Abstract
Rationale
A major clinical concern with the use of cannabinoid receptor 1 (CB1) direct agonists is that these compounds increase alcohol drinking and drug abuse-related behaviours. As an alternative approach, CB1-receptor-mediated activity can be facilitated by increasing anandamide levels with the use of hydrolase fatty acid amide hydrolase (FAAH) inhibitors.
Objective
Using the selective FAAH inhibitor URB597, we investigated whether activation of the endogenous cannabinoid tone increases alcohol abuse liability, as what happens with the CB1 receptor direct agonists.
Materials and methods
URB597 was tested on alcohol self-administration in Wistar rats and on homecage alcohol drinking in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. In Wistar rats, URB597 effects on alcohol-induced anxiety and on stress-, yohimbine- and cue-induced reinstatement of alcohol seeking were also evaluated. For comparison, the effect of the CB1 receptor antagonist rimonabant on ethanol self-administration was also tested.
Results
Under our experimental condition, intraperitoneal (IP) administration of URB597 (0.0, 0.3 and 1.0 mg/kg) neither increased voluntary homecage alcohol drinking in msP rats nor facilitated fixed ratio 1 and progressive ratio alcohol self-administration in nonselected Wistars. In the reinstatement tests, the compound did not have effects on cue-, footshock stress- and yohimbine-induced relapse. Conversely, URB597 completely abolished the anxiogenic response measured during withdrawal after an acute IP administration of alcohol (3.0 g/kg). Rimonabant (0.0, 0.3, 1.0 and 3.0 mg/kg) significantly reduced ethanol self-administration.
Conclusions
Results demonstrate that activation of the endocannabinoid anandamide system by selective inhibition of FAAH does not increase alcohol abuse risks but does reduce anxiety associated to alcohol withdrawal. We thus can speculate that medication based on the use of endocannabinoid system modulators such as URB597 may offer important advantages compared to treatment with direct CB1 receptor activators.
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References
Abercrombie ED, Keller RW Jr, Zigmond MJ (1988) Characterization of hippocampal norepinephrine release as measured by microdialysis perfusion: pharmacological and behavioral studies. Neuroscience 27:897–904
Aghajanian GK, VanderMaelen CP (1982) Alpha 2-adrenoceptormediated hyperpolarization of locus coeruleus neurons: intracellular studies in vivo. Science 215:1394–1396
American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington D.C
Arnold JM, Roberts DCS (1997) A critique of fixed and progressive ratio schedules used to examine the neural substrates of drug reinforcement. Pharmacol Biochem Behav 57:441–447
Beltramo M, Stella N, Calignano A, Lin SY, Makriyannis A, Piomelli D (1997) Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 277:1094–1097
Blednov YA, Cravatt BF, Boehm SL 2nd, Walker D, Harris RA (2007) Role of endocannabinoids in alcohol consumption and intoxication: studies of mice lacking fatty acid amide hydrolase. Neuropsychopharmacology 32:1570–1582
Bortolato M, Campolongo P, Mangieri RA, Scattoni ML, Frau R, Trezza V, La Rana G, Russo R, Calignano A, Gessa GL, Cuomo V, Piomelli D (2006) Anxiolytic-like properties of the anandamide transport inhibitor AM404. Neuropsychopharmacology 31:2652–2659
Bremner JD, Krystal JH, Southwick SM, Charney DS (1996a) Noradrenergic mechanisms in stress and anxiety. I. Preclinical studies. Synapse 23:28–38
Bremner JD, Krystal JH, Southwick SM, Charney DS (1996b) Noradrenergic mechanisms in stress and anxiety. II. Clinical studies. Synapse 23:39–51
Chaperon F, Thiebot MH (1999) Behavioral effects of cannabinoid agents in animals. Crit Rev Neurobiol 13:243–281
Charney DS, Heninger GR, Redmond DE Jr (1983) Yohimbine induced anxiety and increased noradrenergic function in humans: effects of diazepam and clonidine. Life Sci 33:19–29
Ciccocioppo R, Sanna PP, Weiss F (2001) Cocaine-predictive stimulus induces drug-seeking behavior and neural activation in limbic brain regions after multiple months of abstinence: reversal by D (1) antagonists. Proc Natl Acad Sci USA 98:1976–1981
Ciccocioppo R, Economidou D, Fedeli A, Angeletti S, Weiss F, Heilig M, Massi M (2004) Attenuation of alcohol self-administration and of conditioned reinstatement of alcohol-seeking behaviour by the antiopioid peptide nociceptin/orphanin FQ in alcohol-preferring rats. Psychopharmacology 172:170–178
Ciccocioppo R, Economidou D, Cippitelli A, Cucculelli M, Ubaldi M, Soverchia L, Lourdusamy A, Massi M (2006) Genetically selected Marchigian Sardinian alcohol-preferring (msP) rats: an animal model to study the neurobiology of alcoholism. Addict Biol 11:339–355
Cippitelli A, Bilbao A, Hansson AC, Del Arco I, Sommer W, Heilig M, Massi M, Bermudez-Silva FJ, Navarro M, Ciccocioppo R, de Fonseca FR (2005) The European TARGALC Consortium Cannabinoid CB1 receptor antagonism reduces conditioned reinstatement of alcohol-seeking behavior in rats. Eur J Neurosci 21:2243–2251
Cippitelli A, Bilbao A, Gorriti MA, Navarro M, Massi M, Piomelli D, Ciccocioppo R, de Fonseca FR (2007) The anandamide transport inhibitor AM404 reduces alcohol self-administration. Eur J Neurosci. 26:476–486
Colombo G, Serra S, Brunetti G, Gómez R, Melis S, Vacca G, Carai MM, Gessa GL (2002) Stimulation of voluntary alcohol intake by cannabinoid receptor agonists in alcohol preferring sP rats. Psychopharmacology 159:181–187
Colombo G, Serra S, Vacca G, Gessa GL, Carai MA (2004) Suppression by baclofen of the stimulation of alcohol intake induced by morphine and WIN 55,212-2 in alcohol-preferring rats. Eur J Pharmacol 492:189–193
Colombo G, Lobina C, Carai MA, Gessa GL (2006) Phenotypic characterization of genetically selected Sardinian alcohol-preferring (sP) and -non-preferring (sNP) rats. Addict Biol 11:324–338
Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB (1996) Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384:83–87
Cruz AP, Frei F, Graeff FG (1994) Ethopharmacological analysis of rat behavior on the elevated plus-maze. Pharmacol Biochem Behav 49:171–176
Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949
De Vries TJ, Shaham Y, Homberg JR, Crombag H, Schuurman K, Dieben J, Vanderschuren LJ Schoffelmeer AN (2001) A cannabinoid mechanism in relapse to cocaine seeking. Nat Med 7:1151–1154
De Vries TJ, Homberg JR, Binnekade R, Raaso H, Schoffelmeer AN (2003) Cannabinoid modulation of the reinforcing and motivational properties of heroin and heroin-associated cues in rats. Psychopharmacology 168:164–169
Economidou D, Mattioli L, Cifani C, Perfumi M, Massi M, Cuomo V, Trabace L, Ciccocioppo R (2006) Effect of the cannabinoid CB1 receptor antagonist SR-141716A on alcohol self-administration and alcohol-seeking behaviour in rats. Psychopharmacology 183:394–403
Fegley D, Gaetani S, Duranti A, Tontini A, Mor M, Tarzia G, Piomelli D (2005) Characterization of the fatty acid amide hydrolase inhibitor cyclohexyl carbamic acid 3′-carbamoyl-biphenyl-3-yl ester (URB597): effects on anandamide and oleoylalcoholamide deactivation. J Pharmacol Exp Ther 313:352–358
Freund TF, Katona I, Piomelli D (2003) Role of endogenous cannabinoids in synaptic signaling. Physiol Rev 83:1017–1066
Gallate JE, Saharov T, Mallet PE, McGregor IS (1999) Increased motivation for beer in rats following administration of a cannabinoid CB1 receptor agonist. Eur J Pharmacol 370:233–240
Gehlert DR, Cippitelli A, Thorsell A, Lê AD, Hipskind PA, Hamdouchi C, Lu J, Hembre EJ, Cramer J, Song M, McKinzie D, Morin M, Ciccocioppo R, Heilig M (2007) 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine: a novel brain-penetrant, orally available corticotropin-releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism. J Neurosci 27:2718–2726
Giuffrida A, Parsons LH, Kerr TM, Rodriguez de Fonseca F, Navarro M, Piomelli D (1999) Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nature Neurosci 2:358–363
Gobbi G, Bambico FR, Mangieri R, Bortolato M, Campolongo P, Solinas M, Cassano T, Morgese MG, Debonnel G, Duranti A, Tontini A, Tarzia G, Mor M, Trezza V, Goldberg SR, Cuomo V, Piomelli D (2005) Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis. Proc Natl Acad Sci USA 102:18620–18625
Gomez R, Navarro M, Ferrer B, Trigo JM, Bilbao A, Del Arco I, Cippitelli A, Nava F, Piomelli D, Rodriguez de Fonseca F (2002) A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding. J Neurosci 22:9612–9617
Hansson AC, Cippitelli A, Sommer WH, Fedeli A, Bjork K, Soverchia L, Terasmaa A, Massi M, Heilig M, Ciccocioppo R (2006) Variation at the rat Crhr1 locus and sensitivity to relapse into alcohol seeking induced by environmental stress. Proc Natl Acad Sci USA 103:15236–15241
Hansson AC, Bermudez-Silva FJ, Malinen H, Hyytia P, Sanchez-Vera I, Rimondini R, Rodriguez de Fonseca F, Kunos G, Sommer WH, Heilig M (2007) Genetic impairment of frontocortical endocannabinoid degradation and high alcohol preference. Neuropsychopharmacology 32:117–126
Hill MN, Ho WS, Sinopoli KJ, Viau V, Hillard CJ, Gorzalka BB (2006) Involvement of the endocannabinoid system in the ability of long-term tricyclic antidepressant treatment to suppress stress-induced activation of the hypothalamic–pituitary–adrenal axis. Neuropsychopharmacology 31:2591–2599
Hohmann AG, Suplita RL, Bolton NM, Neely MH, Fegley D, Mangieri R, Krey JF, Walker JM, Holmes PV, Crystal JD, Duranti A, Tontini A, Mor M, Tarzia G, Piomelli D (2005) An endocannabinoid mechanism for stress-induced analgesia. Nature 435:1108–1112
Holmberg G, Gershon S, Beck LH (1962) Yohimbine as an autonomic test drug. Nature 193:1313–1314
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 (2003) Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med 9:76–81
Lê AD, Shaham Y (2002) Neurobiology of relapse to alcohol in rats. Pharmacol Ther 94:137–156
Lê AD, Quan B, Juzytch W, Fletcher PJ, Joharchi N, Shaham Y (1998) Reinstatement of alcohol-seeking by priming injections of alcohol and exposure to stress in rats. Psychopharmacology 135:169–174
Lê AD, Harding S, Juzytsch W, Watchus J, Shalev U, Shaham Y (2000) The role of corticotrophin-releasing factor in stress-induced relapse to alcohol-seeking behavior in rats. Psychopharmacology 150:317–324
Lê AD, Harding S, Juzytsch W, Funk D, Shaham Y (2005) Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats. Psychopharmacology 179:366–373
Lee B, Tiefenbacher S, Platt DM, Spealman RD (2004) Pharmacological blockade of alpha(2)-adrenoceptors induces reinstatement of cocaine-seeking behavior in squirrel monkeys. Neuropsychopharmacology. 29:686–693
Liu X, Weiss F (2002) Additive effect of stress and drug cues on reinstatement of alcohol seeking: exacerbation by history of dependence and role of concurrent activation of corticotropin-releasing factor and opioid mechanisms. J Neurosci 22:7856–7861
Lopez-Moreno JA, Gonzalez-Cuevas G, Rodriguez de Fonseca F, Navarro M (2004) Long-lasting increase of alcohol relapse by the cannabinoid receptor agonist WIN 55,212-2 during alcohol deprivation. J Neurosci 24:8245–8252
McGregor IS, Dam KD, Mallet PE, Gallate JE (2005) Delta9-THC reinstates beer- and sucrose-seeking behaviour in abstinent rats: comparison with midazolam, food deprivation and predator odour. Alcohol Alcohol 40:35–45
Mor M, Rivara S, Lodola A, Plazzi PV, Tarzia G, Duranti A, Tontini A, Piersanti G, Kathuria S, Piomelli D (2004) Cyclohexylcarbamic acid 3′- or 4′-substituted biphenyl-3-yl esters as fatty acid amide hydrolase inhibitors: synthesis, quantitative structure–activity relationships, and molecular modeling studies. J Med Chem 47:4998–5008
O’Brien CP, McLellan AT (1996) Myths about the treatment of addiction. Lancet 347:237–240
O’Brien CP, Childress AR, McLellan AT, Ehrman R (1990) Integrating systematic cue exposure with standard treatment in recovering drug dependent patients. Addict Behav 15:355–365
O’Brien CP, Childress AR, Ehrman R, Robbins SJ (1998) Conditioning factors in drug abuse: can they explain compulsion? J Psychopharmacol 12:15–22
Pacher P, Batkai S, Kunos G (2006) The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 58:389–462
Patel S, Roelke CT, Rademacher DJ, Hillard CJ (2005) Inhibition of restraint stress-induced neural and behavioural activation by endogenous cannabinoid signalling. Eur J Neurosci 21:1057–1069
Piomelli D (2003) The molecular logic of endocannabinoid signalling. Nat Rev Neurosci 4:873–884
Piomelli D, Tarzia G, Duranti A, Tontini A, Mor M, Compton TR, Dasse O, Monaghan EP, Parrott JA, Putman D (2006) Pharmacological profile of the selective FAAH inhibitor KDS-4103 (URB597). CNS Drug Rev 12:21–38
Rademacher DJ, Hillard CJ (2007) Interactions between endocannabinoids and stress-induced decreased sensitivity to natural reward. Prog Neuropsychopharmacol Biol Psychiatry 31:633–641
Shaham Y, Erb S, Stewart J (2000) Stress-induced relapse to heroin and cocaine seeking in rats: a review. Brain Res Brain Res Rev 33:13–33
Shalev U, Grimm JW, Shaham Y (2002) Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol Rev 54:1–42
Shepard JD, Bossert JM, Liu SY, Shaham Y (2004) The anxiogenic drug yohimbine reinstates methamphetamine seeking in a rat model of drug relapse. Biol Psych 55:1082–1089
Vinod KY, Yalamanchili R, Xie S, Cooper TB, Hungund BL (2006) Effect of chronic alcohol exposure and its withdrawal on the endocannabinoid system. Neurochem Int 49:619–625
Weiss F, Lorang MT, Bloom FE, Koob GF (1993) Oral alcohol self-administration stimulates dopamine release in the rat nucleus accumbens: genetic and motivational determinants. J Pharmacol Exp Ther 267:250–258
Williams CM, Rogers PJ, Kirkham TC (1998) Hyperphagia in pre-fed rats following oral D9-THC-THC. Physiol Behav 65:343–346
Wilson RI, Nicoll RA (2002) Endocannabinoid signaling in the brain. Science 296:678–682
Acknowledgements
This work was supported by the Italian MUR (Ministero dell’Università e della Ricerca), the University of Urbino, the Plan Nacional Sobre Drogas, REDES TEMATICAS RD06/001 and the 5th Framework Programme, grants TARGALC QLRT-2001-01048. The authors have no financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
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An erratum to this article can be found at http://dx.doi.org/10.1007/s00213-011-2333-1
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Cippitelli, A., Cannella, N., Braconi, S. et al. Increase of brain endocannabinoid anandamide levels by FAAH inhibition and alcohol abuse behaviours in the rat. Psychopharmacology 198, 449–460 (2008). https://doi.org/10.1007/s00213-008-1104-0
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DOI: https://doi.org/10.1007/s00213-008-1104-0