Cannabis/cannabinoids are widely used for recreational and therapy purposes, but their risks are largely disregarded. However, cannabinoid-associated use disorders and dependence are alarmingly increasing and an effective treatment is lacking. Recently, the growth hormone secretagogue receptor (GHSR1A) antagonism was proposed as a promising mechanism for drug addiction therapy. However, the role of GHS-R1A and its endogenous ligand ghrelin in cannabinoid abuse remains unclear. Therefore, the aim of our study was to investigate whether the GHS-R1A antagonist JMV2959 could reduce the tetrahydrocannabinol (THC)-induced conditioned place preference (CPP) and behavioral stimulation, the WIN55,212-2 intravenous self-administration (IVSA), and the tendency to relapse. Following an ongoing WIN55,212-2 self-administration, JMV2959 3 mg/kg was administered intraperitoneally 20 min before three consequent daily 120-min IVSA sessions under a fixed ratio FR1, which significantly reduced the number of the active lever-pressing, the number of infusions, and the cannabinoid intake. Pretreatment with JMV2959 suggested reduction of the WIN55,212-2-seeking/relapse-like behavior tested in rats on the twelfth day of the forced abstinence period. On the contrary, pretreatment with ghrelin significantly increased the cannabinoid IVSA as well as enhanced the relapse-like behavior. Co-administration of ghrelin with JMV2959 abolished/reduced the significant efficacy of the GHS-R1A antagonist in the cannabinoid IVSA. Pretreatment with JMV2959 significantly and dose-dependently reduced the manifestation of THC-induced CPP. The THC-CPP development was reduced after the simultaneous administration of JMV2959 with THC during conditioning. JMV2959 also significantly reduced the THC-induced behavioral stimulation in the LABORAS cage. Our findings suggest that GHS-R1A importantly participates in the rewarding/reinforcing effects of cannabinoids.

Department of Addictology 1st Faculty of Medicine Charles University Apolinarska 4 128 00 Prague 2 Czech Republic

Department of Pharmacology 3rd Faculty of Medicine Charles University Ruska 87 100 00 Prague 10 Czech Republic

Department of Physiology 3rd Faculty of Medicine Charles University Ke Karlovu 4 120 00 Prague 2 Czech Republic

Forensic Laboratory of Biologically Active Substances Department of Chemistry of Natural Compounds University of Chemistry and Technology Prague Technicka 5 166 28 Prague 6 Czech Republic

See more in PubMed

European Drug Report . European Monitoring Centre for Drugs and Drug Addiction. Publications Office of the European Union; Luxembourg: 2019. Trends and Developments 2019.

Hasin D.S. US epidemiology of cannabis use and associated problems. Neuropsychopharmacology. 2018;43:195–212. doi: 10.1038/npp.2017.198. PubMed DOI PMC

European Monitoring Centre for Drugs and Drug Addiction . Czech Republic, Country Drug Report 2018. Governmental Cabinet Office National Monitoring Centre for Drugs and Addiction; Prague, Czech Republic: 2019.

Zehra A., Burns J., Liu C.K., Manza P., Wiers C.E., Volkow N.D., Wang G.J. Cannabis addiction and the brain: A Review. J. Neuroimmune. Pharmacol. 2018;13:438–452. doi: 10.1007/s11481-018-9782-9. PubMed DOI PMC

Kondo K.K., Morasco B.J., Nugent S.M., Ayers C.K., O’Neil M.E., Freeman M., Kansagara D. Pharmacotherapy for the treatment of cannabis use disorder: A systematic review. Ann. Intern. Med. 2020;6:398–412. doi: 10.7326/M19-1105. PubMed DOI

Jerlhag E., Egecioglu E., Dickson S.L., Andersson M., Svensson L., Engel J.A. Ghrelin stimulates locomotor activity and accumbal dopamine-overflow via central cholinergic systems in mice: Implications for its involvement in brain reward. Addict. Biol. 2006;11:45–54. doi: 10.1111/j.1369-1600.2006.00002.x. PubMed DOI

Muller T.D., Nogueiras R., Andermann M.L., Andrews Z.B., Anker S.D., Argente J., Batterham R.L., Be-noit S.C., Bowers C.Y., Broglio F., et al. Ghrelin. Mol. Metab. 2015;4:437–460. doi: 10.1016/j.molmet.2015.03.005. PubMed DOI PMC

Abizaid A., Hougland J.L. Ghrelin signaling: Goat and GHS-R1a Take a LEAP in complexity. Trends Endocrinol. Metab. 2020;31:107–117. doi: 10.1016/j.tem.2019.09.006. PubMed DOI PMC

Cleverdon E.R., McGovern-Gooch K.R., Hougland J.L. The octanoylated energy regulating hormone ghrelin: An expanded view of ghrelin’s biological interactions and avenues for controlling ghrelin signaling. Mol. Membr. Biol. 2016;33:111–124. doi: 10.1080/09687688.2017.1388930. PubMed DOI

Panagopoulos V.N., Ralevski E. The role of ghrelin in addiction: A review. Psychopharmacology. 2014;231:2725–2740. doi: 10.1007/s00213-014-3640-0. PubMed DOI

Engel J.A., Jerlhag E. Role of appetite-regulating peptides in the pathophysiology of addiction: Implications for pharmacotherapy. CNS Drugs. 2014;28:875–886. doi: 10.1007/s40263-014-0178-y. PubMed DOI PMC

Jerlhag E. Gut-brain axis and addictive disorders: A review with focus on alcohol and drugs of abuse. Pharmacol. Ther. 2019;196:1–14. doi: 10.1016/j.pharmthera.2018.11.005. PubMed DOI

Zallar L.J., Farokhnia M., Tunstall B.J., Vendruscolo L.F., Leggio L. The role of the ghrelin system in drug addiction. Int. Rev. Neurobiol. 2017;136:89–119. doi: 10.1016/bs.irn.2017.08.002. PubMed DOI

Lee M.R., Tapocik J.D., Ghareeb M., Schwandt M.L., Dias A.A., Le A.N., Cobbina E., Farinelli L.A., Bouhlal S., Farokhnia M., et al. The novel ghrelin receptor inverse agonist PF-5190457 administered with alcohol: Preclinical safety experiments and a phase 1b human laboratory study. Mol. Psychiatry. 2020;25:461–475. doi: 10.1038/s41380-018-0064-y. PubMed DOI PMC

Mazidi M., Taraghdari S.B., Rezaee P., Kamgar M., Jomezadeh M.R., Hasani O.A., Soukhtanloo M., Hosseini M., Gholamnezhad Z., Rakhshandeh H., et al. The effect of hydroalcoholic extract of Cannabis Sativa on appetite hormone in rat. J. Complement. Integr. Med. 2014;11:253–257. doi: 10.1515/jcim-2014-0006. PubMed DOI

Zbucki R.L., Sawicki B., Hryniewicz A., Winnicka M.M. Cannabinoids enhance gastric X/A-like cells activity. Folia Histochem. Cytobiol. 2008;46:219–224. doi: 10.2478/v10042-008-0033-4. PubMed DOI

Farokhnia M., McDiarmid G.R., Newmeyer M.N., Munjal V., Abulseoud O.A., Huestis M.A., Leggio L. Effects of oral, smoked, and vaporized cannabis on endocrine pathways related to appetite and metabolism: A randomized, double-blind, placebo-controlled, human laboratory study. Transl. Psychiatry. 2020;10:1–11. doi: 10.1038/s41398-020-0756-3. PubMed DOI PMC

Riggs P.K., Vaida F., Rossi S.S., Sorkin L.S., Gouaux B., Grant I., Ellis R.J. A pilot study of the effects of cannabis on appetite hormones in HIV-infected adult men. Brain Res. 2012;1431:46–52. doi: 10.1016/j.brainres.2011.11.001. PubMed DOI PMC

Volkow N.D., Hampson A.J., Baler R.D. Don’t worry, be happy: Endocannabinoids and Cannabis at the Intersection of stress and reward. Annu. Rev. Pharmacol. Toxicol. 2017;57:285–308. doi: 10.1146/annurev-pharmtox-010716-104615. PubMed DOI

Manzanares J., Cabanero D., Puente N., Garcia-Gutierrez M.S., Grandes P., Maldonado R. Role of the endocannabinoid system in drug addiction. Biochem. Pharmacol. 2018;157:108–121. doi: 10.1016/j.bcp.2018.09.013. PubMed DOI

Maldonado R., Valverde O., Berrendero F. Involvement of the endocannabinoid system in drug addiction. Trends Neurosci. 2006;29:225–232. doi: 10.1016/j.tins.2006.01.008. PubMed DOI

Edwards A., Abizaid A. Driving the need to feed: Insight into the collaborative interaction between ghrelin and endocannabinoid systems in modulating brain reward systems. Neurosci. Biobehav. Rev. 2016;66:33–53. doi: 10.1016/j.neubiorev.2016.03.032. PubMed DOI

Kola B., Farkas I., Christ-Crain M., Wittmann G., Lolli F., Amin F., Harvey-White J., Liposits Z., Kunos G., Grossman A.B., et al. The orexigenic effect of ghrelin is mediated through central activation of the endogenous cannabinoid system. PLoS ONE. 2008;3:e1797. doi: 10.1371/journal.pone.0001797. PubMed DOI PMC

Tucci S.A., Rogers E.K., Korbonits M., Kirkham T.C. The cannabinoid CB1 receptor antagonist SR141716 blocks the orexigenic effects of intrahypothalamic ghrelin. Br. J. Pharmacol. 2004;143:520–523. doi: 10.1038/sj.bjp.0705968. PubMed DOI PMC

Kalafateli A.L., Vallöf D., Jörnulf J.W., Heilig M., Jerlhag E. A cannabinoid receptor antagonist attenuates ghrelin-induced activation of the mesolimbic dopamine system in mice. Physiol. Behav. 2018;184:211–219. doi: 10.1016/j.physbeh.2017.12.005. PubMed DOI

Moulin A., Brunel L., Boeglin D., Demange L., Ryan J., M’Kadmi C., Denoyelle S., Martinez J., Fehrentz J.-A. The 1,2,4-triazole as a scaffold for the design of ghrelin receptor ligands: Development of JMV 2959, a potent antagonist. Amino Acids. 2012;44:301–314. doi: 10.1007/s00726-012-1355-2. PubMed DOI

Moulin A., Ryan J., Martinez J., Fehrentz J.A. Recent developments in ghrelin receptor ligands. ChemMedChem. 2007;2:1242–1259. doi: 10.1002/cmdc.200700015. PubMed DOI

Jerabek P., Havlickova T., Puskina N., Charalambous C., Lapka M., Kacer P., Sustkova-Fiserova M. Ghrelin receptor antagonism of morphine-induced conditioned place preference and behavioral and accumbens dopaminergic sensitization in rats. Neurochem. Int. 2017;110:101–113. doi: 10.1016/j.neuint.2017.09.013. PubMed DOI

Sustkova-Fiserova M., Puskina N., Havlickova T., Lapka M., Syslova K., Pohorala V., Charalambous C. Ghrelin receptor antagonism of fentanyl-induced conditioned place preference, intravenous self-administration, and dopamine release in the nucleus accumbens in rats. Addict. Biol. 2020;25:e12845. doi: 10.1111/adb.12845. PubMed DOI

Sustkova-Fiserova M., Jerabek P., Havlickova T., Kacer P., Krsiak M. Ghrelin receptor antagonism of morphine-induced accumbens dopamine release and behavioral stimulation in rats. Psychopharmacology. 2014;231:2899–2908. doi: 10.1007/s00213-014-3466-9. PubMed DOI

Sustkova-Fiserova M., Jerabek P., Havlickova T., Syslova K., Kacer P. Ghrelin and endocannabinoids participation in morphine-induced effects in the rat nucleus accumbens. Psychopharmacology. 2016;233:469–484. doi: 10.1007/s00213-015-4119-3. PubMed DOI

Sustkova-Fiserova M., Charalambous C., Havlickova T., Lapka M., Jerabek P., Puskina N., Syslova K. Alterations in rat accumbens endocannabinoid and GABA content during fentanyl treatment: The role of ghrelin. Int. J. Mol. Sci. 2017;18:2486. doi: 10.3390/ijms18112486. PubMed DOI PMC

Charalambous C., Lapka M., Havlickova T., Syslova K., Sustkova-Fiserova M. Alterations in rat accumbens dopamine, endocannabinoids and GABA content during WIN55,212-2 treatment: The role of ghrelin. Int. J. Mol. Sci. 2020;22:210. doi: 10.3390/ijms22010210. PubMed DOI PMC

Compton D.R., Gold L.H., Ward S.J., Balster R.L., Martin B.R. Aminoalkylindole analogs: Cannabimimetic activity of a class of compounds structurally distinct from delta 9-tetrahydrocannabinol. J. Pharmacol. Exp. Ther. 1992;263:1118–1126. PubMed

D’Ambra T.E., Estep K.G., Bell M.R., Eissenstat M.A., Josef K.A., Ward S.J., Haycock D.A., Baizman E.R., Casiano F.M., Beglin N.C., et al. Conformationally restrained analogues of pravadoline: Nanomolar potent, enantioselective, (aminoalkyl) indole agonists of the cannabinoid receptor. J. Med. Chem. 1992;35:124–135. doi: 10.1021/jm00079a016. PubMed DOI

Fattore L., Cossu G., Martellotta C.M., Fratta W. Intravenous self-administration of the cannabinoid CB1 receptor agonist WIN 55,212–2 in rats. Psychopharmacology. 2001;156:410–416. doi: 10.1007/s002130100734. PubMed DOI

Lefever T.W., Marusich J.A., Antonazzo K.R., Wiley J.L. Evaluation of WIN55,212-2 self-administration in rats as a potential cannabinoid abuse liability model. Pharmacol. Biochem. Behav. 2014;118:30–35. doi: 10.1016/j.pbb.2014.01.002. PubMed DOI PMC

Amchova P., Kucerova J., Giugliano V., Babinska Z., Zanda M.T., Scherma M., Dušek L., Fadda P., Micale V., Sulcova A., et al. Enhanced self-administration of the CB1 receptor agonist WIN55,212-2 in olfactory bulbectomized rats: Evaluation of possible serotonergic and dopaminergic underlying mechanisms. Front. Pharmacol. 2014;5:44. doi: 10.3389/fphar.2014.00044. PubMed DOI PMC

Sharma P., Murthy P., Bharath M.M. Chemistry, metabolism, and toxicology of cannabis: Clinical implications. Iran. J. Psychiatry. 2012;7:149–156. PubMed PMC

Aceto M.D., Scates S.M., Martin B.B. Spontaneous and precipitated withdrawal with a synthetic cannabinoid, WIN 55212-2. Eur. J. Pharmacol. 2001;416:75–81. doi: 10.1016/S0014-2999(01)00873-1. PubMed DOI

Aceto M.D., Scates S.M., Lowe J.A., Martin B.R. Dependence on delta 9-tetrahydrocannabinol: Studies on precipitated and abrupt withdrawal. J. Pharmacol. Exp. Ther. 1996;278:1290–1295. PubMed

Tai S., Fantegrossi W.E. Synthetic cannabinoids: Pharmacology, behavioral effects, and abuse potential. Curr. Addict. Rep. 2014;1:129–136. doi: 10.1007/s40429-014-0014-y. PubMed DOI PMC

Spiller K.J., Bi G.-H., He Y., Galaj E., Gardner E.L., Xi Z.-X. Cannabinoid CB 1 and CB 2 receptor mechanisms underlie cannabis reward and aversion in rats. Br. J. Pharmacol. 2019;176:1268–1281. doi: 10.1111/bph.14625. PubMed DOI PMC

Jerlhag E., Egecioglu E., Landgren S., Salomé N., Heilig M., Moechars D., Datta R., Perrissoud D., Dickson S.L., Engel J.A. Requirement of central ghrelin signaling for alcohol reward. Proc. Natl. Acad. Sci. USA. 2009;106:11318–11323. doi: 10.1073/pnas.0812809106. PubMed DOI PMC

Katsidoni V., Kastellakis A., Panagis G. Biphasic effects of Delta9-tetrahydrocannabinol on brain stimulation reward and motor activity. Int. J. Neuropsychopharmacol. 2013;16:2273–2284. doi: 10.1017/S1461145713000709. PubMed DOI

Sanudo-Pena M.C., Romero J., Seale G.E., Fernandez-Ruiz J.J., Walker J.M. Activational role of cannabinoids on movement. Eur. J. Pharmacol. 2000;391:269–274. doi: 10.1016/S0014-2999(00)00044-3. PubMed DOI

Bardo M., Bevins R. Conditioned place preference: What does it add to our preclinical understanding of drug reward? Psychopharmacology. 2000;153:31–43. doi: 10.1007/s002130000569. PubMed DOI

Lupica C.R., Riegel A.C., Hoffman A.F. Marijuana and cannabinoid regulation of brain reward circuits. Br. J. Pharmacol. 2004;143:227–234. doi: 10.1038/sj.bjp.0705931. PubMed DOI PMC

Le Foll B., Wiggins M., Goldberg S.R. Nicotine pre-exposure does not potentiate the locomotor or rewarding effects of Delta-9-tetrahydrocannabinol in rats. Behav. Pharmacol. 2006;17:195–199. doi: 10.1097/01.fbp.0000197460.16516.81. PubMed DOI

Tanda G., Goldberg S.R. Cannabinoids: Reward, dependence, and underlying neurochemical mechanisms? A review of recent preclinical data. Psychopharmacology. 2003;169:115–134. doi: 10.1007/s00213-003-1485-z. PubMed DOI

Gardner E.L. Addictive potential of cannabinoids: The underlying neurobiology. Chem. Phys. Lipids. 2002;121:267–290. doi: 10.1016/S0009-3084(02)00162-7. PubMed DOI

Tanda G., Pontieri F.E., Di Chiara G. Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu1 opioid receptor mechanism. Science. 1997;276:2048–2050. doi: 10.1126/science.276.5321.2048. PubMed DOI

Jerlhag E., Egecioglu E., Dickson S.L., Engel J.A. Ghrelin receptor antagonism attenuates cocaine- and amphetamine-induced locomotor stimulation, accumbal dopamine release, and conditioned place preference. Psychopharmacology. 2010;211:415–422. doi: 10.1007/s00213-010-1907-7. PubMed DOI PMC

Jerlhag E., Engel J.A. Ghrelin receptor antagonism attenuates nicotine-induced locomotor stimulation, accumbal dopamine release and conditioned place preference in mice. Drug Alcohol Depend. 2011;117:126–131. doi: 10.1016/j.drugalcdep.2011.01.010. PubMed DOI

Engel J.A., Nylander I., Jerlhag E. A ghrelin receptor (GHS-R1A) antagonist attenuates the rewarding proper-ties of morphine and increases opioid peptide levels in reward areas in mice. Eur. Neuropsychopharmacol. 2015;25:2364–2371. doi: 10.1016/j.euroneuro.2015.10.004. PubMed DOI

Havlickova T., Charalambous C., Lapka M., Puskina N., Jerabek P., Sustkova-Fiserova M. Ghrelin Receptor antagonism of methamphetamine-induced conditioned place preference and intravenous self-administration in rats. Int. J. Mol. Sci. 2018;19:2925. doi: 10.3390/ijms19102925. PubMed DOI PMC

Rodriguez J.A., Fehrentz J.-A., Martinez J., Salah K.B.H., Wellman P.J. The GHR-R antagonist JMV 2959 neither induces malaise nor alters the malaise property of LiCl in the adult male rat. Physiol. Behav. 2018;183:46–48. doi: 10.1016/j.physbeh.2017.10.017. PubMed DOI

Wise R.A. Psychomotor stimulant properties of addictive drugs. Ann. N. Y. Acad. Sci. 1988;537:228–234. doi: 10.1111/j.1749-6632.1988.tb42109.x. PubMed DOI

Justinova Z., Tanda G., Redhi G.H., Goldberg S.R. Self-administration of delta9-tetrahydrocannabinol (THC) by drug naive squirrel monkeys. Psychopharmacology. 2003;169:135–140. doi: 10.1007/s00213-003-1484-0. PubMed DOI

Takahashi R.N., Singer G. Self-administration of delta 9-tetrahydrocannabinol by rats. Pharmacol. Biochem. Behav. 1979;11:737–740. doi: 10.1016/0091-3057(79)90274-0. PubMed DOI

Neuhofer D., Spencer S.M., Chioma V.C., Beloate L.N., Schwartz D., Kalivas P.W. The loss of NMDAR-dependent LTD following cannabinoid self-administration is restored by positive allosteric modulation of CB1 receptors. Addict. Biol. 2020;25:e12843. doi: 10.1111/adb.12843. PubMed DOI PMC

Braida D., Iosue S., Pegorini S., Sala M. Delta9-tetrahydrocannabinol-induced conditioned place preference and intracerebroventricular self-administration in rats. Eur. J. Pharmacol. 2004;506:63–69. doi: 10.1016/j.ejphar.2004.10.043. PubMed DOI

Braida D., Pozzi M., Parolaro D., Sala M. Intracerebral self-administration of the cannabinoid receptor agonist CP 55,940 in the rat: Interaction with the opioid system. Eur. J. Pharmacol. 2001;413:227–234. doi: 10.1016/S0014-2999(01)00766-X. PubMed DOI

Martellotta M.C., Cossu G., Fattore L., Gessa G.L., Fratta W. Self-administration of the cannabinoid receptor agonist WIN 55,212–2 in drug-naive mice. Neuroscience. 1998;85:327–330. doi: 10.1016/S0306-4522(98)00052-9. PubMed DOI

Kirschmann E.K., Pollock M.W., Nagarajan V., Torregrossa M.M. Effects of adolescent cannabinoid self-administration in rats on addiction-related behaviors and working memory. Neuropsychopharmacology. 2016;42:989–1000. doi: 10.1038/npp.2016.178. PubMed DOI PMC

Gomez J.L., Cunningham C.L., Finn D.A., Young E.A., Helpenstell L.K., Schuette L.M., Fidler T.L., Kosten T.A., Ryabinin A.E. Differential effects of ghrelin antagonists on alcohol drinking and reinforcement in mouse and rat models of alcohol dependence. Neuropharmacology. 2015;97:182–193. doi: 10.1016/j.neuropharm.2015.05.026. PubMed DOI PMC

Suchankova P., Steensland P., Fredriksson I., Engel J.A., Jerlhag E. Ghrelin receptor (GHS-R1A) Antagonism suppresses both alcohol consumption and the alcohol deprivation effect in rats following long-term voluntary alcohol consumption. PLoS ONE. 2013;8:e71284. doi: 10.1371/journal.pone.0071284. PubMed DOI PMC

Landgren S., Simms J.A., Thelle D.S., Strandhagen E., Bartlett S.E., Engel J.A., Jerlhag E. The ghrelin signalling system is involved in the consumption of sweets. PLoS ONE. 2011;6:e18170. doi: 10.1371/journal.pone.0018170. PubMed DOI PMC

Landgren S., Simms J.A., Hyytia P., Engel J.A., Bartlett S.E., Jerlhag E. Ghrelin receptor (GHS-R1A) antagonism suppresses both operant alcohol self-administration and high alcohol consumption in rats. Addict. Biol. 2012;17:86–94. doi: 10.1111/j.1369-1600.2010.00280.x. PubMed DOI

Esler W.P., Rudolph J., Claus T.H., Tang W., Barucci N., Brown S.-E., Bullock W., Daly M., DeCarr L., Li Y., et al. Small-Molecule ghrelin receptor antagonists improve glucose tolerance, suppress appetite, and promote weight loss. Endocrinology. 2007;148:5175–5185. doi: 10.1210/en.2007-0239. PubMed DOI

Maric T., Sedki F., Ronfard B., Chafetz D., Shalev U. A limited role for ghrelin in heroin self-administration and food deprivation-induced reinstatement of heroin seeking in rats. Addict. Biol. 2011;17:613–622. doi: 10.1111/j.1369-1600.2011.00396.x. PubMed DOI

Cepko L.C., Selva J.A., Merfeld E.B., Fimmel A.I., Goldberg S.A., Currie P.J. Ghrelin alters the stimulatory effect of cocaine on ethanol intake following mesolimbic or systemic administration. Neuropharmacology. 2014;85:224–231. doi: 10.1016/j.neuropharm.2014.05.030. PubMed DOI

Wellman P.J., Davis K.W., Nation J.R. Augmentation of cocaine hyperactivity in rats by systemic ghrelin. Regul. Pept. 2005;125:151–154. doi: 10.1016/j.regpep.2004.08.013. PubMed DOI

Skibicka K.P., Hansson C., Egecioglu E., Dickson S.L. Role of ghrelin in food reward: Impact of ghrelin on sucrose self-administration and mesolimbic dopamine and acetylcholine receptor gene expression. Addict. Biol. 2011;17:95–107. doi: 10.1111/j.1369-1600.2010.00294.x. PubMed DOI PMC

Bake T., Edvardsson C.E., Cummings C.J., Dickson S.L. Ghrelin’s effects on food motivation in rats are not limited to palatable foods. J. Neuroendocrinol. 2019;31:e12665. doi: 10.1111/jne.12665. PubMed DOI PMC

Abizaid A., Liu Z.W., Andrews Z.B., Shanabrough M., Borok E., Elsworth J.D., Roth R.H., Sleeman M.W., Picciotto M.R., Tschop M.H., et al. Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J. Clin. Investig. 2006;116:3229–3239. doi: 10.1172/JCI29867. PubMed DOI PMC

Jerlhag E., Egecioglu E., Dickson S.L., Douhan A., Svensson L., Engel J.A. Ghrelin administration into tegmental areas stimulates locomotor activity and increases extracellular concentration of dopamine in the nucleus accumbens. Addict. Biol. 2007;12:6–16. doi: 10.1111/j.1369-1600.2006.00041.x. PubMed DOI

Bloomfield M.A., Ashok A.H., Volkow N.D., Howes O.D. The effects of Delta(9)-tetrahydrocannabinol on the dopamine system. Nature. 2016;539:369–377. doi: 10.1038/nature20153. PubMed DOI PMC

Parsons L.H., Hurd Y.L. Endocannabinoid signalling in reward and addiction. Nat. Rev. Neurosci. 2015;16:579–594. doi: 10.1038/nrn4004. PubMed DOI PMC

Panlilio L.V., Justinova Z., Goldberg S.R. Inhibition of FAAH and activation of PPAR: New approaches to the treatment of cognitive dysfunction and drug addiction. Pharmacol. Ther. 2013;138:84–102. doi: 10.1016/j.pharmthera.2013.01.003. PubMed DOI PMC

Wijayendran S.B., O’Neill A., Bhattacharyya S. The effects of cannabis use on salience attribution: A systematic review. Acta Neuropsychiatr. 2018;30:43–57. doi: 10.1017/neu.2016.58. PubMed DOI PMC

Wellman M., Abizaid A. Growth hormone secretagogue receptor dimers: A new pharmacological target. Eneuro. 2015;2:1–16. doi: 10.1523/ENEURO.0053-14.2015. PubMed DOI PMC

M’Kadmi C., Leyris J.P., Onfroy L., Gales C., Sauliere A., Gagne D., Damian M., Mary S., Maingot M., Denoyelle S., et al. Agonism, Antagonism, and In-verse agonism bias at the ghrelin receptor signaling. J. Biol. Chem. 2015;290:27021–27039. doi: 10.1074/jbc.M115.659250. PubMed DOI PMC

Holst B., Cygankiewicz A., Jensen T.H., Ankersen M., Schwartz T.W. High constitutive signaling of the ghrelin receptor—identification of a potent inverse agonist. Mol. Endocrinol. 2003;17:2201–2210. doi: 10.1210/me.2003-0069. PubMed DOI

Mear Y.L., Enjalbert A., Thirion S. GHS-R1a constitutive activity and its physiological relevance. Front. Neurosci. 2013;7:87. doi: 10.3389/fnins.2013.00087. PubMed DOI PMC

Lim C.T., Kola B., Feltrin D., Perez-Tilve D., Tschop M.H., Grossman A.B., Korbonits M. Ghrelin and cannabinoids require the ghrelin receptor to affect cellular energy metabolism. Mol. Cell. Endocrinol. 2013;365:303–308. doi: 10.1016/j.mce.2012.11.007. PubMed DOI PMC

Sanchis-Segura C., Spanagel R. Behavioural assessment of drug reinforcement and addictive features in rodents: An overview. Addict. Biol. 2006;11:2–38. doi: 10.1111/j.1369-1600.2006.00012.x. PubMed DOI

Schutova B., Hruba L., Rokyta R., Slamberova R. Gender differences in behavioral changes elicited by pre-natal methamphetamine exposure and application of the same drug in adulthood. Dev. Psychobiol. 2013;55:232–242. doi: 10.1002/dev.21016. PubMed DOI

The Role of Ghrelin/GHS-R1A Signaling in Nonalcohol Drug Addictions