Endocannabinoids acting at CB1 cannabinoid receptors (CB1) increase appetite. In view of the predominant presynaptic localization of CB1 in the brain, we tested the hypothesis that the orexigenic effect of endocannabinoids involves inhibition of the release of a tonically active anorexigenic mediator, such as the peptide product of the cocaine- and amphetamine-related transcript (CART). The CB1 antagonist rimonabant inhibited food intake in food-restricted wild-type mice, but not in their CART-deficient littermates. Mice deficient in fatty acid amide hydrolase (FAAH), the enzyme responsible for the in vivo metabolism of the endocannabinoid anandamide, have reduced levels of CART-immunoreactive nerve fibers and terminals in several brain regions implicated in appetite control, including the arcuate, dorsomedial and periventricular nuclei of the hypothalamus, the amygdala, the bed nucleus of the stria terminalis and the nucleus accumbens, and treatment of FAAH–/– mice with rimonabant, 3 mg/kg/day for 7 days, increased CART levels toward those seen in FAAH+/+ wild-type controls. In contrast, no difference in the density of CART-immunoreactive fibers was observed in the median eminence and the paraventricular nucleus of FAAH+/+ and FAAH–/– mice. Acute treatment of wild-type mice with the cannabinoid agonist HU-210 resulted in elevated CART levels in the dorsomedial nucleus and the shell portion of the nucleus accumbens. These observations are compatible with CART being a downstream mediator of the CB1-mediated orexigenic effect of endogenous anandamide.

Keywords:
Food intake behavior, Endocannabinoids, Cannabinoid receptors, Fatty acid amide hydrolase, Cocaine- and amphetamine-related transcript peptide, Transgenic mice, Arcuate nucleus, Paraventricular nucleus, Periventricular hypothalamic area, Amygdala
1.
Kalra SP, Dube MG, Pu S, Xu B, Horvath TL, Kalra PS: Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr Rev 1999;20:68–100.
2.
Saper CB, Thou TC, Elmquist JK: The need to feed: homeostatic and hedonic control of eating. Neuron 2002;36:199–211.
3.
Palkovits M: Hypothalamic regulation of the food intake. Clin Neurosci 2003;56:288–302.
4.
Williams CM, Kirkham TC: Anandamide induces overeating: mediation by central cannabinoids (CB1) receptors. Psychopharmacology 1999;143:315–317.
5.
Hao S, Avraham Y, Mechoulam R, Berry EM: Low-dose anandamide affects food intake, cognitive function, neurotransmitter and corticosterone levels in diet-restricted mice. Eur J Pharmacol 2000;392:147–156.
6.
Jamshidi N, Taylor DA: Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats. Br J Pharmcol 2001;134:1151–1154.
7.
Di Marzo V, Goparaju SK, Wang L, Liu J, Batkai S, Jarai Z, Fezza F, Miura GI, Palmiter RD, Sugiura T, Kunos G: Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 2001;410:822–825.
8.
Colombo G, Agabio R, Diaz G, Lobina C, Reali R, Gessa GL: Appetite suppression and weight loss after the cannabinoids antagonist SR141716. Life Sci 1998;63:113–117.
9.
Freedland CS, Poston JS, Porrino LJ: Effects of SR141716A, a central cannabinoids receptor antagonist, on food-maintained responding. Pharmacol Biochem Behav 2000;67:265–270.
10.
Kirkham TC, Williams CM: Synergistic effects of opioid and cannabinoid antagonists on food intake. Psychopharmacology 2001;153:267–270.
11.
Rowland NE, Mukherjee M, Robertson K: Effects of the cannabinoids receptor antagonist SR141716, alone and in combination with dexfenfluramine or naloxone, on food intake in rats. Psychopharmacology 2001;159:111–116.
12.
Ravinet Trillou C, Arnone M, Delgorge C, Gonalons N, Keane P, Maffrand JP, Soubrie P: Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice. Am J Physiol 2003;284:R345–R353.
13.
Hildebrandt AL, Kelly-Sullivan DM, Black SC: Antiobesity effects of chronic cannabinoids CB1 receptor antagonist treatment in diet-induced obese mice. Eur J Pharmacol 2003;462:125–132.
14.
Vickers SP, Webster LJ, Wyatt A, Dourish CT, Kennett GA: Preferential effects of the cannabinoid CB1 receptor antagonist, SR141716, on food intake and body weight gain of obese (fa/fa) compared to lean Zucker rats. Psychopharmacology 2003;167:103–111.
15.
Kirkham TC, Williams CM, Fezza F, Di Marzo V: Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br J Pharmacol 2002;136:550–557.
16.
Gómez R, Navarro M, Ferrer B, Trigo JM, Bilbao A, Arco ID, Cippitelli A, Nava F, Piomelli D, de Fonseca FR: A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding. J Neurosci 2002;22:9612–9617.
17.
Miller CC, Murray TF, Freeman KG, Edwards GL: Cannabinoid agonist, CP 55,940, facilitates intake of palatable foods when injected into the hindbrain. Physiol Behav 2004;80:611–616.
18.
Freund TF, Katona I, Piomelli D: Role of endogenous cannabinoids in synaptic signaling. Physiol Rev 2003;83:1017–1066.
19.
Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD: Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 1997;385:165–168.
20.
Kristensen P, Judge ME, Thim L, Ribel U, Christjansen KN, Wulff BS, Clausen JT, Jensen PB, Madsen OD, Vrang N, Larsen PJ, Hastrup S: Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature 1998;393:72–76.
21.
Bannon AW, Seda J, Carmouche M, Francis JM, Jarosinski MA, Douglass J: Multiple behavioral effects of cocaine- and amphetamine-regulated transcript (CART) peptides in mice: CART 42-89 and CART 49-89 differ in potency and activity. J Pharmacol Exp Ther 2001;299:1021–1026.
22.
Hunter RG, Philpot K, Vicentic A, Dominguez G, Hubert GW, Kuhar MJ: CART in feeding and obesity. Trends Endocrinol Metab 2004;15:454–459.
23.
Britton DR, Koob GF, Rivier J, Vale W: Intraventricular corticotrophin-releasing factor enhances behavioral effects of novelty. Life Sci 1982;31:363–367.
24.
Krahn DD, Gosnell BA, Grace M, Levine AS: CRF antagonist partially reverses CRF- and stress-induced effects on feeding. Brain Res Bull 1986;17:285–289.
25.
Kunos G, Osei-Hyiaman D, Palkovits M, Kuhar MJ, Mackie K, Bannon AW: Endocannabinoids and appetite: possible interactions with other neurotransmitter systems. International Cannabinoid Research Society – Symposium on the Cannabinoids, Burlington, Vt 2002.
26.
Hájos N, Katona I, Naiem SS, Mackie K, Ledent C, Mody I, Freund TF: Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations. Eur J Neurosci 2000;12:3239–3249.
27.
Koylu EO, Couceyro PR, Lambert PD, Ling NC, DeSouza EB, Kuhar MJ: Immunohistochemical localization of novel CART peptides in rat hypothalamus, pituitary and adrenal gland. J Neuroendocrinol 1997;9:823–833.
28.
Wierup N, Richards WG, Bannon AW, Kuhar MJ, Ahren B, Sundler F: CART knockout mice have impaired insulin secretion and glucose intolerance, altered β-cell morphology and increased body weight. Regul Pept 2005;129:203–211.
29.
Cravatt BF, Demarest K, Patricelli MP, Bracey MH, Giang DK, Martin BR, Lichtman AH: Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci USA 2001;98:9371–9376.
30.
Wang L, Liu J, Harvey-White J, Zimmer A, Kunos G: Endocannabinoid signaling via cannabinoid receptor 1 is involved in ethanol preference and its age-dependent decline in mice. Proc Natl Acad Sci USA 2003;100:1393–1398.
31.
Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB: Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 1996;384:83–87.
32.
Piomelli D: The molecular logic of endocannabinoid signalling. Nat Rev Neurosci 2003;4:873–884.
33.
Wilson RI, Kunos G, Nicoll RA: Presynaptic specificity of endocannabinoid signaling in the hippocampus. Neuron 2001;31:453–462.
34.
Lambert PD, Couceyro PR, McGirr KM, Dall Vechia SE, Smith Y, Kuhar MJ: CART peptides in the central control of feeding and interactions with neuropeptide Y. Synapse 1998;29:293–298.
35.
Elias CF, Lee C, Kelly J, Aschkenasi C, Ahima RS, Couceyro PR, Kuhar MJ, Saper CB Elmquist JK: Leptin activates hypothalamic CART neurons projecting to the spinal cord. Neuron 1998;21:1375–1385.
36.
McAlister ED, Van Vogt DA: Effect of leptin administration versus re-feeding on hypothalamic neuropeptide gene expression in fasted male rats. Can J Physiol Pharmacol 2004;82:1128–1134.
37.
Vicentic A, Lakatos A, Hunter R, Philpot K, Dominguez G, Kuhar MJ: CART peptide diurnal rhythm in brain and effect of fasting. Brain Res 2005;1032:111–115.
38.
Asnicar MA, Smith DP, Yang DD, Heiman ML, Fox N, Chen YF, Hsiung HM, Köster A: Absence of cocaine- and amphetamine-regulated transcript results in obesity in mice fed a high caloric diet. Endocrinology 2001;142:4394–4400.
39.
Freedland CS, Whitlow CT, Smith HR, Porrino LJ: Functional consequences of the acute administration of the cannabinoid receptor antagonist, SR141716A, in cannabinoid-naïve and -tolerant animals: a quantitative 2-[14C]deoxyglucose study. Brain Res 2003;962:169–179.
40.
Cota D, Giovanni M, Tschöp M, Grübler Y, Flachskamm C, Schubert M, Auer D, Yossouridis A, Thöne-Reineke C, Ortmann S, Tomassoni F, Cervino C, Nisoli E, Linthorst ACE, Pasquali R, Lutz B, Stalla GK, Pagotto U: The endogenous cannabinoids system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest 2003;112:423–431.
41.
Katona I, Rancz EA, Acsady L, Ledent C, Mackie K, Hajos N, Freund TF: Distribution of CB1 cannabinoid receptors in the amygdala and their role in the control of GABAergic transmission. J Neurosci 2001;21:9506–9518.
42.
McDonald AJ, Mascagni F: Localization of the CB1-type cannabinoid receptor in the rat basolateral amygdala: high concentrations in a subpopulation of cholecystokinin-containing interneurons. Neuroscience 2001;107:641–652.
43.
Kathuria S, Gaetani S, Fegley D, Valino F, Duranti A, Tontini A, Mor M, Tarzia G, La Rana G, Calignano A, Giustino A, Tattoli M, Palmery M, Cuomo V, Piomelli D: Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med 2003;9:76–81.
44.
Lichtman AH, Shelton CC, Advani T, Cravatt BF: Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia. Pain 2004;109:319–327.
45.
Ciccocioppo R, Fedeli A, Economidou D, Policani F, Weiss F, Massi M: The bed nucleus is a neuroanatomical substrate for the anorectic effect of corticotropin-releasing factor and for its reversal by nociceptin/orphanin FQ. J Neurosci 2003;23:9445–9451.
46.
Wang C, Billington CJ, Levine AS, Kotz CM: Effect of CART in the hypothalamic paraventricular nucleus on feeding and uncoupling protein gene expression. Neuroreport 2000;11:3251–3255.
47.
Abbott CR, Rossi M, Wren AM, Murphy KG, Kennedy AR, Stanley SA, Zollner AN, Morgan DGA, Morgan I, Ghatei MA, Small CJ, Bloom SR: Evidence of an orexigenic role for cocaine- and amphetamine-regulated transcript after administration into discrete hypothalamic nuclei. Endocrinology 2001;142:3457–3463.
48.
Hermann H, Lutz B: Coexpression of cannabinoid receptor type 1 with the corticotrophin-releasing hormone receptor type 1 in distinct regions of the adult mouse forebrain. Neurosci Lett 2005;375:13–18.
49.
Verty ANA, McFarlane JR, McGregor IS, Mallet PE: Evidence for an interaction between CB1 cannabinoid and melanocortin MCR-4 receptors in regulating food intake. Endocrinology 2004;145:3224–3231.
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2005
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