Table of Contents

    Topic review

    Central Type-1 Cannabinoid Receptor Gene

    View times: 11
    Submitted by: Mauro Maccarrone


    Different neuromodulatory systems are involved in long-term energy balance and body weight and, among these, evidence shows that the endocannabinoid system, in particular the activation of type-1 cannabinoid receptor, plays a key role.

    1. Introduction

    Food intake might be considered the integration of humoral and neuronal signals processed by the nervous system for the balance of energy and of sensory cues, as well as of the motivational and emotional state of an individual. Thus, different eating behaviors are finely driven by both homeostatic and hedonic signals, whose functions may vary between individuals according to previous experiences and/or epigenetic variations [1][2][3][4][5][6][7].

    Homeostatic and hedonic central circuitries are interconnected, in fact feeding behaviors are affected by brain regions classically viewed as mainly involved in homeostatic feeding; however, these are also influenced by brain corticolimbic and hedonic areas, and vice versa [8][9]. The homeostatic feeding will be terminated once the organism is repleted with energy and nutrients, while hedonic feeding might continue. An imbalance toward the hedonic aspect of feeding without restriction may provoke changes in the food intake with serious consequences on the weight gain/loss [10][11].

    The hypothalamus (HYP) is the center for the integration and control of essential bodily functions, such as circadian rhythm, body temperature and plasma-osmolarity, and traditionally recognized as the main brain region regulating food intake. It regulates feeding as a function of caloric and nutritional requirements, by sensing macronutrients and through the action of circulating regulatory hormones, neuropeptides and neuromodulators, such as leptin, cholecystokinin, ghrelin, orexin/hypocretin, insulin, neuropeptide Y, and notably lipid signals like endocannabinoids [12][13][14][15]. The imbalance in hypothalamic function may provoke an altered food intake, potentially leading to eating disorders (EDs) and obesity [16][17][18].

    Besides HYP, several limbic brain areas including ventral tegmental area, nucleus accumbens (NAc), amygdala, and hippocampus, as well as cortical brain regions, have also been implicated in the hedonic aspects of feeding [19][20][21].

    Studies on the role played by the reward circuits in defining hedonic aspects of feeding allowed to define how common mechanisms are shared by drug abuse and food addiction [22][23][24]. Both are compulsive behavioral disorders that induce alterations in brain mechanisms underlying synaptic plasticity and energy homeostasis, showing common vulnerabilities and pathophysiological aspects [25].

    Among the different neuromodulatory systems involved in long-term energy balance and body weight regulation, many preclinical and clinical evidence show the key role of the endocannabinoid system (ECS) [26], and in particular, the activation of type-1 cannabinoid receptors (CB1R) [27][28].

    Indeed, several preclinical studies show that orexigenic stimuli induce CB1R activation in the rat brain, specifically in the HYP [29][30] where CB1R positive neurons are present in different nuclei [31], although at low density [32], and support a role in food and energy balance [33][34][35][36]. Brain reward pathways are largely responsible for processing information related to the motivation, expectation, and pursuit of pleasurable experiences, and CB1R signaling was reported to modulate dopaminergic signaling in the ventral tegmental area and NAc to control hedonic eating [37][38][39][40]. CB1R signaling also plays a role in the functional activity of caudal brainstem nuclei: parabrachial nucleus, nucleus of the solitary tract, and dorsal motor nucleus of the vagus nerve. Herein, CB1R mainly controls food preferences, e.g., digestion of fat rich palatable food [37]. Several experimental findings already pointed to CB1R as therapeutic target to treat altered feeding behavior and obesity [30][34][41][42], due to the hyperphagic role of this receptor, and the possible exploitation of its pharmacological blockade, as recently reviewed [43]. It should be recalled that rimonabant, a CB1R antagonist/inverse agonist [44], entered the European mass market, showing weight loss benefits but it was soon withdrawn due to the significant side effects [45]. Here, we focused mainly on the role of type-1 Cannabinoid Receptor gene (CNR1) gene, which encodes for CB1R, and its regulation in food intake and eating behaviors.

    2. CNR1 Gene in the Control of Energy Homeostasis and Obesity

    Circuits in the HYP regulate appetite and energy homeostasis [46] and a key role is played by hypothalamic CB1R signaling intertwined with the pathways of metabolic hormones. In fact, for instance, the reduced hypothalamic eCB levels are associated with appetite suppression by leptin [26], while the increased hypothalamic eCB levels are correlated with orexigenic actions of ghrelin, with the involvement of the activation of AMP-activated protein kinase and the inhibition of paraventricular neurons [47].

    Using mice lacking CNR1 gene, it has been documented that eCBs actions on food intake and body weight depend on the functional expression and activity of CB1R [48]. In this work, Cota and colleagues demonstrated that germline deletion of CNR1 in male mice resulted in a phenotype characterized by decreased body weight, reduced fat mass, and hypophagia. Moreover, the study highlighted that CNR1 mRNA is co-expressed in the HYP with neuropeptides known to modulate food intake [48].

    A significantly reduction in body weight was also reported in mice, where CNR1 gene expression was selectively deleted in the HYP, after 9 weeks of viral-mediated deletion. This effect, without any changes in food intake, suggested an increase in energy expenditure [49]. Further, adult mice, in which CNR1 gene was deleted in adipocytes, resulted to be protected from diet-induced obesity and associated with metabolic alterations [50].

    Again, conditional mutant mice, with CNR1 deletion in forebrain and sympathetic neurons, known to control energy balance, are resistant to diet-induced obesity and display a lean phenotype [51].

    Moreover, the relevant role of CB1R in the initiation of milk suckling in pups has been observed [52][53] and, in particular, CNR1-knock-out (KO) newborns did not ingest milk on the first day of life, significantly affecting their survival rate [53].

    Furthermore, central dysregulation of CNR1 gene expression has been documented in animal models of obesity in different brain areas, implicated in both homeostatic and hedonic aspects of eating [54][55][56].

    In particular, the exposure to a palatable diet resulted in tissue and sex-specific changes in the gene expression of both CB1R and type-2 cannabinoid receptor (CB2R) in the HYP of offspring and adults. These results clearly indicate that the maternal diet has long-term effects on the development of pups through multiple alterations of signaling homeostatic pathways that include cannabinoid receptors [56].

    Gamelin and colleagues (2016) found in the hippocampus of rats, fed with High Fat Diet (HFD), an increase in the CNR1 mRNA expression compared to rats fed with standard diet. The up-regulation of hippocampal CNR1 expression was increased with exercise training combined with HFD. Indeed, chronic exercise did not appear to counteract ECS overactivation and, in fact, seems even to induce this effect independently from diet. Moreover, the authors showed that CNR1 expression in the HYP is not affected by HFD in rats [54].

    It was also reported, in rats exposed to HFD, the reduction in CB1R binding sites in extrahypothalamic brain regions and CB1R density was related to the intake of palatable food, whereas no changes have been observed in the HYP [57]. This does not exclude transient changes in CB1R levels or CNR1 expression over time. Indeed, a transient increase in mouse hypothalamic CB1R density, after 3 weeks of HFD, was normalized at the end of the 20 weeks of HFD, suggesting a temporal CB1R alteration during the development of obesity [58]. A temporal transcriptional regulation of CNR1 gene was also proved in the HYP of rats exposed to diet-induced obesity. The analysis of ECS components gene expression revealed a significant and selective increase in CNR1 mRNA levels at the beginning of obesity development (5 weeks on HFD) as well as after 21 weeks of exposure, when the phenotype was already well-established. Moreover, a consistent selective and significant reduction in DNA methylation at specific Cytosine–phosphate–Guanine (CpG) sites of CNR1 gene promoter in overweight rats was observed just after 5 weeks, but not 21 weeks on HFD [55].

    In the same study, the DNA methylation status of CNR1 gene was assessed in peripheral blood mononuclear cells from a subset of obese human subjects. An age-based stratification of DNA methylation levels showed a significant reduction of the epigenetic hallmark at CNR1 promoter in younger (<30 years old) humans with obesity, when compared to age-matching controls. These findings suggest that the regulation of CNR1 gene is altered mainly at early life stage of phenotype development [55].

    Considering other epigenetic modifications possibly occurring in the development of obesity, recently a hypothalamic increase in histone acetylation was reported at CNR1 gene promoter and was linked to increased receptor expression [59]. Almeida and colleagues hypothesized that maternal fat enriched diet would up-regulate CNR1 mRNA levels in the HYP of the male offspring at birth [59].

    These latter findings support the relevance of environment and lifestyle in the facilitation of diseases progression, including obesity, by engaging epigenetic mechanisms [60], and in meantime could represent an innovative field to produce new strategies of intervention.

    Genetic studies have identified several polymorphisms at different locations across the CNR1 gene that have been associated with obesity and related phenotypes, such as metabolic syndrome and dyslipidemia [61][62][63][64][65][66][67][68][69].

    Among others, particular attention has been focused on a silent intragenic biallelic polymorphism in codon 435 of CNR1 gene, substitution of G to A at nucleotide position 1359 (1359 G/A rs1049353) [70]. This Single Nucleotide Polymorphism (SNP) was reported to be associated with abdominal adiposity [71], Body Mass Index (BMI) [72], intermuscular fat mass [73], and longitudinal changes from healthy to metabolic syndrome occurrence [74]. However, the literature has been inconsistent with respect to CNR1 polymorphisms and obesity-related markers, with many studies not finding any relevant association with CNR1 gene variants [75][76][77].

    The entry is from 10.3390/ijms22010398


    1. Berthoud, H.-R. The neurobiology of food intake in an obesogenic environment. In Nutrition Society; Cambridge University Press (CUP): Cambridge, UK, 2012; Volume 71, pp. 478–487.
    2. Johnson, A.W. Eating beyond metabolic need: How environmental cues influence feeding behavior. Trends Neurosci. 2013, 36, 101–109.
    3. Schneeberger, M.; Gomis, R.; Claret, M. Hypothalamic and brainstem neuronal circuits controlling homeostatic energy balance. J. Endocrinol. 2014, 220, T25–T46.
    4. Yeo, G.; Heisler, L.K. Unraveling the brain regulation of appetite: Lessons from genetics. Nat. Neurosci. 2012, 15, 1343–1349.
    5. Cifani, C.; Di Bonaventura, M.V.E.; Epucci, M.; Egiusepponi, M.E.; Eromano, A.; Francesco, A.E.; Emaccarrone, M.; D’Addario, C. Regulation of hypothalamic neuropeptides gene expression in diet induced obesity resistant rats: Possible targets for obesity prediction? Front. Neurosci. 2015, 9, 187.
    6. Di Bonaventura, M.V.M.; Pucci, M.; Giusepponi, M.E.; Romano, A.; Lambertucci, C.; Volpini, R.; Di Bonaventura, E.M.; Gaetani, S.; Maccarrone, M.; D’Addario, C.; et al. Regulation of adenosine A2A receptor gene expression in a model of binge eating in the amygdaloid complex of female rats. J. Psychopharmacol. 2019, 33, 1550–1561.
    7. Pucci, M.; Di Bonaventura, M.V.M.; Giusepponi, M.E.; Romano, A.; Filaferro, M.; Maccarrone, M.; Ciccocioppo, R.; Cifani, C.; D’Addario, C. Epigenetic regulation of nociceptin/orphanin FQ and corticotropin-releasing factor system genes in frustration stress-induced binge-like palatable food consumption. Addict. Biol. 2015, 21, 1168–1185.
    8. Garfield, A.S.; Shah, B.P.; Burgess, C.R.; Li, M.M.; Li, C.; Steger, J.S.; Madara, J.C.; Campbell, J.N.; Kroeger, D.; Scammell, T.E.; et al. Dynamic GABAergic afferent modulation of AgRP neurons. Nat. Neurosci. 2016, 19, 1628–1635.
    9. Rossi, M.A.; Stuber, G.D. Overlapping Brain Circuits for Homeostatic and Hedonic Feeding. Cell Metab. 2018, 27, 42–56.
    10. Jager, G.; Witkamp, R.F. The endocannabinoid system and appetite: Relevance for food reward. Nutr. Res. Rev. 2014, 27, 172–185.
    11. Novelle, M.G.; Dieguez, C. Food Addiction and Binge Eating: Lessons Learned from Animal Models. Nutrients 2018, 10, 71.
    12. Blouet, C.; Schwartz, G.J. Hypothalamic nutrient sensing in the control of energy homeostasis. Behav. Brain Res. 2010, 209, 1–12.
    13. Coll, A.P.; Farooqi, I.S.; O’Rahilly, S. The Hormonal Control of Food Intake. Cell 2007, 129, 251–262.
    14. Dietrich, M.O.; Horvath, T.L. Hypothalamic control of energy balance: Insights into the role of synaptic plasticity. Trends Neurosci. 2013, 36, 65–73.
    15. Volkow, N.D.; Wang, G.-J.; Baler, R.D. Reward, dopamine and the control of food intake: Implications for obesity. Trends Cogn. Sci. 2011, 15, 37–46.
    16. Belgardt, B.F.; Okamura, T.; Brüning, J.C. Hormone and glucose signalling in POMC and AgRP neurons. J. Physiol. 2009, 587, 5305–5314.
    17. Goldstone, A.P. The hypothalamus, hormones, and hunger: Alterations in human obesity and illness. Neural Regen. 2006, 153, 57–73.
    18. Wang, H.; Astarita, G.; Taussig, M.D.; Bharadwaj, K.G.; DiPatrizio, N.V.; Nave, K.-A.; Piomelli, D.; Goldberg, I.J.; Eckel, R.H. Deficiency of Lipoprotein Lipase in Neurons Modifies the Regulation of Energy Balance and Leads to Obesity. Cell Metab. 2011, 13, 105–113.
    19. Land, B.B.; Narayanan, N.S.; Liu, R.-J.; Gianessi, C.A.; Brayton, C.E.; Grimaldi, D.M.; Sarhan, M.; Guarnieri, D.J.; Deisseroth, K.; Aghajanian, G.K.; et al. Medial prefrontal D1 dopamine neurons control food intake. Nat. Neurosci. 2014, 17, 248–253.
    20. Petrovich, G.D.; Holland, P.C.; Gallagher, M. Amygdalar and Prefrontal Pathways to the Lateral Hypothalamus Are Activated by a Learned Cue That Stimulates Eating. J. Neurosci. 2005, 25, 8295–8302.
    21. Volkow, N.D.; Fowler, J.; Wang, G.; Baler, R.; Telang, F. Imaging dopamine’s role in drug abuse and addiction. Neuropharmacology 2009, 56, 3–8.
    22. Herkenham, M.; Lynn, A.B.; Little, M.D.; Johnson, M.R.; Melvin, L.S.; De Costa, B.R.; Rice, K.C. Cannabinoid receptor localization in brain. Proc. Natl. Acad. Sci. USA 1990, 87, 1932–1936.
    23. Hryhorowicz, S.; Kaczmarek-Ryś, M.; Andrzejewska, A.; Staszak, K.; Korcz, A.; Słomski, R. Allosteric Modulation of Cannabinoid Receptor 1—Current Challenges and Future Opportunities. Int. J. Mol. Sci. 2019, 20, 5874.
    24. Di Marzo, V.; Stella, N.; Zimmer, A. Endocannabinoid signalling and the deteriorating brain. Nat. Rev. Neurosci. 2015, 16, 30–42.
    25. DiPatrizio, N.V.; Piomelli, D. Intestinal lipid–derived signals that sense dietary fat. J. Clin. Investig. 2015, 125, 891–898.
    26. Maccarrone, M.; Bab, I.; Bíró, T.; Cabral, G.A.; Dey, S.K.; Di Marzo, V.; Konje, J.C.; Kunos, G.; Mechoulam, R.; Pacher, P.; et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol. Sci. 2015, 36, 277–296.
    27. Begg, M.; Pacher, P.; Bátkai, S.; Osei-Hyiaman, D.; Offertáler, L.; Mo, F.M.; Liu, J.; Kunos, G. Evidence for novel cannabinoid receptors. Pharmacol. Ther. 2005, 106, 133–145.
    28. Ryberg, E.; Larsson, N.; Sjögren, S.; Hjorth, S.; Hermansson, N.-O.; Leonova, J.; Elebring, T.; Nilsson, K.; Drmota, T.; Greasley, P.J. The orphan receptor GPR55 is a novel cannabinoid receptor. Br. J. Pharmacol. 2007, 152, 1092–1101.
    29. Matsuda, L.A.; Lolait, S.J.; Brownstein, M.J.; Young, A.C.; Bonner, T.I. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nat. Cell Biol. 1990, 346, 561–564.
    30. Ruehle, S.; Wager-Miller, J.; Straiker, A.; Farnsworth, J.; Murphy, M.N.; Loch, S.; Monory, K.; Mackie, K.; Lutz, B. Discovery and characterization of two novel CB1 receptor splice variants with modified N-termini in mouse. J. Neurochem. 2017, 142, 521–533.
    31. Bonner, T. Molecular biology of cannabinoid receptors. J. Neuroimmunol. 1996, 69, 15–17.
    32. McCaw, E.A.; Hu, H.; Gomez, G.T.; Hebb, A.L.O.; Kelly, M.E.M.; Denovan-Wright, E.M. Structure, expression and regulation of the cannabinoid receptor gene (CB1) in Huntington’s disease transgenic mice. JBIC J. Biol. Inorg. Chem. 2004, 271, 4909–4920.
    33. Zhang, P.-W.; Ishiguro, H.; Ohtsuki, T.; Hess, J.; Carillo, F.; Walther, D.; Onaivi, E.S.; Arinami, T.; Uhl, G.R. Human cannabinoid receptor 1:5′ exons, candidate regulatory regions, polymorphisms, haplotypes and association with polysubstance abuse. Mol. Psychiatry 2004, 9, 916–931.
    34. Miller, L.K.; Devi, L.A. The Highs and Lows of Cannabinoid Receptor Expression in Disease: Mechanisms and Their Therapeutic Implications. Pharmacol. Rev. 2011, 63, 461–470.
    35. Shire, D.; Calandra, B.; Delpech, M.; Dumont, X.; Kaghad, M.; Le Fur, G.; Caput, D.; Ferrara, P. Structural Features of the Central Cannabinoid CB1 Receptor Involved in the Binding of the Specific CB1 Antagonist SR 141716A. J. Biol. Chem. 1996, 271, 6941–6946.
    36. Gustafsson, K.; Wang, X.; Severa, D.; Eriksson, M.; Kimby, E.; Merup, M.; Christensson, B.; Flygare, J.; Sander, B. Expression of cannabinoid receptors type 1 and type 2 in non-Hodgkin lymphoma: Growth inhibition by receptor activation. Int. J. Cancer 2008, 123, 1025–1033.
    37. Palermo, F.A.; Angelini, M.; Cottone, E.; Virgili, M.; Franzoni, M.F.; Mosconi, G.; Polzonetti-Magni, A.M. Involvement of Endocannabinoid CB1 Receptor in the Modulation of Stress Responses Related to Xenoestrogen Exposure. Ann. N. Y. Acad. Sci. 2009, 1163, 504–507.
    38. Ryberg, E.; Vu, H.K.; Larsson, N.; Groblewski, T.; Hjorth, S.; Elebring, T.; Sjögren, S.; Greasley, P.J. Identification and characterisation of a novel splice variant of the human CB1 receptor. FEBS Lett. 2004, 579, 259–264.
    39. Agrawal, A.; Wetherill, L.; Dick, D.M.; Xuei, X.; Hinrichs, A.; Hesselbrock, V.; Kramer, J.; Nurnberger, J.I., Jr.; Schuckit, M.; Bierut, L.J.; et al. Evidence for association between polymorphisms in the cannabinoid receptor 1 (CNR1) gene and cannabis dependence. Am. J. Med. Genet. Part B Neuropsychiatr. Genet. 2009, 150B, 736–740.
    40. Feng, Q.; Vickers, K.C.; Anderson, M.; Levin, M.; Chen, W.; Harrison, D.G.; Wilke, R.A. A common functional promoter variant links CNR1 gene expression to HDL cholesterol level. Nat. Commun. 2013, 4, 1–7.
    41. Gadzicki, D.; Müller-Vahl, K.; Stuhrmann, M. A frequent polymorphism in the coding exon of the human cannabinoid receptor (CNR1) gene. Mol. Cell. Probes 1999, 13, 321–323.
    42. Hartman, C.A.; Hopfer, C.J.; Haberstick, B.; Rhee, S.H.; Crowley, T.J.; Corley, R.P.; Hewitt, J.K.; Ehringer, M.A. The association between cannabinoid receptor 1 gene (CNR1) and cannabis dependence symptoms in adolescents and young adults. Drug Alcohol Depend. 2009, 104, 11–16.
    43. Ruiz-Contreras, A.E.; Román-López, T.V.; Caballero-Sánchez, U.; Rosas-Escobar, C.B.; Ortega-Mora, E.I.; Barrera-Tlapa, M.A.; Romero-Hidalgo, S.; Carrillo-Sánchez, K.; Hernández-Morales, S.; Vadillo-Ortega, F.; et al. Because difficulty is not the same for everyone: The impact of complexity in working memory is associated with cannabinoid 1 receptor genetic variation in young adults. Memory 2016, 25, 335–343.
    44. González-Mariscal, I.; Krzysik-Walker, S.M.; Doyle, M.E.; Liu, Q.-R.; Cimbro, R.; Calvo, S.S.-C.; Ghosh, S.; Ciesla, L.; Moaddel, R.; Carlson, O.D.; et al. Human CB1 Receptor Isoforms, present in Hepatocytes and β-cells, are Involved in Regulating Metabolism. Sci. Rep. 2016, 6, 33302.
    45. Shire, D.; Carillon, C.; Kaghad, M.; Calandra, B.; Rinaldi-Carmona, M.; Le Fur, G.; Caput, D.; Ferrara, P. An Amino-terminal Variant of the Central Cannabinoid Receptor Resulting from Alternative Splicing. J. Biol. Chem. 1995, 270, 3726–3731.
    46. Sadeghian, M.; Rahmani, S.; Mansoori, A. G1359A Variant of the Cannabinoid Receptor Gene (rs1049353) and Obesity-Related Traits and Related Endophenotypes: A Meta-Analysis. Ann. Nutr. Metab. 2018, 73, 76–85.
    47. Peeters, A.; Beckers, S.; Mertens, I.; Van Hul, W.; Van Gaal, L. The G1422A variant of the cannabinoid receptor gene (CNR1) is associated with abdominal adiposity in obese men. Endocrine 2007, 31, 138–141.
    48. Gazzerro, P.; Caruso, M.G.; Notarnicola, M.; Misciagna, G.; Guerra, V.; Laezza, C.; Bifulco, M. Association between cannabinoid type-1 receptor polymorphism and body mass index in a southern Italian population. Int. J. Obes. 2006, 31, 908–912.
    49. Frost, M.; Nielsen, T.L.; Wraae, K.; Hagen, C.; Piters, E.; Beckers, S.; De Freitas, F.; Brixen, K.; Van Hul, W.; Andersen, M.S. Polymorphisms in the endocannabinoid receptor 1 in relation to fat mass distribution. Eur. J. Endocrinol. 2010, 163, 407–412.
    50. Kvaløy, K.; Holmen, J.; Hveem, K.; Holmen, T.L. Genetic Effects on Longitudinal Changes from Healthy to Adverse Weight and Metabolic Status—The HUNT Study. PLoS ONE 2015, 10, e0139632.
    51. De Luis, D.A.; Pacheco, D.; Aller, R.; Sagrado, M.G.; Conde, R.; Izaola, O.; Cuellar, L.; Terroba, M.C.; Martin, T.; Ventosa, M. G 1359A polymorphism of the cannabinoid receptor gene (CNR1) and clinical results of biliopancreatic diversion. Eur. Rev. Med. Pharmacol. Sci. 2010, 14, 197–201.
    52. Łaczmański, Ł.; Milewicz, A.; Dunajska, K.; Jędrzejczuk, D.; Pawlak, M.; Lwow, F. Endocannabinoid type 1 receptor gene (CNR1) polymorphisms (rs806381, rs10485170, rs6454674, rs2023239) and cardiovascular risk factors in postmenopausal women. Gynecol. Endocrinol. 2011, 27, 1023–1027.
    53. Lutter, M.; Nestler, E.J. Homeostatic and Hedonic Signals Interact in the Regulation of Food Intake. J. Nutr. 2009, 139, 629–632.
    54. Volkow, N.D.; Wang, G.-J.; Tomasi, D.; Baler, R.D. Obesity and addiction: Neurobiological overlaps. Obes. Rev. Off. J. Int. Assoc. Study Obes. 2013, 14, 2–18.
    55. D’Addario, C.; Di Bonaventura, M.M.; Pucci, M.; Romano, A.; Gaetani, S.; Ciccocioppo, R.; Cifani, C.; Maccarrone, M. Endocannabinoid signaling and food addiction. Neurosci. Biobehav. Rev. 2014, 47, 203–224.
    56. Coccurello, R.; Maccarrone, M. Hedonic Eating and the “Delicious Circle”: From Lipid-Derived Mediators to Brain Dopamine and Back. Front. Neurosci. 2018, 12, 271.
    57. Di Marzo, V.; Goparaju, S.K.; Wang, L.; Liu, J.; Bátkai, S.; Járai, Z.; Fezza, F.; Miura, G.I.; Palmiter, R.D.; Sugiura, T.; et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nat. Cell Biol. 2001, 410, 822–825.
    58. Berry, E.M.; Mechoulam, R. Tetrahydrocannabinol and endocannabinoids in feeding and appetite. Pharmacol. Ther. 2002, 95, 185–190.
    59. Pi-Sunyer, X.; Aronne, L.J.; Heshmati, H.M.; Devin, J.; Rosenstock, J.; for the RIO-North America Study Group. Effect of Rimonabant, a Cannabinoid-1 Receptor Blocker, on Weight and Cardiometabolic Risk Factors in Overweight or Obese Patients. JAMA 2006, 295, 761–775.
    60. Engeli, S. Dysregulation of the Endocannabinoid System in Obesity. J. Neuroendocrinol. 2008, 20, 110–115.
    61. Mazier, W.; Saucisse, N.; Gatta-Cherifi, B.; Cota, D. The Endocannabinoid System: Pivotal Orchestrator of Obesity and Metabolic Disease. Trends Endocrinol. Metab. 2015, 26, 524–537.
    62. Zou, S.; Somvanshi, R.K.; Paik, S.; Kumar, U. Colocalization of Cannabinoid Receptor 1 with Somatostatin and Neuronal Nitric Oxide Synthase in Rat Brain Hypothalamus. J. Mol. Neurosci. 2014, 55, 480–491.
    63. Moldrich, G.; Wenger, T. Localization of the CB1 cannabinoid receptor in the rat brain. An immunohistochemical study. Peptides 2000, 21, 1735–1742.
    64. Bellocchio, L.; Cervino, C.; Pasquali, R.; Pagotto, U. The Endocannabinoid System and Energy Metabolism. J. Neuroendocrinol. 2008, 20, 850–857.
    65. Di Marzo, V.; Matias, I. Endocannabinoid control of food intake and energy balance. Nat. Neurosci. 2005, 8, 585–589.
    66. Hillard, C.J.; Beatka, M.; Sarvaideo, J. Endocannabinoid Signaling and the Hypothalamic-Pituitary-Adrenal Axis. Compr. Physiol. 2016, 7, 1–15.
    67. Silvestri, C.; Di Marzo, V. The Endocannabinoid System in Energy Homeostasis and the Etiopathology of Metabolic Disorders. Cell Metab. 2013, 17, 475–490.
    68. Melis, T.; Succu, S.; Sanna, F.; Boi, A.; Argiolas, A.; Melis, M.R. The cannabinoid antagonist SR 141716A (Rimonabant) reduces the increase of extra-cellular dopamine release in the rat nucleus accumbens induced by a novel high palatable food. Neurosci. Lett. 2007, 419, 231–235.
    69. DiPatrizio, N.V.; Simansky, K.J. Activating Parabrachial Cannabinoid CB1 Receptors Selectively Stimulates Feeding of Palatable Foods in Rats. J. Neurosci. 2008, 28, 9702–9709.
    70. Seagard, J.L.; Dean, C.; Patel, S.; Rademacher, D.J.; Hopp, F.A.; Schmeling, W.T.; Hillard, C.J. Anandamide content and interaction of endocannabinoid/GABA modulatory effects in the NTS on baroreflex-evoked sympathoinhibition. Am. J. Physiol. Circ. Physiol. 2004, 286, H992–H1000.
    71. Derbenev, A.V.; Stuart, T.C.; Smith, B.N. Cannabinoids suppress synaptic input to neurones of the rat dorsal motor nucleus of the vagus nerve. J. Physiol. 2004, 559, 923–938.
    72. Cota, D.; Genghini, S.; Pasquali, R.; Pagotto, U. Antagonizing the cannabinoid receptor Type 1: A dual way to fight obesity. J. Endocrinol. Investig. 2003, 26, 1041–1044.
    73. Williams, C.M.; Kirkham, T.C. Anandamide induces overeating: Mediation by central cannabinoid (CB1) receptors. Psychopharmacology 1999, 143, 315–317.
    74. Lau, B.K.; Cota, D.; Cristino, L.; Borgland, S.L. Endocannabinoid modulation of homeostatic and non-homeostatic feeding circuits. Neuropharmacology 2017, 124, 38–51.
    75. Ravula, A.; Chandasana, H.; Setlow, B.; Febo, M.; Bruijnzeel, A.W.; Derendorf, H. Simultaneous quantification of cannabinoids tetrahydrocannabinol, cannabidiol and CB1 receptor antagonist in rat plasma: An application to characterize pharmacokinetics after passive cannabis smoke inhalation and co-administration of rimonabant. J. Pharm. Biomed. Anal. 2018, 160, 119–125.
    76. Sam, A.H.; Salem, V.; Ghatei, M.A. Rimonabant: From RIO to Ban. J. Obes. 2011, 2011, 1–4.
    77. Müller, T.D.; Reichwald, K.; Brönner, G.; Kirschner, J.; Nguyen, T.T.; Scherag, A.; Herzog, W.; Herpertz-Dahlmann, B.; Lichtner, P.; Meitinger, T.; et al. Lack of association of genetic variants in genes of the endocannabinoid system with anorexia nervosa. Child Adolesc. Psychiatry Ment. Health 2008, 2, 33.
    1. Please check and comment entries here.