Cannabinoid Cb1 Receptor Antagonists/Inverse Agonists and Food-Seeking Behavior

Salamone, John D.; Sink, Kelly; Segovia, Kristen N.; Randall, Patrick A.; McLaughlin, Peter J.; Vemuri, V. Kiran; Makriyannis, Alexandros

doi:10.1007/978-0-387-92271-3_29

Cannabinoid Cb₁ Receptor Antagonists/Inverse Agonists and Food-Seeking Behavior

John D. Salamone⁴,
Kelly Sink,
Kristen N. Segovia,
Patrick A. Randall,
Peter J. McLaughlin,
V. Kiran Vemuri &
…
Alexandros Makriyannis

Chapter
First Online: 01 January 2011

226 Accesses

Abstract

For the last few years, drugs that interfere with cannabinoid CB1 receptor transmission have been assessed for their potential utility as appetite suppressants. CB1 antagonists and inverse agonists have been shown to suppress a number of food-related behaviors, including food-reinforced behaviors. In addition to rimonabant (SR141716A), several other compounds have been evaluated, including AM251, AM1387, AM4113, and AM6545. Based upon biochemical studies of signal transduction, it appears that most of the drugs assessed thus far have been CB1 inverse agonists. CB1 receptor inverse agonists such as rimonabant act to suppress food intake and disrupt food-reinforced behavior. Furthermore, CB1 receptor inverse agonists do not appear to produce severe motor impairments that disrupt feeding behavior. However, there is evidence that they can induce nausea and malaise, and also can increase signs of anxiety and depression. Because of these problems, recent studies have been undertaken to characterize the behavioral effects of CB1 receptor neutral antagonists such as AM4113 to determine if these drugs can reduce feeding and food-reinforced behaviors. Neither the neutral antagonist AM4113 nor the inverse agonist AM251 produces effects that closely resemble those of dopamine antagonists. Across a variety of different tests, AM4113 affects food-motivated behavior in ways that are very similar to the effects of CB1 inverse agonists. In addition, AM4113 did not induce conditioned gaping in rats or vomiting in ferrets, and did not produce an anxiogenic effect in the elevated plus maze. These results suggest that CB1 receptor neutral antagonists may decrease appetite by blocking endogenous cannabinoid tone, and that these drugs may be less associated with aversive effects than is the case for CB1 inverse agonists. Additional studies also have focused upon the potential peripheral effects of drugs that to interfere with CB1 transmission. Therefore, despite some current difficulties with the potential use of CB1 receptor inverse agonists for the treatment of obesity, it is possible that neutral antagonists, or drugs that have actions primarily on the periphery, could ultimately be useful for clinical assessment as appetite suppressants.

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Abbreviations

THC:: delta-9-tetrahydrocannabinol
DA:: dopamine
FR:: fixed ratio
c-AMP:: cyclic-adenosine monophosphate

References

Addy C, Rothenberg P, Li S, Majumdar A, Agrawal N, Li H, et al. J Clin Pharmacol. 2008;48:734–44.
PubMed CAS Google Scholar
Arnone M, Maruani J, Chaperon F, Thiebot MH, Poncelet M, Soubrie P, et al. Psychopharmacology (Berl). 1997;132:104–6.
CAS Google Scholar
Baldo BA, Sadeghian K, Basso AM, Kelley AE. Behav Brain Res. 2002;137:165–77.
PubMed CAS Google Scholar
Carriero D, Aberman J, Lin SY, Hill A, Makriyannis A, Salamone JD. Psychopharmacology. 1998;137:147–56.
PubMed CAS Google Scholar
Chambers AP, Vemuri VK, Peng Y, Wood JT, Olzewska T, Pittman QJ, et al. Am J Physiol Regul Integr Comp Physiol. 2007;293:R2185–93.
PubMed CAS Google Scholar
Chen RZ, Huang RR, Shen CP, MacNeil DJ, Fong TM. Brain Res. 2004;999:227–30.
PubMed CAS Google Scholar
Chen RZ, Frassetto A, Lao JZ, Huang RR, Xiao JC, Clements MJ, et al. Eur J Pharmacol. 2008a;584:338–42.
PubMed CAS Google Scholar
Cohen C, Perrault G, Voltz C, Steinberg R, Soubrie P. Behav Pharmacol. 2002;13:451–63.
PubMed CAS Google Scholar
Colombo G, Agabio R, Diaz G, Lobina C, Reali R, Gessa GL. Life Sci. 1998;63:PL113–7.
PubMed CAS Google Scholar
Correa M, Carlson BB, Wisniecki A, Salamone JD. Behav Brain Res. 2002;137:179–87.
PubMed CAS Google Scholar
Cousins MS, Salamone JD. Pharmacol Biochem Behav. 1994;49:85–91.
PubMed CAS Google Scholar
Cousins MS, Sokolowski JD, Salamone JD. Pharmacol Biochem Behav. 1993;46:943–51.
PubMed CAS Google Scholar
Cousins MS, Wei W, Salamone JD. Psychopharmacology. 1994;116:529–37.
PubMed CAS Google Scholar
Curioni C, Andre C. Cochrane Database Syst Rev. 2006;4:CD006162.
PubMed Google Scholar
Darley CF, Tinklenberg JR, Hollister TE, Atkinson RC. Psychopharmacologia. 1973;29:231–8.
PubMed CAS Google Scholar
Darmani NA. Neuropsychopharmacology. 2001;24:198–203.
PubMed CAS Google Scholar
Darmani NA, Johnson JC. Eur J Pharmacol. 2004;488:201–12.
PubMed CAS Google Scholar
Darmani NA, Pandya DK. J Neural Transm. 2000;107:931–45.
PubMed CAS Google Scholar
De Vry J, Schreiber R, Eckel G, Jentzsch KR. Eur J Pharmacol. 2004;483:55–63.
PubMed Google Scholar
Despres JP, Golay A, Sjostrom L, Rimonabant in Obesity-Lipids Study Group. N Engl J Med. 2005;353:2121–34.
PubMed CAS Google Scholar
Drewnowski A, Grinker JA. Pharmacol Biochem Behav. 1978;9:619–30.
PubMed CAS Google Scholar
Egertova M, Elphick MR. J Comp Neurol. 2000;422:159–71.
PubMed CAS Google Scholar
Farrar AM, Pereira M, Velasco F, Hockemeyer J, Muller CE, Salamone JD. Psychopharmacology. 2007;191:579–86.
PubMed CAS Google Scholar
Fattore L, Fadda P, Fratta W. Pharmacol Res. 2007;56:418–27.
PubMed CAS Google Scholar
Foltin RW, Brady JV, Fischman MF. Pharmacol Biochem Behav. 1986;25:577–82.
PubMed CAS Google Scholar
Foltin RW, Fischman MW, Byrne MF. Appetite. 1988;11:1–14.
PubMed CAS Google Scholar
Freedland CS, Poston JS, Porrino LJ. Pharmacol Biochem Behav. 2000;67:265–70.
PubMed CAS Google Scholar
Gardner EL. Pharmacol Biochem Behav. 2005;81:263–84.
PubMed CAS Google Scholar
Gardner EL, Lowinson JH. Pharmacol Biochem Behav. 1991;40:571–80.
PubMed CAS Google Scholar
Gardner A, Mallet PE. Eur J Pharmacol. 2006;530:103–6.
PubMed CAS Google Scholar
Giuliani D, Ottani A, Ferrari F. Eur J Pharmacol. 2000;391:275–9.
PubMed CAS Google Scholar
Gomez R, Navarro M, Ferrer B, Trigo JM, Bilbao A, Del Arco I, et al. J Neurosci. 2002;22:9612–7.
PubMed CAS Google Scholar
Gonzalez-Rosales F, Walsh D. J Pain Symptom Manage. 1997;14:311–4.
PubMed CAS Google Scholar
Greenberg I, Kuehnle J, Mendelson JH, Bernstein JG. Psychopharmacology. 1976;49:79–84.
PubMed CAS Google Scholar
Halikas JA, Weller RA, Morse CL, Hoffmann RG. Int J Addiction. 1985;20:701–11.
CAS Google Scholar
Hao S, Avraham Y, Mechoulam R, Berry EM. Eur J Pharmacol. 2000;392:147–56.
PubMed CAS Google Scholar
Heishman SJ, Huestis MA, Henningfield JE, Cone EJ. Pharmacol Biochem Behav. 1990;37:561–5.
PubMed CAS Google Scholar
Herkenham M. Ann NY Acad Sci. 1992;654:19–32.
PubMed CAS Google Scholar
Hildebrandt AL, Kelly-Sullivan DM, Black SC. Eur J Pharmacol. 2003;462:125–32.
PubMed CAS Google Scholar
Hodge J, Bow JP, Plyler KS, Vemuri VK, Wisniecki A, Salamone JD, et al. Behav Brain Res. 2008;193:298–305.
PubMed CAS Google Scholar
Ilan AB, Smith ME, Gevins A. Psychopharmacology (Berl). 2004;176:214–22.
CAS Google Scholar
Ishiwari K, Weber SM, Mingote S, Correa M, Salamone JD. Behav Brain Res. 2004;151:83–91.
PubMed CAS Google Scholar
Jamshidi N, Taylor DA. Br J Pharmacol. 2001;134:1151–4.
PubMed CAS Google Scholar
Järbe TUC, Andrzejewski ME, DiPatrizio NV. Pharmacol Biochem Behav. 2002;73:911–9.
PubMed Google Scholar
Jicha GA, Salamone JD. J Neurosci. 1991;11:3822–9.
PubMed CAS Google Scholar
Johansson JO, Jarbe TU, Henriksson BG. TIT J Life Sci. 1975;5:17–27.
PubMed CAS Google Scholar
Kelley AE, Baldo BA, Pratt WE, Will MJ. Physiol Behav. 2005;86:773–95.
PubMed CAS Google Scholar
Koch JE. Pharmacol Biochem Behav. 2001;68:539–43.
PubMed CAS Google Scholar
Koch M, Schmid A, Scnhnitzler HU. Psychopharmacology. 2000;152:67–73.
PubMed CAS Google Scholar
Koob GF, Riley SJ, Smith SC, Robbins TW. J Comp Physiol Psychol. 1978;92:917–27.
PubMed CAS Google Scholar
Landsman RS, Burkey TH, Consroe P, Roeske WR, Yamamura HI. Eur J Pharmacol. 1997;334:R1–2.
PubMed CAS Google Scholar
Le Foll B, Gorelick DA, Goldberg SR. Psychopharmacology. 2009;205:171–4.
PubMed Google Scholar
Limebeer CL, Parker LA. J Exp Psychol Anim Behav Process. 2000;26:371–84.
PubMed CAS Google Scholar
Limebeer CL, Parker LA, Fletcher PJ. Behav Neurosci. 2004;118:1391–9.
PubMed CAS Google Scholar
Martin BR, Compton DR, Thomas BF, Prescott WR, Little PJ, Razdan RK, et al. Pharmacol Biochem Behav. 1991;40:471–8.
PubMed CAS Google Scholar
Mato S, Pazos A, Valdizan EM. Eur J Pharmacol. 2002;443:43–6.
PubMed CAS Google Scholar
McLaughlin PJ, Winston K, Swezey L, Wisniecki A, Aberman J, Tardif DJ, et al. Behav Pharmacol. 2003;14:583–8.
PubMed CAS Google Scholar
McLaughlin PJ, Lu D, Winston KM, Thakur G, Swezey LA, Makriyannis A, et al. Pharmacol Biochem Behav. 2005a;81:78–88.
PubMed CAS Google Scholar
McLaughlin PJ, Brown CM, Winston KM, Thakur G, Lu D, Makriyannis A, et al. Behav Pharmacol. 2005b;16:477–86.
PubMed CAS Google Scholar
McLaughlin PJ, Winston KM, Limebeer CL, Parker LA, Makriyannis A, Salamone JD. Psychopharmacology (Berl). 2005c;180:286–93.
CAS Google Scholar
McLaughlin PJ, Qian L, Wood JT, Wisniecki A, Winston KM, Swezey LA, et al. Pharmacol Biochem Behav. 2006;83:396–402.
PubMed CAS Google Scholar
Melis T, Succu S, Sanna F, Boi A, Argiolas A, Melis MR. Neurosci Lett. 2007;419:231–5.
PubMed CAS Google Scholar
Nowend KL, Arizzi M, Carlson BB, Salamone JD. Pharmacol Biochem Behav. 2001;69:373–82.
PubMed CAS Google Scholar
Parker LA, Limebeer CL. Auton Neurosci. 2006;129:36–41.
PubMed Google Scholar
Parker LA, Limebeer CL, Simpson GR. Pharmacol Biochem Behav. 1998;59:33–7.
PubMed CAS Google Scholar
Parker LA, Mechoulam R, Schlievert C, Abbott L, Fudge ML, Burton P. Psychopharmacology (Berl). 2003;166:156–62.
CAS Google Scholar
Pavón FJ, Bilbao A, Hernandez-Folgado L, Cippitelli A, Jagerovic N, Abellan G, et al. Neuropharmacology. 2006;51:358–66.
PubMed Google Scholar
Pavón FJ, Serrano A, Pérez-Valero V, Jagerovic N, Hernández-Folgado L, Bermúdez-Silva FJ, et al. J Neuroendocrinol. 2008;20 suppl 1:116–23.
PubMed Google Scholar
Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J, RIO-North America Study Group. JAMA. 2006;295:761–75.
PubMed CAS Google Scholar
Randall PA, Vemuri VK, Segovia KN, Torres EF, Hosmer S, Nunes EJ, Santerre JL, Makriyannis A, Salamone JD. Pharmacol Biochem Behav. 2010;97:179–184.
Google Scholar
Rigotti NA, Gonzales D, Dale LC, Lawrence D, Chang Y. Addiction. 2009;104:266–76.
PubMed Google Scholar
Rinaldi-Carmona M, Barth F, Héaulme M, Shire D, Calandra B, Congy C, et al. FEBS Lett. 1994;350:240–4.
PubMed CAS Google Scholar
Rowland NE, Mukherjee M, Robertson K. Psychopharmacology. 2001;159:111–6.
PubMed CAS Google Scholar
Salamone JD, Correa M. Behav Brain Res. 2002;137:3–25.
PubMed CAS Google Scholar
Salamone JD, Zigmond MJ, Stricker EM. Neuroscience. 1990;39:17–24.
PubMed CAS Google Scholar
Salamone JD, Steinpreis RE, McCullough LD, Smith P, Grebel D, Mahan K. Psychopharmacology. 1991;104:515–21.
PubMed CAS Google Scholar
Salamone JD, Mahan K, Rogers S. Pharmacol Biochem Behav. 1993;44:605–10.
PubMed CAS Google Scholar
Salamone JD, Cousins MS, Bucher S. Behav Brain Res. 1994;65:221–9.
PubMed CAS Google Scholar
Salamone JD, Cousins MS, Maio C, Champion M, Turski T, Kovach J. Psychopharmacology. 1996;125:105–12.
PubMed CAS Google Scholar
Salamone JD, Cousins MS, Snyder BJ. Neurosci Biobehav Rev. 1997;21:341–59.
PubMed CAS Google Scholar
Salamone JD, Aberman JE, Sokolowski JD, Cousins MS. Psychobiology. 1999;27:236–47.
CAS Google Scholar
Salamone JD, Wisniecki A, Carlson BB, Correa M. Neuroscience. 2001;105:863–70.
PubMed CAS Google Scholar
Salamone JD, Arizzi M, Sandoval MD, Cervone KM, Aberman JE. Psychopharmacology. 2002;160:371–80.
PubMed CAS Google Scholar
Salamone JD, Correa M, Mingote S, Weber SM. J Pharmacol Exp Ther. 2003;305:1–8.
PubMed CAS Google Scholar
Salamone JD, Correa M, Mingote SM, Weber SM. Curr Opin Pharmacol. 2005;5:34–41.
PubMed CAS Google Scholar
Salamone JD, Correa M, Mingote SM, Weber SM, Farrar AM. Curr Psychiatry Rev. 2006;2:267–80.
Google Scholar
Salamone JD, McLaughlin PJ, Sink K, Makriyannis A, Parker LA. Physiol Behav. 2007a;91:383–8.
PubMed CAS Google Scholar
Salamone JD, Correa M, Farrar A, Mingote SM. Psychopharmacology. 2007b;191:461–82.
PubMed CAS Google Scholar
Salamone JD, Randall P, Hosmer S, Sink KS, Segovia KN, Stopper CM, et al. Abstract viewer/itinerary planner. Washington, DC: Society for Neuroscience, 2009; 2009. Online.
Google Scholar
Shearman LP, Rosko KM, Fleischer R, Wang J, Xu S, Tong XS, et al. Behav Pharmacol. 2003;14:573–82.
PubMed CAS Google Scholar
Simiand J, Keane M, Keane PE, Soubrie P. Behav Pharmacol. 1998;9:179–81.
PubMed CAS Google Scholar
Simoneau II, Hamza MS, Mata HP, Siegel EM, Vanderah TW, Porreca F, et al. Anesthesiology. 2001;94:882–7.
PubMed CAS Google Scholar
Sink KS, McLaughlin PJ, Wood JA, Brown C, Fan P, Vemuri VK, et al. Neuropsychopharmacology. 2008a;33:946–66.
PubMed CAS Google Scholar
Sink KS, Segovia KN, Sink J, Randall PA, Collins LE, Correa M, Markus EJ, Vemuri VK, Makriyannis A, Salamone JD. Eur Neuropsychopharmacol. 2010;20:112–122.
Google Scholar
Sink KS, Vemuri VK, Olszewska T, Makriyannis A, Salamone JD. Psychopharmacology. 2008b;196:565–74.
PubMed CAS Google Scholar
Sink KS, Vemuri VK, Wood J, Makriyannis A, Salamone JD. Pharmacol Biochem Behav. 2009;91:303–6.
PubMed CAS Google Scholar
Sink KS, Segovia KN, Nunes EJ, Collins LE, Vemuri VK, Thakur G, Makriyannis A, Salamone JD. Psychopharmacology. in press.
Google Scholar
Sokolowski JD, Salamone JD. Pharmacol Biochem Behav. 1998;59:557–566.
Google Scholar
Solinas M, Panlilio LV, Antoniou K, Pappas LA, Goldberg SR. J Pharmacol Exp Ther. 2003;306:93–102.
PubMed CAS Google Scholar
Soria-Gomez E, Matias I, Rueda-Orozco PE, Cisneros M, Petrosino S, Navarro L, et al. Br J Pharmacol. 2007;151:1109–16.
PubMed CAS Google Scholar
Stapleton JA. Addiction. 2009;104:277–8.
PubMed Google Scholar
Tallett AJ, Blundell JE, Rodgers RJ. Psychopharmacology. 2007;195:27–39.
PubMed CAS Google Scholar
Tallett AJ, Blundell JE, Rodgers RJ. Pharmacol Biochem Behav. 2009;91:358–66.
PubMed CAS Google Scholar
Tanda G, Pontieri FE, Di Chiara G. Science. 1997;276:2048–50.
PubMed CAS Google Scholar
Ungerstedt U. Acta Physiol Scand Suppl. 1971;367:95–122.
PubMed CAS Google Scholar
US Food and Drug Administration Advisory Committee. FDA briefing document: zimulti (rimonabant) Tablets, 20 mg, FDA, Rockville. 2007. [WWW document]. URL (http://www.fda.gov/OHRMS/DOCKETS/AC/07/briefing/2007-4306b1-00-index.htm). Accessed September 2008.
Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S, RIO-Europe Study Group. Lancet. 2005;365:1389–97.
PubMed Google Scholar
Van Sickle MD, Oland LD, Mackie K, Davison JS, Sharkey KA. Am J Physiol Gastrointest Liver Physiol. 2003;285:G566–76.
PubMed Google Scholar
Verty AN, Mallet PE. Neuropharmacology. 2005;49:1101–9.
PubMed CAS Google Scholar
Verty AN, McGregor IS, Mallet PE. Neurosci Lett. 2004a;354:217–20.
PubMed CAS Google Scholar
Verty AN, McFarlane JR, McGregor IS, Mallet PE. Neuropharmacology. 2004b;47:593–603.
PubMed CAS Google Scholar
Verty AN, McFarlane JR, McGregor IS, Mallet PE. Endocrinology. 2004c;145:3224–31.
PubMed CAS Google Scholar
Ward SJ, Dykstra LA. Behav Pharmacol. 2005;16:381–8.
PubMed CAS Google Scholar
Wenger T, Moldrich G, Furst S. Brain Res Bull. 2003;61:125–8.
PubMed CAS Google Scholar
Werner NA, Koch JE. Brain Res. 2003;967:290–2.
PubMed CAS Google Scholar
Wiley JL, Burston JJ, Leggett DC, Alekseeva OO, Razdan RK, Mahadevan A, et al. Br J Pharmacol. 2005;145:293–300.
PubMed CAS Google Scholar
Williams CM, Kirkham TC. Psychopharmacology. 1999;143:315–7.
PubMed CAS Google Scholar
Williams CM, Kirkham TC. Physiol Behav. 2002;76:241–50.
PubMed CAS Google Scholar
Williams CM, Rogers PJ, Kirkham TC. Physiol Behav. 1998;65:343–6.
PubMed CAS Google Scholar

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Acknowledgments

This work was supported by grants to J.S. and A.M. from NIH/NIDA (U01DA016194).

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Department of Psychology, University of Connecticut, 406 Babbidge Road, Storrs, CT, 06269-1020, USA
John D. Salamone

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John D. Salamone
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Kelly Sink
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Kristen N. Segovia
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Patrick A. Randall
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Peter J. McLaughlin
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V. Kiran Vemuri
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Alexandros Makriyannis
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Dept. Nutrition & Dietetics, King's College, Stamford St. 150, London, SE1 9NH, United Kingdom
Victor R. Preedy
Arizona Health Science Center, Mel and Enid Zuckerman College of Public, University of Arizona, 1501 N. Campbell Ave. Room 4335, Tucson, 85724-5155, Arizona, USA
Ronald Ross Watson
University of the West of Scotland, Ayr Campus, Ayr, KA8 0SR, United Kingdom
Colin R. Martin

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Salamone, J.D. et al. (2011). Cannabinoid Cb₁ Receptor Antagonists/Inverse Agonists and Food-Seeking Behavior. In: Preedy, V., Watson, R., Martin, C. (eds) Handbook of Behavior, Food and Nutrition. Springer, New York, NY. https://doi.org/10.1007/978-0-387-92271-3_29

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