2005) " Endocannabinoids 2-AG; AE CB2-R Mimura et al. (2012) and Buckley et al. (2006) CNS protection 2-AG CB2-R Lourbopoulos et al. (2011) HU-308 CB2-R Palazuelos et al. (2006) WIN 55, 212-2 CB2-R Rock et al. (2007) CP55940 CB1-R and CB2-R Lu et al. (2008) AE CB1-R and CB2-R Eljaschewitsch et al. (2006) WIN 55,212-2; CB1-R Pryce et al. (2003) CP55940 ; Dendritic cell migration CB2-R Adhikary et al. (2012) in brain ; Leukocyte activation in JWH-133; O- CB2-R Rom et al. (2013) brain 1966; Gp1a; AM1241 Gp1a CB2-R Gorantla et al. (2010) JWH-133 CB2-R Ramirez et al. (2012) WIN 55, 212-2 CB2-R Ni et al. (2004) ; MHC-II in dendritic cells AE Wacnik et al. (2008) Tumoral cells Apoptosis HL-60 cells 2-AG CB2-R Gokoh et al. (2007) Apoptosis jurkatt leukemia D9THC Lombard et al. (2005) cells Inhibition migration of DEA, AE CB1-R Joseph et al. (2004) colon carcinoma cells Apoptosis human breast D9THC CB2-R McKallip et al. (2005) cells ;IL6 secretion by prostate Methanandamide Olea-Herrero et al. (2009) cancer cells "IL8 secretion by HL-60 2-AG Kishimoto et al. leukaemia cells Apoptosis hepatocellular WIN 55, 212-2 Pellerito et al. (2010) carcinoma cells

Abbreviations: 2-AG, 2-arachidonylglycerol; D9THC, tetrahydrocannabinol; ACEA, arachidonyl-2-chloroethylamide; ACPA, arachidonylcyclopropylamide; AE, anandamide; CBD. cannabidiol; CB-R, cannabinoid receptor; CNS, central nervous system; COX-2, cyclooxygenase-2; DEA, docosatetraenoylethanolamine; GPR18, putative abnormal cannabinoid receptor; Gp1a, N-(piperidin-1-y1)-1-(2,4-dichlorophenil)-1,4-dihydro-6-methylindeno [1,2-C] pyrazole-3-carboxamide; MDSC, myeloid-derived suppressor cells; NADA, N-arachidonyl-dopamine; N-PEA, N-palmitoylethanolamide; SCh.336, selective for the human cannabinoid CB2 receptor; TRPV1, transient receptor potential vanilloid receptor.

384 noted, though, that other authors did not observe any potential With regard to other leukocyte lines, one study conducted in 387 385 effect on polymorphonuclear leukocyte function using D9THC humans demonstrated an inhibition of natural killer (NK) cells 388 386 (Deusch et al., 2003). and neutrophil differentiation, following the ingestion of D9THC 389

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390 derivates (El-Gohary and Eid, 2004). Both exo- and endocannabi- cells in the periphery but also in the CNS. This effect was not rep- 421 391 noids inhibited mast cell activation under in vitro conditions licated with the in vitro administration of the CB1-R agonist, arach- 422 392 (Vannacci et al., 2004). idonyl-2-chloroethylamide (ACEA) Cencioni et al., 2010. The use of 423 CB1 antagonists in vivo with mice and in vitro, such as SR- 424 141716A, did not reverse the inhibition of proinflammatory cyto- 425 393 3.6. Cytokine regulation kines produced by cannabinoids (Rockwell and Kaminski, 2004). 426 Furthermore, in vivo mouse studies showed that a blockade of 427 394 In vitro (Cencioni et al., 2010; Krishnan and Chatterjee, 2012; CB2-R, not CB1-R, with selective antagonists exacerbated inflam- 428 395 Rockwell and Kaminski, 2004) and in vivo (Rockwell and Kaminski, matory pathologies (Michler et al., 2013). However, the role of 429 396 2004; Rettori et al., 2012; Mestre et al., 2005) murine studies have CB-R in cytokine regulation and whether this action is coupled to 430 397 found that endocannabinoids suppress the production and release CB1-R or CB2-R are still poorly defined. Some authors have sug- 431 398 of pro-inflammatory cytokines, such as IL-1b, IL-2, TNF-a, and IFN- gested a CB1-R/CB2-R independent signal in in vivo mouse studies 432 399 c. However, they did not exert any cytotoxic effect on resting cells (Braun et al., 2011; Ribeiro et al., 2013). Paradoxically, selective 433 400 (Cencioni et al., 2010; Krishnan and Chatterjee, 2012). Exogenous CB1-R antagonism in mice was shown to inhibit the release of such 434 401 cannabinoid stimulation, in vivo (Jan et al., 2007; Hegde et al., proinflammatory cytokines (Mnich et al., 2010). Morinda citrofolia 435 402 2008; Gaffal et al., 2013) and in vitro (Borner et al., 2009; Kaplan (Noni), which activates CB2-R and inhibits CB1-R at the same time, 436 403 et al., 2008; Karmaus et al., 2013; Faubert Kaplan and Kaminski, resulted in the suppression of IL-4 but an increase in IFN-c, under 437 404 2003; Cabral and Marciano-Cabral, 2004; Bento et al., 2011), inhib- in vitro and in vivo conditions in mice (Palu et al., 2008). 438 405 ited the activation of an extracellular signal-regulated kinase, a 406 subgroup of the MAPKs, and therefore, suppressed IL-2 and IFN-c 407 production. Moreover, in vivo studies carried out in CB1 and 408 CB2-R knock-out mice found increased levels of proinflammatory 3.7. The effects of cannabinoids on tumor cells related to the immune 439 409 cytokines (Dutra et al., 2012). Concerning anti-inflammatory cyto- system 440 410 kines, in vitro stimulation with the exocannabinoid N-alkyl-amide 411 enhanced IL-10 production (Chicca et al., 2009). However, different Eight of the included studies were based on cultured tumor cells 441 412 results were found in another in vitro and in vivo mouse study, related to the immune system. Studies conducted in vitro showed 442 413 indicating a significant reduction of IL-10 after CBD administration that the endocannabinoid 2-AG enhanced adhesion in HL-60 cells, 443 414 (Sacerdote et al., 2005). via CB2-R (Gokoh et al., 2007), and AE together with docosatetrae- 444 415 Several studies have demonstrated the key role of CB2-R in noylethanolamaine (DEA), inhibited the migration of carcinoma 445 416 modulating peripheral cytokine levels. Thus, CB2-R selective colon cells, through CB1-R (Joseph et al., 2004). In-vitro exocanna- 446 417 agonists (Cencioni et al., 2010; Chicca et al., 2009; Malfitano binoid exposure induced the apoptosis of human hepatocellular 447 418 et al., 2013; Harvey et al., 2013; Downer et al., 2011; Correa cells (Pellerito et al., 2010), Jurkatt leukemia cells (Lombard et al., 448 419 et al., 2009), in vitro and in vivo in mice exerted a suppressive 2005), and U373MG glioma cells, via CB1-R (Widmer et al., 449 420 action on the secretion of proinflammatory cytokine by immune 2008). Interestingly, exocannabinoids exert antitumoral effects 450

Fig. 2. The effects of cannabinoids on T and B lymphocytes. Abbreviations: D9THC, D9 tetrahydrocannabinol; CB-R, cannabinoid receptor; ICOS, inducible co-stimulator of T- cells; IL1R, interleukin-1 receptor; TcR, T-cell receptor.

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451 on glioma cells, but they protect the non-transformed counterparts attenuated monocyte adhesion and migration across human brain 515 452 from apoptosis (Torres et al., 2011). microvascular cells and diminished the damage to the BBB (Rom 516 453 In vitro studies with human breast cancer cells and in vivo stud- et al., 2013). Interestingly, selective CB1 inverse agonism inhibited 517 454 ies with mouse mammary carcinoma cells revealed that tumor the T cell adhesion to inﬂamed brain venules in vitro (Rossi et al., 518 455 cells were resistant to the cytolytic action of D9THC if they ex- 2011). 519 456 pressed a low level of CB2-R (McKallip et al., 2005). It is important Cannabinoids are also involved in neurogenesis. One study 520 457 to note that D9THC doses were pharmacologically relevant (50 mg/ demonstrated, with in vitro and in vivo techniques, that the selec- 521 458 kg). Moreover, in vitro studies showed that methanandamide tive agonism of CB2-R with HU-308 promoted neural progenitor 522 459 enhanced the secretion of IL-6 in prostate cancer PC3 cells cell proliferation and neurosphere generation, demonstrating 523 460 (Olea-Herrero et al., 2009), and 2-AG induced IL-8 secretion in CB2-R expression in neural progenitor cells (Palazuelos et al., 524 461 HL-60 leukemia cells (Kishimoto et al., 2004), both via CB2-R 2006). Another study using EAE in a rodent model of MS found that 525 462 dependent mechanisms. An important limitation of these studies mice deﬁcient in CB1-R have been found to tolerate insults poorly 526 463 is that these cells are usually genetically heterogeneous, and it is and develop substantial neurodegeneration compared to the wild- 527 464 possible that other lines may behave differently under cannabinoid type mice (Pryce et al., 2003). 528 465 stimulation (Widmer et al., 2008). Fig. 3 summarizes cannabinoids actions in CNS cell types. 529

466 3.8. The role of cannabinoids in CNS cell types 4. Discussion 530 467 Under acute neuroinflammatory conditions, an increase in 468 endocannabinoid synthesis was observed (Esposito et al., 2011). The present review confirms that the endocannabinoid system 531 469 Different in vivo and in vitro studies found that endocannabi- plays a key role in the regulation of immune homeostasis. The 532 470 noids have neuroprotective effects. In-vivo studies showed that influence of cannabinoids on the immune system is well-known 533 471 2-AG ameliorated experimental autoimmune encephalomyelitis in relation to long-term effects and has been described by several 534 472 (EAE) in a mouse model of multiple sclerosis (MS) and reduced ax- authors (Lombard et al., 2011; Buckley et al., 2006; Tanasescu 535 473 onal pathology (Lourbopoulos et al., 2011). N-palmitoylethanol- and Constantinescu, 2010). 536 474 amine (N-PEA) down-modulated mast cell activation, via CB2-R, Although immunological dysfunction has been described as a 537 475 and potentiated microglia migration through cannabinoid recep- vulnerability factor for schizophrenia (Kinney et al., 2010; Knight 538 476 tors, independent of CB1 and CB2-R (Franklin and Stella, 2003; et al., 1992), the underlying mechanisms are not well understood. 539 477 Franklin et al., 2003). Likewise, in vitro exposure to AE (Eljasche- The results of this review indicate that cannabinoids, such as 540 478 witsch et al., 2006; Correa et al., 2010) and its metabolite N-arach- D9THC, alter cytokine production and secretion in most immune 541 479 idonyl glycine (NAGly) McHugh et al., 2010 protected microglia system cell lines, including CNS cells. It is crucial to note that cyto- 542 480 cells via CB1 and CB2-R and also recruited microglia to sites of kines are involved in normal CNS development and may play a key 543 481 interest, via GPR18. role in the pathogenesis of neuropsychiatric disorders by modulat- 544 482 With regard to exocannabinoids, they also seem to have neuro- ing neurotransmitter and neuropeptide systems (Kronfol and Re- 545 483 protective actions. In vitro (Walter et al., 2003; Gongora et al., mick, 2000; Muller and Ackenheil, 1998) such as central 546 484 2004) and in vivo rodent studies (Torres et al., 2010; Amenta monoamine activity (Zalcman et al., 1994). Taken together, these 547 485 et al., 2012; Mecha et al., 2013) have reported a decrease in two events may partly explain why the onset of cannabis con- 548 486 microglia activation, especially via CB2-R, which was constitutively sumption at an earlier age has been identified by several authors 549 487 expressed at the mRNA level in primary cultured microglia cells as a factor contributing to poor prognosis in schizophrenia (DeLisi, 550 488 (Ehrhart et al., 2005). In vivo mouse studies have reported an 1992; Veen et al., 2004). Moreover, recent GWAS data have shown 551 489 attenuation of leukocyte adhesion and infiltration (Ramirez et al., an aberrant expression of certain genes that can contribute to 552 490 2012; Gorantla et al., 2010; Ni et al., 2004) and an abolition of den- schizophrenia. One of them, the TCF4 (transcription factor 4) gene, 553 491 dritic cell migration (Adhikary et al., 2012) after the administration encodes a protein that is expressed in immune as well as neuronal 554 492 of exocannabinoids. cells and is required for neuronal differentiation in the developing 555 493 Stimulation of CB2-R in vitro with the selective synthetic ago- brain. The aberrant expression of this gene may explain, in part, 556 494 nist JWH-015 produced a long-term inhibition of the release of immune alterations in schizophrenia patients (Ayalew et al., 2012). 557 495 reactive oxygen species by cultured microglia cells (Merighi Microglia dysfunction has been posited as another fundamental 558 496 et al., 2012). In vitro and in situ studies revealed that CB2-R activa- factor in schizophrenia development (Bernstein et al., 2009; Stei- 559 497 tion with JWH-015 induced the removal of b-amyloid from human ner et al., 2006; Stella, 2009). During the early stages of psychosis, 560 498 frozen tissue (Tolon et al., 2009). Exocannabinoids, such as WIN anomalies and changes in the function of glial cells have been ob- 561 499 55,212-2 and CP55940, resulted in an in vitro suppression of the served, leading to alterations in white matter, with higher microg- 562 500 replication of human immunodeficiency virus (HIV) within lial cell numbers and decreased oligodendrocytes, which might 563 501 microglia cells and inhibited the permeability of human BBB, via clarify connectivity abnormalities between white matter and cells 564 502 CB2-R (Rock et al., 2007; Lu et al., 2008). Limitations that are high- (Chew et al., 2013; Bernstein et al., 2009). Microglia cells are re- 565 503 lighted for these studies are the different cell response depending lated to synaptic metabolism, and they enhance CB2-R expression 566 504 on the environment, and the discrepancies between physiologic during inflammation (Cabral and Griffin-Thomas, 2008). The re- 567 505 and cultured microglia cells. sults described in this review are consistent with this fact and 568 506 Studies have found that cannabinoid receptor activation medi- show a modulation of microglia function by cannabinoids, both 569 507 ate immunomodulatory actions in CNS cells. Both CB1 and CB2-R endogenous and synthetic cannabinoids. This dysregulation might 570 508 seem to be involved in this activity. During neuroinflammation cause an alteration in the neuronal architecture or the neurotrans- 571 509 or CNS damage, in vivo mouse studies revealed an over-expression mitter flow (Busse et al., 2012; Hickie et al., 2009; Bernstein et al., 572 510 of CB2-R in neurons, macrophages, microglia cells, and astrocytes 2009; Leweke and Koethe, 2008). This response means that 573 511 as well as in peripheral immune cells (Lou et al., 2011; Cutando cannabinoid action may not be limited to direct changes at the 574 512 et al., 2013; Sisay et al., 2013). Neurons, macrophages, and microg- neurotransmitter level; it may alter the ‘‘immune atmosphere’’ of 575 513 lia were also found to express CB1-R (Lou et al., 2012). In an in vitro the brain directly or by means of a mast cell-glia communication 576 514 model of the blood brain barrier (BBB), CB2-R synthetic agonists (Skaper et al., 2013). In light of these findings, we would like to 577

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Fig. 3. The role of cannabinoids in central nervous system cell types. Abbreviations: BBB, brain–blood barrier; CB-R, cannabinoid receptor; CNS, central nervous system; NAGly: N-arachidonyl glycine.

578 speculate that these changes may be a significant factor in under- produces pro-inflammatory cytokines, whereas the Th2 cells pro- 611 579 standing the relationship between some cannabinoids, such as mote humoral immune responses and mainly secrete anti-inflam- 612 580 D9THC, and the pathogenesis of psychosis. matory cytokines. However, it is unclear which response is altered 613 581 Overall, our results show a general neuroprotective effect of in schizophrenia and whether this factor may be implicated in the 614 582 both, endo and exocannabinoids, which may support their use in genesis of the mental illness. Several studies show contradictory 615 583 the treatment of schizophrenia. Their anti-inflammatory properties results: some authors have found a decrease in the plasma levels 616 584 are equal to those of aspirin and non-steroidal anti-inflammatory of Th1 type cytokines and an increase in the production of Th2 617 585 drugs, which are also being investigated for potential use as a psy- cytokines in medicated patients with psychosis (Wilke et al., 618 586 chosis treatment (Nitta et al., 2013). CBD inhibits the degradation 1996; Cazzullo et al., 1998; Schwarz et al., 2001; Borovcanin 619 587 of AE in serum and cerebrospinal fluid (CSF) of patients, and it et al., 2012; Muller et al., 2000) as well as in never-medicated sub- 620 588 resulted in a significant improvement of psychotic symptoms jects (Ganguli et al., 1995) and in the cerebrospinal fluid of child- 621 589 (Leweke et al., 2012). hood-onset schizophrenia patients (Mittleman et al., 1997). 622 590 The nature of cannabinoids, synthetic or endogenous, plays an However, other authors have failed to corroborate these findings 623 591 important role and has been formally summarized. Endocannabi- in schizophrenia patients (Muller et al., 2000), and still other inves- 624 592 noids may enhance the immune response, whereas exogenous can- tigations seem to point to an overactivation of Th1 activity at the 625 593 nabinoids may have immunosuppressant effects (Tanasescu and onset of the illness (Crespo-Facorro et al., 2008; Kim et al., 2004). 626 594 Constantinescu, 2010). Furthermore, endocannabinoids show These differences suggest that the bias shown under cannabinoid 627 595 localized, long-term stimulatory effects, whereas exocannabinoids stimulation may be influenced by the cell line and the nature of 628 596 exert more generalized and longer effects with a suppressive char- the inflammation. It may be speculated that this is not a polarized 629 597 acter. The biological targets for cannabinoids include CB1 and CB2- imbalance between Th1 and Th2 and that it depends on each par- 630 598 R. CB1-Rs are the main receptors responsible of the psychoactive ticular cytokine and also on the time cut-off for measurement. 631 599 effects of cannabinoids. Endocannabinoids activate CB1 and CB2- Therefore, there is evidence for a neuroinflammatory state in 632 600 R but with a significantly higher affinity for CB1-R, whereas the schizophrenia, that can increase the serum concentration of some 633 601 synthetic cannabinoids can be joined to both or can be selective pro-inflammatory cytokines (Muller et al., 2000). On the other 634 602 for each of them. D9THC is targeted to both, CB1 and CB2-R in a hand, it seems that the treatment with antipsychotic drugs may 635 603 similar manner (Huffman, 2005; Palmer et al., 2000; Cabral and affect the cytokine network, most likely through a shift in the 636 604 Staab, 2005). Therefore, alterations in the expression of immune response toward the Th2 type (Chen et al., 2012), in the 637 605 cannabinoid receptor expression may lead to a different same way as cannabinoids. 638 606 physiological response and may be related to psychotic diseases In addition, it has been postulated that the peripheral immune 639 607 (Fernandez-Espejo et al., 2009). system mirrors the activity of the CNS (Centonze et al., 2008). Thus, 640 608 Moreover, a general change in the immune response from Th1 a range of autoimmune diseases are related to schizophrenia 641 609 to Th2 is also observed for cannabinoid action in this review. The (Eaton et al., 2010) and may cause the increased permeability of 642 610 Th1 system promotes cell-mediated immune responses and mainly the BBB (Pathmanandavel et al., 2013). Dysfunctions in the BBB 643

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644 have been detected in patients with psychosis (Busse et al., 2012) model of multiple sclerosis by restoring self-tolerance to myelin. 710 Neuropharmacology 63 (3), 385–393. 711 645 and together with T and B cell infiltration, may contribute to the Auclair, N., Otani, S., Soubrie, P., Crepel, F., 2000. Cannabinoids modulate synaptic 712 646 pathophysiology of the illness. strength and plasticity at glutamatergic synapses of rat prefrontal cortex 713 647 Finally, a general apoptotic effect of cannabinoids has been pyramidal neurons. J. Neurophysiol. 83 (6), 3287–3293. 714 715 648 found in tumor cells. However, cannabinoids seem to exert a pro- Avraham, Y., Amer, J., Doron, S., Abu-Tair, L., Mahamid, M., Khatib, A., et al., 2012. The direct profibrotic and indirect immune antifibrotic balance of blocking the 716 649 tective function in normal cells, thereby preventing oxidative cannabinoid 2 receptor. Am. J. Physiol. Gastrointest. Liver Physiol. 302 (12), 717 650 stress and apoptosis (Torres et al., 2011). Similarly, atypical anti- G1364–G1372. 718 719 651 psychotics seem to have a protective effect (Wang et al., 2005). Ayalew, M., Le-Niculescu, H., Levey, D.F., Jain, N., Changala, B., Patel, S.D., et al., 2012. Convergent functional genomics of schizophrenia: from comprehensive 720 652 Some authors have described increased apoptosis in the fibroblasts understanding to genetic risk prediction. Mol. Psychiatry 17 (9), 887–905. 721 653 of schizophrenia patients (Catts et al., 2006). In contrast, recent Balenga, N.A., Aflaki, E., Kargl, J., Platzer, W., Schroder, R., Blattermann, S., et al., 722 654 data support the notion that abnormal proliferation due to anti- 2011. GPR55 regulates cannabinoid 2 receptor-mediated responses in human 723 neutrophils. Cell Res. 21 (10), 1452–1469. 724 655 apoptotic mechanisms may represent a relevant factor in the path- Basu, S., Ray, A., Dittel, B.N., 2013. Cannabinoid receptor 2 (CB2) plays a role in the 725 656 ogenesis of psychosis in which glutamatergic neurotransmission generation of germinal center and memory B cells, but not in the production of 726 657 might play an important role (Genius et al., 2012). Thus, it can be antigen-specific IgG and IgM, in response to T-dependent antigens. PLoS ONE 8 727 (6), e67587. 728 658 speculated that an imbalance in the cannabinoid system may alter Bento, A.F., Marcon, R., Dutra, R.C., Claudino, R.F., Cola, M., Leite, D.F., et al., 2011. 729 659 the neuronal proliferation that may be involved in the pathogene- Beta-caryophyllene inhibits dextran sulfate sodium-induced colitis in mice 730 660 sis of neuropsychiatric disorders. through CB2 receptor activation and PPARgamma pathway. Am. J. Pathol. 178 731 (3), 1153–1166. 732 661 This review is subject to some limitations that are worth noting. Bernstein, H.G., Steiner, J., Bogerts, B., 2009. Glial cells in schizophrenia: 733 662 Some of the drawbacks are inherent in the original studies; how- pathophysiological significance and possible consequences for therapy. Expert 734 663 ever, the limitations of these studies were included in the sum- Rev. Neurother. 9 (7), 1059–1071. 735 736 664 mary of findings at the time that they were addressed. Bioque, M., Garcia-Bueno, B., Macdowell, K.S., Meseguer, A., Saiz, P.A., Parellada, M., et al., 2013. Peripheral endocannabinoid system dysregulation in first-episode 737 665 Furthermore, even though several of the cell lines were studied psychosis. Neuropsychopharmacology 38 (13), 2568–2577. 738 666 in the articles included in the review, some are not represented Borner, C., Smida, M., Hollt, V., Schraven, B., Kraus, J., 2009. Cannabinoid receptor 739 740 667 sufficiently to enable clear conclusions to be drawn. Finally, it type 1- and 2-mediated increase in cyclic AMP inhibits T cell receptor-triggered signaling. J. Biol. Chem. 284 (51), 35450–35460. 741 668 should be noted that four of the 122 studies were conducted Borovcanin, M., Jovanovic, I., Radosavljevic, G., Djukic Dejanovic, S., Bankovic, D., 742 669 in vivo in humans apparently not suffering from psychosis (El-Goh- Arsenijevic, N., et al., 2012. Elevated serum level of type-2 cytokine and low IL- 743 670 ary and Eid, 2004; Saunders et al., 2009; Kaufmann et al., 2008; 17 in first episode psychosis and schizophrenia in relapse. J. Psychiatr. Res. 46 744 (11), 1421–1426. 745 671 Balenga et al., 2011), and this fact should be considered when Braun, A., Engel, T., Aguilar-Pimentel, J.A., Zimmer, A., Jakob, T., Behrendt, H., et al., 746 672 interpreting the results. Among the strengths of this review is 2011. Beneficial effects of cannabinoids (CB) in a murine model of allergen- 747 673 the fact that, to our knowledge, it is the largest systematic effort induced airway inflammation: role of CB1/CB2 receptors. Immunobiology 216 748 (4), 466–476. 749 674 to summarize data on the interaction of endocannabinoids and Buchweitz, J.P., Karmaus, P.W., Harkema, J.R., Williams, K.J., Kaminski, N.E., 2007. 750 675 the immune system. Modulation of airway responses to influenza A/PR/8/34 by Delta9- 751 676 In conclusion, the actions of cannabinoids throughout the im- tetrahydrocannabinol in C57BL/6 mice. J. Pharmacol. Exp. Ther. 323 (2), 675– 752 683. 753 677 mune system are quite regular and predictable in the peripheral Buckley, N.E., McCoy, K.L., Mezey, E., Bonner, T., Zimmer, A., Felder, C.C., et al., 2000. 754 678 nervous system but not always in the CNS. However, a consistent Immunomodulation by cannabinoids is absent in mice deficient for the 755 679 explanation for their relationship with immunity and psychotic cannabinoid CB(2) receptor. Eur. J. Pharmacol. 396 (2–3), 141–149. 756 757 680 diseases remains fuzzy. Despite this uncertainty, it may be Buckley, N.E., Burbridge, D., Buranapramest, M., Ferguson, T., Paau, R.Y., 2006. Experimental methods to study the role of the peripheral cannabinoid receptor 758 681 hypothesized that exposure to exocannabinoids, in particular in immune function. Methods Mol. Med. 123, 19–40. 759 682 during adolescence, might prompt immunological dysfunctions Busse, S., Busse, M., Schiltz, K., Bielau, H., Gos, T., Brisch, R., et al., 2012. Different 760 761 683 that potentially cause a latent vulnerability to psychosis and in distribution patterns of lymphocytes and microglia in the hippocampus of patients with residual versus paranoid schizophrenia: further evidence for 762 684 turn increase the risk of schizophrenia. Further investigations are disease course-related immune alterations? Brain Behav. Immun. 26 (8), 1273– 763 685 warranted to clarify the relationship between the immunological 1279. 764 686 effects of cannabis and psychosis. Cabral, G.A., Griffin-Thomas, L., 2008. Cannabinoids as therapeutic agents for 765 ablating neuroinflammatory disease. Endocr. Metab. Immune Disord. Drug 766 Targets 8 (3), 159–172. 767 768 687 Appendix A. Supplementary data Cabral, G.A., Marciano-Cabral, F., 2004. Cannabinoid-mediated exacerbation of brain infection by opportunistic amebae. J. Neuroimmunol. 147 (1–2), 127–130. 769 Cabral, G.A., Staab, A., 2005. Effects on the immune system. Handb. Exp. Pharmacol. 770 688 Supplementary data associated with this article can be found, in 168, 385–423. 771 689 the online version, at http://dx.doi.org/10.1016/j.bbi.2014.01.018. Cannon, T.D., Kaprio, J., Lonnqvist, J., Huttunen, M., Koskenvuo, M., 1998. The 772 genetic epidemiology of schizophrenia in a Finnish twin cohort. A population- 773 based modeling study. Arch. Gen. Psychiatry 55 (1), 67–74. 774 690 Q3 References Caraceni, P., Pertosa, A.M., Giannone, F., Domenicali, M., Grattagliano, I., Principe, A., 775 et al., 2009. Antagonism of the cannabinoid CB-1 receptor protects rat liver 776 against ischaemia-reperfusion injury complicated by endotoxaemia. Gut 58 (8), 777 691 Adhikary, S., Kocieda, V.P., Yen, J.H., Tuma, R.F., Ganea, D., 2012. Signaling through 1135–1143. 778 692 cannabinoid receptor 2 suppresses murine dendritic cell migration by Catts, V.S., Catts, S.V., McGrath, J.J., Feron, F., McLean, D., Coulson, E.J., et al., 2006. 779 693 inhibiting matrix metalloproteinase 9 expression. Blood 120 (18), 3741–3749. Apoptosis and schizophrenia: a pilot study based on dermal fibroblast cell lines. 780 694 Agudelo, M., Newton, C., Widen, R., Sherwood, T., Nong, L., Friedman, H., et al., 2008. Schizophr. Res. 84 (1), 20–28. 781 695 Cannabinoid receptor 2 (CB2) mediates immunoglobulin class switching from Cazzullo, C.L., Scarone, S., Grassi, B., Vismara, C., Trabattoni, D., Clerici, M., 1998. 782 696 IgM to IgE in cultures of murine-purified B lymphocytes. J. Neuroimmune Cytokines production in chronic schizophrenia patients with or without 783 697 Pharmacol. 3 (1), 35–42. paranoid behaviour. Prog. Neuropsychopharmacol. Biol. Psychiatry 22 (6), 784 698 Altinsoy, A., Dilekoz, E., Kul, O., Ilhan, S.O., Tunccan, O.G., Seven, I., et al., 2011. A 947–957. 785 699 cannabinoid ligand, anandamide, exacerbates endotoxin-induced uveitis in Cencioni, M.T., Chiurchiu, V., Catanzaro, G., Borsellino, G., Bernardi, G., Battistini, L., 786 700 rabbits. J. Ocul. Pharmacol. Ther. 27 (6), 545–552. et al., 2010. Anandamide suppresses proliferation and cytokine release from 787 701 Alvaro-Bartolome, M., Esteban, S., Garcia-Gutierrez, M.S., Manzanares, J., Valverde, primary human T-lymphocytes mainly via CB2 receptors. PLoS ONE 5 (1), e8688. 788 702 O., Garcia-Sevilla, J.A., 2010. Regulation of Fas receptor/Fas-associated protein Centonze, D., Battistini, L., Maccarrone, M., 2008. The endocannabinoid system in 789 703 with death domain apoptotic complex and associated signalling systems by peripheral lymphocytes as a mirror of neuroinflammatory diseases. Curr. 790 704 cannabinoid receptors in the mouse brain. Br. J. Pharmacol. 160 (3), 643–656. Pharm. Des. 14 (23), 2370–2382. Q4 791 705 Amenta, P.S., Jallo, J.I., Tuma, R.F., Elliott, M.B., 2012. A cannabinoid type 2 receptor Chen, M.L., Tsai, T.C., Wang, L.K., Lin, Y.Y., Tsai, Y.M., Lee, M.C., et al., 2012. 792 706 agonist attenuates blood-brain barrier damage and neurodegeneration in a Risperidone modulates the cytokine and chemokine release of dendritic cells 793 707 murine model of traumatic brain injury. J. Neurosci. Res. 90 (12), 2293–2305. and induces TNF-alpha-directed cell apoptosis in neutrophils. Int. 794 708 Arevalo-Martin, A., Molina-Holgado, E., Guaza, C., 2012. A CB(1)/CB(2) receptor Immunopharmacol. 12 (1), 197–204. 795 709 agonist, WIN 55,212-2, exerts its therapeutic effect in a viral autoimmune

P. Suárez-Pinilla et al. / Brain, Behavior, and Immunity xxx (2014) xxx–xxx 11

796 Chevaleyre, V., Takahashi, K.A., Castillo, P.E., 2006. Endocannabinoid-mediated Fernandez-Espejo, E., Viveros, M.P., Nunez, L., Ellenbroek, B.A., Rodriguez de 882 797 synaptic plasticity in the CNS. Annu. Rev. Neurosci. 29, 37–76. Fonseca, F., 2009. Role of cannabis and endocannabinoids in the genesis of 883 798 Chew, L.J., Fusar-Poli, P., Schmitz, T., 2013. Oligodendroglial alterations and the role schizophrenia. Psychopharmacology (Berl) 206 (4), 531–549. 884 799 of microglia in white matter injury: relevance to schizophrenia. Dev. Neurosci. Finlay, B.L., Darlington, R.B., 1995. Linked regularities in the development and 885 800 35 (2–3), 102–129. evolution of mammalian brains. Science 268 (5217), 1578–1584. 886 801 Chicca, A., Raduner, S., Pellati, F., Strompen, T., Altmann, K.H., Schoop, R., et al., 2009. Franklin, A., Stella, N., 2003. Arachidonylcyclopropylamide increases microglial cell 887 802 Synergistic immunomopharmacological effects of N-alkylamides in Echinacea migration through cannabinoid CB2 and abnormal-cannabidiol-sensitive 888 803 purpurea herbal extracts. Int. Immunopharmacol. 9 (7–8), 850–858. receptors. Eur. J. Pharmacol. 474 (2–3), 195–198. 889 804 Childers, S.R., Pacheco, M.A., Bennett, B.A., Edwards, T.A., Hampson, R.E., Mu, J., et al., Franklin, A., Parmentier-Batteur, S., Walter, L., Greenberg, D.A., Stella, N., 2003. 890 805 1993. Cannabinoid receptors: G-protein-mediated signal transduction Palmitoylethanolamide increases after focal cerebral ischemia and potentiates 891 806 mechanisms. Biochem. Soc. Symp. 59, 27–50. microglial cell motility. J. Neurosci. 23 (21), 7767–7775. 892 807 Coopman, K., Smith, L.D., Wright, K.L., Ward, S.G., 2007. Temporal variation in CB2R Fride, E., 2004. The endocannabinoid-CB receptor system: importance for 893 808 levels following T lymphocyte activation: evidence that cannabinoids modulate development and in pediatric disease. Neuro. Endocrinol. Lett. 25 (1–2), 24–30. 894 809 CXCL12-induced chemotaxis. Int. Immunopharmacol. 7 (3), 360–371. Gaffal, E., Cron, M., Glodde, N., Tuting, T., 2013. Anti-inflammatory activity of topical 895 810 Correa, F., Docagne, F., Mestre, L., Clemente, D., Hernangomez, M., Loria, F., et al., THC in DNFB-mediated mouse allergic contact dermatitis independent of CB1 896 811 2009. A role for CB2 receptors in anandamide signalling pathways involved in and CB2 receptors. Allergy 68 (8), 994–1000. 897 812 the regulation of IL-12 and IL-23 in microglial cells. Biochem. Pharmacol. 77 (1), Ganguli, R., Brar, J.S., Chengappa, K.R., DeLeo, M., Yang, Z.W., Shurin, G., et al., 1995. 898 813 86–100. Mitogen-stimulated interleukin-2 production in never-medicated, first-episode 899 814 Correa, F., Hernangomez, M., Mestre, L., Loria, F., Spagnolo, A., Docagne, F., et al., 2010. schizophrenic patients. The influence of age at onset and negative symptoms. 900 815 Anandamide enhances IL-10 production in activated microglia by targeting CB(2) Arch. Gen. Psychiatry 52 (8), 668–672. 901 816 receptors: roles of ERK1/2, JNK, and NF-kappaB. Glia 58 (2), 135–147. Garcia-Bueno, B., Bioque, M., Mac-Dowell, K.S., Barcones, M.F., Martinez- 902 817 Crespo-Facorro, B., Carrasco-Marin, E., Perez-Iglesias, R., Pelayo-Teran, J.M., Cengotitabengoa, M., Pina-Camacho, L., et al., 2013. Pro-/anti-inflammatory 903 818 Fernandez-Prieto, L., Leyva-Cobian, F., et al., 2008. Interleukin-12 plasma dysregulation in patients with first episode of psychosis: toward an integrative 904 819 levels in drug-naive patients with a first episode of psychosis: effects of inflammatory hypothesis of schizophrenia. Schizophr. Bull.. Q5 905 820 antipsychotic drugs. Psychiatry Res. 158 (2), 206–216. Genius, J., Benninghoff, J., Reuter, N., Braun, I., Giegling, I., Hartmann, A., et al., 2012. 906 821 Croxford, J.L., Wang, K., Miller, S.D., Engman, D.M., Tyler, K.M., 2005. Effects of Dysequilibrium of neuronal proliferation and apoptosis in a pharmacological 907 822 cannabinoid treatment on Chagas disease pathogenesis: balancing inhibition of animal model of psychosis. Methods 56 (4), 519–527. 908 823 parasite invasion and immunosuppression. Cell. Microbiol. 7 (11), 1592–1602. Ghosh, S., Preet, A., Groopman, J.E., Ganju, R.K., 2006. Cannabinoid receptor CB2 909 824 Cutando, L., Busquets-Garcia, A., Puighermanal, E., Gomis-Gonzalez, M., Delgado- modulates the CXCL12/CXCR4-mediated chemotaxis of T lymphocytes. Mol. 910 825 Garcia, J.M., Gruart, A., et al., 2013. Microglial activation underlies cerebellar Immunol. 43 (14), 2169–2179. 911 826 deficits produced by repeated cannabis exposure. J. Clin. Invest. 123 (7), 2816– Gokoh, M., Kishimoto, S., Oka, S., Sugiura, T., 2007. 2-Arachidonoylglycerol enhances 912 827 2831. the phagocytosis of opsonized zymosan by HL-60 cells differentiated into 913 828 Dalton, V.S., Verdurand, M., Walker, A., Hodgson, D.M., Zavitsanou, K., 2012. macrophage-like cells. Biol. Pharm. Bull. 30 (7), 1199–1205. 914 829 Synergistic effect between maternal infection and adolescent cannabinoid Gongora, C., Hose, S., O’Brien, T.P., Sinha, D., 2004. Downregulation of class II 915 830 exposure on serotonin 5HT1A receptor binding in the hippocampus: testing the transactivator (CIITA) expression by synthetic cannabinoid CP55,940. Immunol. 916 831 ‘‘Two Hit’’ hypothesis for the development of schizophrenia. ISRN Psychiatr. Lett. 91 (1), 11–16. 917 832 2012, 451865. Gorantla, S., Makarov, E., Roy, D., Finke-Dwyer, J., Murrin, L.C., Gendelman, H.E., 918 833 De Filippis, D., Esposito, G., Cirillo, C., Cipriano, M., De Winter, B.Y., Scuderi, C., et al., et al., 2010. Immunoregulation of a CB2 receptor agonist in a murine model of 919 834 2011. Cannabidiol reduces intestinal inflammation through the control of neuroAIDS. J. Neuroimmune Pharmacol. 5 (3), 456–468. 920 835 neuroimmune axis. PLoS ONE 6 (12), e28159. Graham, E.S., Ashton, J.C., Glass, M., 2009. Cannabinoid receptors: a brief history and 921 836 DeLisi, L.E., 1992. The significance of age of onset for schizophrenia. Schizophr. Bull. ‘‘what’s hot’’. Front. Biosci. (Landmark Ed.) 14, 944–957. 922 837 18 (2), 209–215. Harvey, B.S., Nicotra, L.L., Vu, M., Smid, S.D., 2013. Cannabinoid CB2 receptor 923 838 Deusch, E., Kraft, B., Nahlik, G., Weigl, L., Hohenegger, M., Kress, H.G., 2003. No activation attenuates cytokine-evoked mucosal damage in a human colonic 924 839 evidence for direct modulatory effects of delta 9-tetrahydrocannabinol on explant model without changing epithelial permeability. Cytokine 63 (2), 209– 925 840 human polymorphonuclear leukocytes. J. Neuroimmunol. 141 (1–2), 99–103. 217. 926 841 Devane, W.A., Hanus, L., Breuer, A., Pertwee, R.G., Stevenson, L.A., Griffin, G., et al., Hegde, V.L., Hegde, S., Cravatt, B.F., Hofseth, L.J., Nagarkatti, M., Nagarkatti, P.S., 927 842 1992. Isolation and structure of a brain constituent that binds to the 2008. Attenuation of experimental autoimmune hepatitis by exogenous and 928 843 cannabinoid receptor. Science 258 (5090), 1946–1949. endogenous cannabinoids: involvement of regulatory T cells. Mol. Pharmacol. 929 844 Do, Y., McKallip, R.J., Nagarkatti, M., Nagarkatti, P.S., 2004. Activation through 74 (1), 20–33. 930 845 cannabinoid receptors 1 and 2 on dendritic cells triggers NF-kappaB-dependent Hegde, V.L., Nagarkatti, M., Nagarkatti, P.S., 2010. Cannabinoid receptor activation 931 846 apoptosis: novel role for endogenous and exogenous cannabinoids in leads to massive mobilization of myeloid-derived suppressor cells with potent 932 847 immunoregulation. J. Immunol. 173 (4), 2373–2382. immunosuppressive properties. Eur. J. Immunol. 40 (12), 3358–3371. 933 848 Downer, E.J., Clifford, E., Gran, B., Nel, H.J., Fallon, P.G., Moynagh, P.N., 2011. Hegde, V.L., Nagarkatti, P.S., Nagarkatti, M., 2011. Role of myeloid-derived 934 849 Identification of the synthetic cannabinoid R(+)WIN55,212–2 as a novel suppressor cells in amelioration of experimental autoimmune hepatitis 935 850 regulator of IFN regulatory factor 3 activation and IFN-beta expression: following activation of TRPV1 receptors by cannabidiol. PLoS ONE 6 (4), e18281. 936 851 relevance to therapeutic effects in models of multiple sclerosis. J. Biol. Chem. Hickie, I.B., Banati, R., Stewart, C.H., Lloyd, A.R., 2009. Are common childhood or 937 852 286 (12), 10316–10328. adolescent infections risk factors for schizophrenia and other psychotic 938 853 Dutra, R.C., Simao da Silva, K.A., Bento, A.F., Marcon, R., Paszcuk, A.F., Meotti, F.C., disorders? Med. J. Aust. 190 (4 Suppl), S17–S21. 939 854 et al., 2012. Euphol, a tetracyclic triterpene produces antinociceptive effects in Huffman, J.W., 2005. CB2 receptor ligands. Mini Rev. Med. Chem. 5 (7), 641–649. 940 855 inflammatory and neuropathic pain: the involvement of cannabinoid system. Ishiguro, H., Horiuchi, Y., Ishikawa, M., Koga, M., Imai, K., Suzuki, Y., et al., 2010. 941 856 Neuropharmacology 63 (4), 593–605. Brain cannabinoid CB2 receptor in schizophrenia. Biol. Psychiatry 67 (10), 974– 942 857 Eaton, W.W., Pedersen, M.G., Nielsen, P.R., Mortensen, P.B., 2010. Autoimmune 982. 943 858 diseases, bipolar disorder, and non-affective psychosis. Bipolar Disord. 12 (6), Jan, T.R., Su, S.T., Wu, H.Y., Liao, M.H., 2007. Suppressive effects of cannabidiol 944 859 638–646. on antigen-specific antibody production and functional activity of 945 860 Eggan, S.M., Hashimoto, T., Lewis, D.A., 2008. Reduced cortical cannabinoid 1 splenocytes in ovalbumin-sensitized BALB/c mice. Int. Immunopharmacol. 7 946 861 receptor messenger RNA and protein expression in schizophrenia. Arch. Gen. (6), 773–780. 947 862 Psychiatry 65 (7), 772–784. Joseph, J., Niggemann, B., Zaenker, K.S., Entschladen, F., 2004. Anandamide is an 948 863 Ehrhart, J., Obregon, D., Mori, T., Hou, H., Sun, N., Bai, Y., et al., 2005. Stimulation of endogenous inhibitor for the migration of tumor cells and T lymphocytes. 949 864 cannabinoid receptor 2 (CB2) suppresses microglial activation. J. Neuroinflamm. Cancer Immunol. Immunother. 53 (8), 723–728. 950 865 2, 29. Kaplan, B.L., Springs, A.E., Kaminski, N.E., 2008. The profile of immune modulation 951 866 Eisenstein, T.K., Meissler, J.J., Wilson, Q., Gaughan, J.P., Adler, M.W., 2007. by cannabidiol (CBD) involves deregulation of nuclear factor of activated T cells 952 867 Anandamide and Delta9-tetrahydrocannabinol directly inhibit cells of the (NFAT). Biochem. Pharmacol. 76 (6), 726–737. 953 868 immune system via CB2 receptors. J. Neuroimmunol. 189 (1–2), 17–22. Karmaus, P.W., Chen, W., Crawford, R.B., Harkema, J.R., Kaplan, B.L., Kaminski, N.E., 954 869 El-Gohary, M., Eid, M.A., 2004. Effect of cannabinoid ingestion (in the form of bhang) 2011. Deletion of cannabinoid receptors 1 and 2 exacerbates APC function to 955 870 on the immune system of high school and university students. Hum. Exp. increase inflammation and cellular immunity during influenza infection. J. 956 871 Toxicol. 23 (3), 149–156. Leukoc. Biol. 90 (5), 983–995. 957 872 Eljaschewitsch, E., Witting, A., Mawrin, C., Lee, T., Schmidt, P.M., Wolf, S., et al., 2006. Karmaus, P.W., Chen, W., Crawford, R., Kaplan, B.L., Kaminski, N.E., 2013. Delta9- 958 873 The endocannabinoid anandamide protects neurons during CNS inflammation tetrahydrocannabinol impairs the inflammatory response to influenza 959 874 by induction of MKP-1 in microglial cells. Neuron 49 (1), 67–79. infection: role of antigen-presenting cells and the cannabinoid receptors 1 960 875 Esposito, E., Paterniti, I., Mazzon, E., Genovese, T., Di Paola, R., Galuppo, M., et al., and 2. Toxicol. Sci. 131 (2), 419–433. 961 876 2011. Effects of palmitoylethanolamide on release of mast cell peptidases and Kaufmann, I., Schelling, G., Eisner, C., Richter, H.P., Krauseneck, T., Vogeser, M., et al., 962 877 neurotrophic factors after spinal cord injury. Brain Behav. Immun. 25 (6), 1099– 2008. Anandamide and neutrophil function in patients with fibromyalgia. 963 878 1112. Psychoneuroendocrinology 33 (5), 676–685. 964 879 Faubert Kaplan BL, B.L., Kaminski, N.E., 2003. Cannabinoids inhibit the activation of Kim, Y.K., Myint, A.M., Lee, B.H., Han, C.S., Lee, H.J., Kim, D.J., et al., 2004. Th1, Th2 965 880 ERK MAPK in PMA/Io-stimulated mouse splenocytes. Int. Immunopharmacol. 3 and Th3 cytokine alteration in schizophrenia. Prog. Neuropsychopharmacol. 966 881 (10–11), 1503–1510. Biol. Psychiatry 28 (7), 1129–1134. 967

12 P. Suárez-Pinilla et al. / Brain, Behavior, and Immunity xxx (2014) xxx–xxx

968 Kinney, D.K., Hintz, K., Shearer, E.M., Barch, D.H., Riffin, C., Whitley, K., et al., 2010. A McKernan, D.P., Dennison, U., Gaszner, G., Cryan, J.F., Dinan, T.G., 2011. Enhanced 1054 969 unifying hypothesis of schizophrenia: abnormal immune system development peripheral toll-like receptor responses in psychosis: further evidence of a pro- 1055 970 may help explain roles of prenatal hazards, post-pubertal onset, stress, inflammatory phenotype. Transl. Psychiatry 1, e36. 1056 971 genes, climate, infections, and brain dysfunction. Med. Hypotheses 74 (3), Mecha, M., Feliu, A., Inigo, P.M., Mestre, L., Carrillo-Salinas, F.J., Guaza, C., 2013. 1057 972 555–563. Cannabidiol provides long-lasting protection against the deleterious effects of 1058 973 Kirkpatrick, B., Miller, B.J., 2013. Inflammation and schizophrenia. Schizophr. Bull. inflammation in a viral model of multiple sclerosis: a role for A2A receptors. 1059 974 39 (6), 1174–1179. Neurobiol. Dis. 59, 141–150. 1060 975 Kishimoto, S., Kobayashi, Y., Oka, S., Gokoh, M., Waku, K., Sugiura, T., 2004. 2- Merighi, S., Gessi, S., Varani, K., Simioni, C., Fazzi, D., Mirandola, P., et al., 2012. 1061 976 Arachidonoylglycerol, an endogenous cannabinoid receptor ligand, induces Cannabinoid CB(2) receptors modulate ERK-1/2 kinase signalling and NO 1062 977 accelerated production of chemokines in HL-60 cells. J. Biochem. 135 (4), 517– release in microglial cells stimulated with bacterial lipopolysaccharide. Br. J. 1063 978 524. Pharmacol. 165 (6), 1773–1788. 1064 979 Knight, J., Knight, A., Ungvari, G., 1992. Can autoimmune mechanisms account for Mestre, L., Correa, F., Arevalo-Martin, A., Molina-Holgado, E., Valenti, M., Ortar, G., 1065 980 the genetic predisposition to schizophrenia? Br. J. Psychiatry 160, 533–540. et al., 2005. Pharmacological modulation of the endocannabinoid system in a 1066 981 Kraft, B., Wintersberger, W., Kress, H.G., 2004. Cannabinoid receptor-independent viral model of multiple sclerosis. J. Neurochem. 92 (6), 1327–1339. 1067 982 suppression of the superoxide generation of human neutrophils (PMN) by CP55 Michler, T., Storr, M., Kramer, J., Ochs, S., Malo, A., Reu, S., et al., 2013. Activation of 1068 983 940, but not by anandamide. Life Sci. 75 (8), 969–977. cannabinoid receptor 2 reduces inflammation in acute experimental 1069 984 Kraus, J., 2012. Expression and functions of mu-opioid receptors and cannabinoid pancreatitis via intra-acinar activation of p38 and MK2-dependent 1070 985 receptors type 1 in T lymphocytes. Ann. N. Y. Acad. Sci. 1261, 1–6. mechanisms. Am. J. Physiol. Gastrointest. Liver Physiol. 304 (2), G181–G192. 1071 986 Kringlen, E., 2000. Twin studies in schizophrenia with special emphasis on Miller, B.J., Buckley, P., Seabolt, W., Mellor, A., Kirkpatrick, B., 2011. Meta-analysis of 1072 987 concordance figures. Am. J. Med. Genet. 97 (1), 4–11. cytokine alterations in schizophrenia: clinical status and antipsychotic effects. 1073 988 Krishnan, G., Chatterjee, N., 2012. Endocannabinoids alleviate proinflammatory Biol. Psychiatry 70 (7), 663–671. 1074 989 conditions by modulating innate immune response in muller glia during Mittleman, B.B., Castellanos, F.X., Jacobsen, L.K., Rapoport, J.L., Swedo, S.E., Shearer, 1075 990 inflammation. Glia 60 (11), 1629–1645. G.M., 1997. Cerebrospinal fluid cytokines in pediatric neuropsychiatric disease. 1076 991 Kronfol, Z., Remick, D.G., 2000. Cytokines and the brain: implications for clinical J. Immunol. 159 (6), 2994–2999. 1077 992 psychiatry. Am. J. Psychiatry 157 (5), 683–694. Mnich, S.J., Hiebsch, R.R., Huff, R.M., Muthian, S., 2010. Anti-inflammatory 1078 993 Leweke, F.M., Koethe, D., 2008. Cannabis and psychiatric disorders: it is not only properties of CB1-receptor antagonist involves beta2 adrenoceptors. J. 1079 994 addiction. Addict. Biol. 13 (2), 264–275. Pharmacol. Exp. Ther. 333 (2), 445–453. 1080 995 Leweke, F.M., Giuffrida, A., Koethe, D., Schreiber, D., Nolden, B.M., Kranaster, L., et al., Muller, N., Ackenheil, M., 1998. Psychoneuroimmunology and the cytokine action in 1081 996 2007. Anandamide levels in cerebrospinal fluid of first-episode schizophrenic the CNS: implications for psychiatric disorders. Prog. Neuropsychopharmacol. 1082 997 patients: impact of cannabis use. Schizophr. Res. 94 (1–3), 29–36. Biol. Psychiatry 22 (1), 1–33. 1083 998 Leweke, F.M., Piomelli, D., Pahlisch, F., Muhl, D., Gerth, C.W., Hoyer, C., et al., 2012. Muller, N., Riedel, M., Ackenheil, M., Schwarz, M.J., 2000. Cellular and humoral 1084 999 Cannabidiol enhances anandamide signaling and alleviates psychotic immune system in schizophrenia: a conceptual re-evaluation. World J. Biol. 1085 1000 symptoms of schizophrenia. Transl. Psychiatry 2, e94. Psychiatry 1 (4), 173–179. 1086 1001 Lombard, C., Nagarkatti, M., Nagarkatti, P.S., 2005. Targeting cannabinoid receptors Muller, N., Riedel, M., Gruber, R., Ackenheil, M., Schwarz, M.J., 2000. The immune 1087 1002 to treat leukemia: role of cross-talk between extrinsic and intrinsic pathways in system and schizophrenia. An integrative view. Ann. N. Y. Acad. Sci. 917, 456– 1088 1003 Delta9-tetrahydrocannabinol (THC)-induced apoptosis of Jurkat cells. Leuk. Res. 467. 1089 1004 29 (8), 915–922. Muller-Vahl, K.R., Emrich, H.M., 2008. Cannabis and schizophrenia: towards a 1090 1005 Lombard, C., Hegde, V.L., Nagarkatti, M., Nagarkatti, P.S., 2011. Perinatal exposure to cannabinoid hypothesis of schizophrenia. Expert Rev. Neurother. 8 (7), 1037– 1091 1006 Delta9-tetrahydrocannabinol triggers profound defects in T cell differentiation 1048. 1092 1007 and function in fetal and postnatal stages of life, including decreased Muppidi, J.R., Arnon, T.I., Bronevetsky, Y., Veerapen, N., Tanaka, M., Besra, G.S., et al., 1093 1008 responsiveness to HIV antigens. J. Pharmacol. Exp. Ther. 339 (2), 607–617. 2011. Cannabinoid receptor 2 positions and retains marginal zone B cells within 1094 1009 Lou, Z.Y., Chen, C., He, Q., Zhao, C.B., Xiao, B.G., 2011. Targeting CB(2) receptor as a the splenic marginal zone. J. Exp. Med. 208 (10), 1941–1948. 1095 1010 neuroinflammatory modulator in experimental autoimmune Newton, C.A., Lu, T., Nazian, S.J., Perkins, I., Friedman, H., Klein, T.W., 2004. The THC- 1096 1011 encephalomyelitis. Mol. Immunol. 49 (3), 453–461. induced suppression of Th1 polarization in response to Legionella pneumophila 1097 1012 Lou, Z.Y., Zhao, C.B., Xiao, B.G., 2012. Immunoregulation of experimental infection is not mediated by increases in corticosterone and PGE2. J. Leukoc. 1098 1013 autoimmune encephalomyelitis by the selective CB1 receptor antagonist. J. Biol. 76 (4), 854–861. 1099 1014 Neurosci. Res. 90 (1), 84–95. Newton, C.A., Chou, P.J., Perkins, I., Klein, T.W., 2009. CB(1) and CB(2) cannabinoid 1100 1015 Lourbopoulos, A., Grigoriadis, N., Lagoudaki, R., Touloumi, O., Polyzoidou, E., receptors mediate different aspects of delta-9-tetrahydrocannabinol (THC)- 1101 1016 Mavromatis, I., et al., 2011. Administration of 2-arachidonoylglycerol induced T helper cell shift following immune activation by Legionella 1102 1017 ameliorates both acute and chronic experimental autoimmune pneumophila infection. J. Neuroimmune Pharmacol. 4 (1), 92–102. 1103 1018 encephalomyelitis. Brain Res. 16 (1390), 126–141. Ni, X., Geller, E.B., Eppihimer, M.J., Eisenstein, T.K., Adler, M.W., Tuma, R.F., 2004. 1104 1019 Lu, T.S., Avraham, H.K., Seng, S., Tachado, S.D., Koziel, H., Makriyannis, A., et al., Win 55212–2, a cannabinoid receptor agonist, attenuates leukocyte/endothelial 1105 1020 2008. Cannabinoids inhibit HIV-1 Gp120-mediated insults in brain interactions in an experimental autoimmune encephalomyelitis model. Mult. 1106 1021 microvascular endothelial cells. J. Immunol. 181 (9), 6406–6416. Scler. 10 (2), 158–164. 1107 1022 Lu, H., Kaplan, B.L., Ngaotepprutaram, T., Kaminski, N.E., 2009. Suppression of T cell Nitta, M., Kishimoto, T., Muller, N., Weiser, M., Davidson, M., Kane, J.M., et al., 2013. 1108 1023 costimulator ICOS by Delta9-tetrahydrocannabinol. J. Leukoc. Biol. 85 (2), 322– Adjunctive use of nonsteroidal anti-inflammatory drugs for schizophrenia: a 1109 1024 329. meta-analytic investigation of randomized controlled trials. Schizophr. Bull. 39 1110 1025 Lunn, C.A., Fine, J.S., Rojas-Triana, A., Jackson, J.V., Fan, X., Kung, T.T., et al., 2006. A (6), 1230–1241. 1111 1026 novel cannabinoid peripheral cannabinoid receptor-selective inverse Olea-Herrero, N., Vara, D., Malagarie-Cazenave, S., Diaz-Laviada, I., 2009. Inhibition 1112 1027 agonist blocks leukocyte recruitment in vivo. J. Pharmacol. Exp. Ther. 316 (2), of human tumour prostate PC-3 cell growth by cannabinoids R(+)- 1113 1028 780–788. Methanandamide and JWH-015: involvement of CB2. Br. J. Cancer 101 (6), 1114 1029 Maestroni, G.J., 2004. The endogenous cannabinoid 2-arachidonoyl glycerol as 940–950. 1115 1030 in vivo chemoattractant for dendritic cells and adjuvant for Th1 response to a Onaivi, E.S., 2009. Cannabinoid receptors in brain: pharmacogenetics, 1116 1031 soluble protein. FASEB J. 18 (15), 1914–1916. neuropharmacology, neurotoxicology, and potential therapeutic applications. 1117 1032 Malfitano, A.M., Laezza, C., D’Alessandro, A., Procaccini, C., Saccomanni, G., Int. Rev. Neurobiol. 88, 335–369. 1118 1033 Tuccinardi, T., et al., 2013. Effects on immune cells of a new 1,8- Onaivi, E.S., Ishiguro, H., Gu, S., Liu, Q.R., 2012. CNS effects of CB2 cannabinoid 1119 1034 naphthyridin-2-one derivative and its analogues as selective CB2 agonists: receptors: beyond neuro-immuno-cannabinoid activity. J. Psychopharmacol. 26 1120 1035 implications in multiple sclerosis. PLoS ONE 8 (5), e62511. (1), 92–103. 1121 1036 Marazzi, J., Kleyer, J., Paredes, J.M., Gertsch, J., 2011. Endocannabinoid content in Palazuelos, J., Aguado, T., Egia, A., Mechoulam, R., Guzman, M., Galve-Roperh, I., 1122 1037 fetal bovine sera – unexpected effects on mononuclear cells and 2006. Non-psychoactive CB2 cannabinoid agonists stimulate neural progenitor 1123 1038 osteoclastogenesis. J. Immunol. Methods 373 (1–2), 219–228. proliferation. FASEB J. 20 (13), 2405–2407. 1124 1039 Marquart, S., Zerr, P., Akhmetshina, A., Palumbo, K., Reich, N., Tomcik, M., et al., Palmer, S.L., Khanolkar, A.D., Makriyannis, A., 2000. Natural and synthetic 1125 1040 2010. Inactivation of the cannabinoid receptor CB1 prevents leukocyte endocannabinoids and their structure-activity relationships. Curr. Pharm. Des. 1126 1041 infiltration and experimental fibrosis. Arthritis Rheum. 62 (11), 3467–3476. 6 (13), 1381–1397. 1127 1042 Matheson, S.L., Shepherd, A.M., Laurens, K.R., Carr, V.J., 2011. A systematic meta- Palu, A.K., Kim, A.H., West, B.J., Deng, S., Jensen, J., White, L., 2008. The effects of 1128 1043 review grading the evidence for non-genetic risk factors and putative Morinda citrifolia L. (noni) on the immune system: its molecular mechanisms of 1129 1044 antecedents of schizophrenia. Schizophr. Res. 133 (1–3), 133–142. action. J. Ethnopharmacol. 115 (3), 502–506. 1130 1045 Mayilyan, K.R., Weinberger, D.R., Sim, R.B., 2008. The complement system in Pandey, R., Hegde, V.L., Nagarkatti, M., Nagarkatti, P.S., 2011. Targeting cannabinoid 1131 1046 schizophrenia. Drug News Perspect. 21 (4), 200–210. receptors as a novel approach in the treatment of graft-versus-host disease: 1132 1047 McHugh, D., Hu, S.S., Rimmerman, N., Juknat, A., Vogel, Z., Walker, J.M., et al., 2010. evidence from an experimental murine model. J. Pharmacol. Exp. Ther. 338 (3), 1133 1048 N-arachidonoyl glycine, an abundant endogenous lipid, potently drives directed 819–828. 1134 1049 cellular migration through GPR18, the putative abnormal cannabidiol receptor. Pathmanandavel, K., Starling, J., Dale, R.C., Brilot, F., 2013. Autoantibodies and the 1135 1050 BMC Neurosci. 11, 44. immune hypothesis in psychotic brain diseases: challenges and perspectives. 1136 1051 McKallip, R.J., Nagarkatti, M., Nagarkatti, P.S., 2005. Delta-9-tetrahydrocannabinol Clin. Dev. Immunol. 2013, 257184. 1137 1052 enhances breast cancer growth and metastasis by suppression of the antitumor Paulsen, K., Tauber, S., Timm, J., Goelz, N., Dumrese, C., Stolzing, A., et al., 2011. The 1138 1053 immune response. J. Immunol. 174 (6), 3281–3289. cannabinoid receptors agonist WIN55212-2 inhibits macrophageal 1139

P. Suárez-Pinilla et al. / Brain, Behavior, and Immunity xxx (2014) xxx–xxx 13

1140 differentiation and alters expression and phosphorylation of cell cycle control Skaper, S.D., Facci, L., Giusti, P., 2013. Glia and mast cells as targets for 1226 1141 proteins. Cell Commun. Signal. 9, 33. palmitoylethanolamide, an anti-inflammatory and neuroprotective lipid 1227 1142 Pellerito, O., Calvaruso, G., Portanova, P., De Blasio, A., Santulli, A., Vento, R., et al., mediator. Mol. Neurobiol. 48 (2), 340–352. 1228 1143 2010. The synthetic cannabinoid WIN 55,212-2 sensitizes hepatocellular Springs, A.E., Karmaus, P.W., Crawford, R.B., Kaplan, B.L., Kaminski, N.E., 2008. 1229 1144 carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand Effects of targeted deletion of cannabinoid receptors CB1 and CB2 on immune 1230 1145 (TRAIL)-induced apoptosis by activating p8/CCAAT/enhancer binding protein competence and sensitivity to immune modulation by Delta9- 1231 1146 homologous protein (CHOP)/death receptor 5 (DR5) axis. Mol. Pharmacol. 77 tetrahydrocannabinol. J. Leukoc. Biol. 84 (6), 1574–1584. 1232 1147 (5), 854–863. Stefansson, H., Ophoff, R.A., Steinberg, S., Andreassen, O.A., Cichon, S., Rujescu, D., 1233 1148 Pertwee, R.G., 1999. Evidence for the presence of CB1 cannabinoid receptors on et al., 2009. Common variants conferring risk of schizophrenia. Nature 460 1234 1149 peripheral neurones and for the existence of neuronal non-CB1 cannabinoid (7256), 744–747. 1235 1150 receptors. Life Sci. 65 (6–7), 597–605. Steiner, J., Mawrin, C., Ziegeler, A., Bielau, H., Ullrich, O., Bernstein, H.G., et al., 2006. 1236 1151 Piomelli, D., 2003. The molecular logic of endocannabinoid signalling. Nat. Rev. Distribution of HLA-DR-positive microglia in schizophrenia reflects impaired 1237 1152 Neurosci. 4 (11), 873–884. cerebral lateralization. Acta Neuropathol. 112 (3), 305–316. 1238 1153 Pryce, G., Ahmed, Z., Hankey, D.J., Jackson, S.J., Croxford, J.L., Pocock, J.M., et al., 2003. Stella, N., 2009. Endocannabinoid signaling in microglial cells. Neuropharmacology 1239 1154 Cannabinoids inhibit neurodegeneration in models of multiple sclerosis. Brain 56 (Suppl. 1), 244–253. 1240 1155 126 (Pt. 10), 2191–2202. Tanasescu, R., Constantinescu, C.S., 2010. Cannabinoids and the immune system: an 1241 1156 Ramirez, S.H., Hasko, J., Skuba, A., Fan, S., Dykstra, H., McCormick, R., et al., 2012. overview. Immunobiology 215 (8), 588–597. 1242 1157 Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell Tanikawa, T., Kurohane, K., Imai, Y., 2007. Induction of preferential chemotaxis of 1243 1158 interactions and blood-brain barrier dysfunction under inflammatory unstimulated B-lymphocytes by 2-arachidonoylglycerol in immunized mice. 1244 1159 conditions. J. Neurosci. 32 (12), 4004–4016. Microbiol. Immunol. 51 (10), 1013–1019. 1245 1160 Rapoport, J.L., Addington, A.M., Frangou, S., Psych, M.R., 2005. The Tanikawa, T., Kurohane, K., Imai, Y., 2011. Regulatory effect of cannabinoid receptor 1246 1161 neurodevelopmental model of schizophrenia: update 2005. Mol. Psychiatry agonist on chemokine-induced lymphocyte chemotaxis. Biol. Pharm. Bull. 34 1247 1162 10 (5), 434–449. (7), 1090–1093. 1248 1163 Realini, N., Rubino, T., Parolaro, D., 2009. Neurobiological alterations at adult age Tolon, R.M., Nunez, E., Pazos, M.R., Benito, C., Castillo, A.I., Martinez-Orgado, J.A., 1249 1164 triggered by adolescent exposure to cannabinoids. Pharmacol. Res. 60 (2), 132– et al., 2009. The activation of cannabinoid CB2 receptors stimulates in situ and 1250 1165 138. in vitro beta-amyloid removal by human macrophages. Brain Res. 4 (1283), 1251 1166 Rettori, E., De Laurentiis, A., Zorrilla Zubilete, M., Rettori, V., Elverdin, J.C., 2012. 148–154. 1252 1167 Anti-inflammatory effect of the endocannabinoid anandamide in experimental Torres, E., Gutierrez-Lopez, M.D., Borcel, E., Peraile, I., Mayado, A., O’Shea, E., et al., 1253 1168 periodontitis and stress in the rat. Neuroimmunomodulation 19 (5), 293–303. 2010. Evidence that MDMA (‘ecstasy’) increases cannabinoid CB2 receptor 1254 1169 Ribeiro, R., Wen, J., Li, S., Zhang, Y., 2013. Involvement of ERK1/2, cPLA2 and NF- expression in microglial cells: role in the neuroinflammatory response in rat 1255 1170 kappaB in microglia suppression by cannabinoid receptor agonists and brain. J. Neurochem. 113 (1), 67–78. 1256 1171 antagonists. Prostaglandins Other Lipid Mediat. 100–101, 1–14. Torres, S., Lorente, M., Rodriguez-Fornes, F., Hernandez-Tiedra, S., Salazar, M., 1257 1172 Robinson, R.H., Meissler, J.J., Breslow-Deckman, J.M., Gaughan, J., Adler, M.W., Garcia-Taboada, E., et al., 2011. A combined preclinical therapy of cannabinoids 1258 1173 Eisenstein, T.K., 2013. Cannabinoids inhibit T-cells via cannabinoid receptor 2 in and temozolomide against glioma. Mol. Cancer Ther. 10 (1), 90–103. 1259 1174 an in vitro assay for graft rejection, the mixed lymphocyte reaction. J. Torrey, E.F., Bartko, J.J., Yolken, R.H., 2012. Toxoplasma gondii and other risk factors 1260 1175 Neuroimmune Pharmacol.. for schizophrenia: an update. Schizophr. Bull. 38 (3), 642–647. 1261 1176 Rock, R.B., Gekker, G., Hu, S., Sheng, W.S., Cabral, G.A., Martin, B.R., et al., 2007. Tschop, J., Kasten, K.R., Nogueiras, R., Goetzman, H.S., Cave, C.M., England, L.G., et al., 1262 1177 WIN55,212-2-mediated inhibition of HIV-1 expression in microglial cells: 2009. The cannabinoid receptor 2 is critical for the host response to sepsis. J. 1263 1178 involvement of cannabinoid receptors. J. Neuroimmune Pharmacol. 2 (2), 178– Immunol. 183 (1), 499–505. 1264 1179 183. van Os, J., Kapur, S., 2010. Psychosis: from diagnosis to syndrome. Ned. Tijdschr. 1265 1180 Rockwell, C.E., Kaminski, N.E., 2004. A cyclooxygenase metabolite of anandamide Geneeskd. 154, A1874. 1266 1181 causes inhibition of interleukin-2 secretion in murine splenocytes. J. Pharmacol. van Os, J., Krabbendam, L., Myin-Germeys, I., Delespaul, P., 2005. The schizophrenia 1267 1182 Exp. Ther. 311 (2), 683–690. envirome. Curr. Opin. Psychiatry 18 (2), 141–145. 1268 1183 Rom, S., Zuluaga-Ramirez, V., Dykstra, H., Reichenbach, N.L., Pacher, P., Persidsky, Y., Vannacci, A., Giannini, L., Passani, M.B., Di Felice, A., Pierpaoli, S., Zagli, G., et al., 1269 1184 2013. Selective activation of cannabinoid receptor 2 in leukocytes suppresses 2004. The endocannabinoid 2-arachidonylglycerol decreases the 1270 1185 their engagement of the brain endothelium and protects the blood-brain immunological activation of Guinea pig mast cells: involvement of nitric 1271 1186 barrier. Am. J. Pathol. 183 (5), 1548–1558. oxide and eicosanoids. J. Pharmacol. Exp. Ther. 311 (1), 256–264. 1272 1187 Rossi, B., Zenaro, E., Angiari, S., Ottoboni, L., Bach, S., Piccio, L., et al., 2011. Inverse Veen, N.D., Selten, J.P., van der Tweel, I., Feller, W.G., Hoek, H.W., Kahn, R.S., 2004. 1273 1188 agonism of cannabinoid CB1 receptor blocks the adhesion of encephalitogenic T Cannabisuse andage at onset ofschizophrenia. Am. J. Psychiatry161(3),501–506. 1274 1189 cells in inflamed brain venules by a protein kinase A-dependent mechanism. J. Vicente-Sanchez, A., Sanchez-Blazquez, P., Rodriguez-Munoz, M., Garzon, J., 2013. 1275 1190 Neuroimmunol. 233 (1–2), 97–105. HINT1 protein cooperates with cannabinoid 1 receptor to negatively regulate 1276 1191 Roth, M.D., Tashkin, D.P., Whittaker, K.M., Choi, R., Baldwin, G.C., 2005. glutamate NMDA receptor activity. Mol. Brain 6 (1), 42. 1277 1192 Tetrahydrocannabinol suppresses immune function and enhances HIV Vuillermot, S., Weber, L., Feldon, J., Meyer, U., 2010. A longitudinal examination of 1278 1193 replication in the huPBL-SCID mouse. Life Sci. 77 (14), 1711–1722. the neurodevelopmental impact of prenatal immune activation in mice reveals 1279 1194 Sacerdote, P., Martucci, C., Vaccani, A., Bariselli, F., Panerai, A.E., Colombo, A., et al., primary defects in dopaminergic development relevant to schizophrenia. J. 1280 1195 2005. The nonpsychoactive component of marijuana cannabidiol modulates Neurosci. 30 (4), 1270–1287. 1281 1196 chemotaxis and IL-10 and IL-12 production of murine macrophages both in vivo Wacnik, P.W., Luhr, K.M., Hill, R.H., Ljunggren, H.G., Kristensson, K., Svensson, M., 1282 1197 and in vitro. J. Neuroimmunol. 159 (1–2), 97–105. 2008. Cannabinoids affect dendritic cell (DC) potassium channel function and 1283 1198 Sainz, J., Mata, I., Barrera, J., Perez-Iglesias, R., Varela, I., Arranz, M.J., et al., 2013. modulate DC T cell stimulatory capacity. J. Immunol. 181 (5), 3057–3066. 1284 1199 Inflammatory and immune response genes have significantly altered expression Walter, L., Franklin, A., Witting, A., Wade, C., Xie, Y., Kunos, G., et al., 2003. 1285 1200 in schizophrenia. Mol. Psychiatry 18 (10), 1056–1057. Nonpsychotropic cannabinoid receptors regulate microglial cell migration. J. 1286 1201 Saunders, C.I., Fassett, R.G., Geraghty, D.P., 2009. Up-regulation of TRPV1 in Neurosci. 23 (4), 1398–1405. 1287 1202 mononuclear cells of end-stage kidney disease patients increases Wang, H., Xu, H., Dyck, L.E., Li, X.M., 2005. Olanzapine and quetiapine protect PC12 1288 1203 susceptibility to N-arachidonoyl-dopamine (NADA)-induced cell death. cells from beta-amyloid peptide(25–35)-induced oxidative stress and the 1289 1204 Biochim. Biophys. Acta 1792 (10), 1019–1026. ensuing apoptosis. J. Neurosci. Res. 81 (4), 572–580. 1290 1205 Schwarz, M.J., Muller, N., Riedel, M., Ackenheil, M., 2001. The Th2-hypothesis of Widmer, M., Hanemann, C.O., Zajicek, J., 2008. High concentrations of cannabinoids 1291 1206 schizophrenia: a strategy to identify a subgroup of schizophrenia caused by activate apoptosis in human U373MG glioma cells. J. Neurosci. Res. 86 (14), 1292 1207 immune mechanisms. Med. Hypotheses 56 (4), 483–486. 3212–3220. 1293 1208 Servettaz, A., Kavian, N., Nicco, C., Deveaux, V., Chereau, C., Wang, A., et al., 2010. Wilke, I., Arolt, V., Rothermundt, M., Weitzsch, C., Hornberg, M., Kirchner, H., 1996. 1294 1209 Targeting the cannabinoid pathway limits the development of fibrosis and Investigations of cytokine production in whole blood cultures of paranoid and 1295 1210 autoimmunity in a mouse model of systemic sclerosis. Am. J. Pathol. 177 (1), residual schizophrenic patients. Eur. Arch. Psychiatry Clin. Neurosci. 246 (5), 1296 1211 187–196. 279–284. 1297 1212 Shiratsuchi, A., Watanabe, I., Yoshida, H., Nakanishi, Y., 2008. Involvement of Xu, H., Cheng, C.L., Chen, M., Manivannan, A., Cabay, L., Pertwee, R.G., et al., 2007. 1298 1213 cannabinoid receptor CB2 in dectin-1-mediated macrophage phagocytosis. Anti-inflammatory property of the cannabinoid receptor-2-selective agonist 1299 1214 Immunol. Cell Biol. 86 (2), 179–184. JWH-133 in a rodent model of autoimmune uveoretinitis. J. Leukoc. Biol. 82 (3), 1300 1215 Singh, U.P., Singh, N.P., Singh, B., Price, R.L., Nagarkatti, M., Nagarkatti, P.S., 2012. 532–541. 1301 1216 Cannabinoid receptor-2 (CB2) agonist ameliorates colitis in IL-10(/) mice by Yamaori, S., Ishii, H., Chiba, K., Yamamoto, I., Watanabe, K., 2013. Delta(8)- 1302 1217 attenuating the activation of T cells and promoting their apoptosis. Toxicol. tetrahydrocannabinol induces cytotoxicity in macrophage J774-1 cells: 1303 1218 Appl. Pharmacol. 258 (2), 256–267. Involvement of cannabinoid receptor 2 and p38 MAPK. Toxicology 314 (2–3), 1304 1219 Sisay, S., Pryce, G., Jackson, S.J., Tanner, C., Ross, R.A., Michael, G.J., et al., 2013. 254–261. 1305 1220 Genetic background can result in a marked or minimal effect of gene knockout Yang, Y., Yang, H., Wang, Z., Varadaraj, K., Kumari, S.S., Mergler, S., et al., 2013. 1306 1221 (GPR55 and CB2 Receptor) in experimental autoimmune encephalomyelitis Cannabinoid receptor 1 suppresses transient receptor potential vanilloid 1- 1307 1222 models of multiple sclerosis. PLoS ONE 8 (10), e76907. induced inflammatory responses to corneal injury. Cell. Signal. 25 (2), 501–511. 1308 1223 Skaper, S.D., Di Marzo, V., 2012. Endocannabinoids in nervous system health and Zalcman, S., Green-Johnson, J.M., Murray, L., Nance, D.M., Dyck, D., Anisman, H., 1309 1224 disease: the big picture in a nutshell. Philos. Trans. R. Soc. Lond. B Biol. Sci. 367 et al., 1994. Cytokine-specific central monoamine alterations induced by 1310 1225 (1607), 3193–3200. interleukin-1, -2 and -6. Brain Res. 643 (1–2), 40–49. 1311

14 P. Suárez-Pinilla et al. / Brain, Behavior, and Immunity xxx (2014) xxx–xxx

1312 Zavitsanou, K., Dalton, V.S., Walker, A.K., Weickert, C.S., Sominsky, L., Hodgson, D.M., Ziring, D., Wei, B., Velazquez, P., Schrage, M., Buckley, N.E., Braun, J., 2006. 1315 1313 2013. Neonatal lipopolysaccharide treatment has long-term effects on Formation of B and T cell subsets require the cannabinoid receptor CB2. 1316 1314 monoaminergic and cannabinoid receptors in the rat. Synapse 67 (6), 290–299. Immunogenetics 58 (9), 714–725. 1317 1318