The endocannabinoid/CB1R system as well as the central ghrelin signalling with its growth hormone secretagogoue receptors (GHS-R1A) are importantly involved in food intake and reward/reinforcement processing and show distinct overlaps in distribution within the relevant brain regions including the hypothalamus (food intake), the ventral tegmental area (VTA) and the nucleus accumbens (NAC) (reward/reinforcement). The significant mutual interaction between these systems in food intake has been documented; however, the possible role of ghrelin/GHS-R1A in the cannabinoid reinforcement effects and addiction remain unclear. Therefore, the principal aim of the present study was to investigate whether pretreatment with GHS-R1A antagonist/JMV2959 could reduce the CB1R agonist/WIN55,212-2-induced dopamine efflux in the nucleus accumbens shell (NACSh), which is considered a crucial trigger impulse of the addiction process. The synthetic aminoalklylindol cannabinoid WIN55,212-2 administration into the posterior VTA induced significant accumbens dopamine release, which was significantly reduced by the 3 mg/kg i.p. JMV2959 pretreatment. Simultaneously, the cannabinoid-increased accumbens dopamine metabolic turnover was significantly augmented by the JMV2959 pretreament. The intracerebral WIN55,212-2 administration also increased the endocannabinoid arachidonoylethanolamide/anandamide and the 2-arachidonoylglycerol/2-AG extracellular levels in the NACSh, which was moderately but significantly attenuated by the JMV2959 pretreatment. Moreover, the cannabinoid-induced decrease in accumbens γ-aminobutyric acid/gamma-aminobutyric acid levels was reversed by the JMV2959 pretreatment. The behavioural study in the LABORAS cage showed that 3 mg/kg JMV2959 pretreatment also significantly reduced the systemic WIN55,212-2-induced behavioural stimulation. Our results demonstrate that the ghrelin/GHS-R1A system significantly participates in the rewarding/reinforcing effects of the cannabinoid/CB1 agonist that are involved in cannabinoid addiction processing.

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 34 Prague 10 Czech Republic

Laboratory of Medicinal Diagnostics Department of Organic Technology University of Chemistry and Technology Prague Technicka 5 166 28 Prague 6 Czech Republic

Zobrazit více v PubMed

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. Pharm. Toxicol. 2017;57:285–308. doi: 10.1146/annurev-pharmtox-010716-104615. PubMed DOI

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 Pharm. 2018;13:438–452. doi: 10.1007/s11481-018-9782-9. 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

Hwang E.K., Lupica C.R. Altered Corticolimbic Control of the Nucleus Accumbens by Long-term Delta(9)-Tetrahydrocannabinol Exposure. Biol. Psychiatry. 2020;87:619–631. doi: 10.1016/j.biopsych.2019.07.024. PubMed DOI PMC

Di Marzo V., Melck D., Bisogno T., De Petrocellis L. Endocannabinoids: Endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci. 1998;21:521–528. doi: 10.1016/S0166-2236(98)01283-1. PubMed DOI

Mechoulam R., Fride E., Di Marzo V. Endocannabinoids. Eur. J. Pharmacol. 1998;359:1–18. doi: 10.1016/S0014-2999(98)00649-9. 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

Scherma M., Masia P., Satta V., Fratta W., Fadda P., Tanda G. Brain activity of anandamide: A rewarding bliss? Acta Pharm. Sin. 2019;40:309–323. doi: 10.1038/s41401-018-0075-x. PubMed DOI PMC

Zlebnik N.E., Cheer J.F. Drug-Induced Alterations of Endocannabinoid-Mediated Plasticity in Brain Reward Regions. J. Neurosci. 2016;36:10230–10238. doi: 10.1523/JNEUROSCI.1712-16.2016. PubMed DOI PMC

Herkenham M. Characterization and localization of cannabinoid receptors in brain: An in vitro technique using slide-mounted tissue sections. NIDA Res. Monogr. 1991;112:129–145. PubMed

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. Nature. 1990;346:561–564. doi: 10.1038/346561a0. PubMed DOI

Spiller K.J., Bi G.H., He Y., Galaj E., Gardner E.L., Xi Z.X. Cannabinoid CB1 and CB2 receptor mechanisms underlie cannabis reward and aversion in rats. Br. J. Pharm. 2019;176:1268–1281. doi: 10.1111/bph.14625. 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

Koob G.F., Volkow N.D. Neurocircuitry of Addiction. Neuropsychopharmacology. 2010;35:217–238. doi: 10.1038/npp.2009.110. PubMed DOI PMC

Hyman S.E., Malenka R.C., Nestler E.J. Neural mechanisms of addiction: The role of reward-related learning and memory. Annu. Rev. Neurosci. 2006;29:565–598. doi: 10.1146/annurev.neuro.29.051605.113009. PubMed DOI

Nestler E.J. Is there a common molecular pathway for addiction? Nat. Neurosci. 2005;8:1445–1449. doi: 10.1038/nn1578. PubMed DOI

Di Chiara G., Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc. Natl. Acad. Sci. USA. 1988;85:5274–5278. doi: 10.1073/pnas.85.14.5274. PubMed DOI PMC

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

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

Gardner E.L. Endocannabinoid signaling system and brain reward: Emphasis on dopamine. Pharm. Biochem. Behav. 2005;81:263–284. doi: 10.1016/j.pbb.2005.01.032. PubMed DOI

Mackie K. Cannabinoid receptor homo- and heterodimerization. Life Sci. 2005;77:1667–1673. doi: 10.1016/j.lfs.2005.05.011. 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

Panlilio L.V., Goldberg S.R., Justinova Z. Cannabinoid abuse and addiction: Clinical and preclinical findings. Clin. Pharm. 2015;97:616–627. doi: 10.1002/cpt.118. PubMed DOI PMC

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. Pharm. 2004;143:520–523. doi: 10.1038/sj.bjp.0705968. 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

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., 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

Muller T.D., Nogueiras R., Andermann M.L., Andrews Z.B., Anker S.D., Argente J., Batterham R.L., Benoit 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

Wellman M., Abizaid A. Growth Hormone Secretagogue Receptor Dimers: A New Pharmacological Target. eNeuro. 2015;2 doi: 10.1523/ENEURO.0053-14.2015. PubMed DOI PMC

Ferrini F., Salio C., Lossi L., Merighi A. Ghrelin in central neurons. Curr. Neuropharmacol. 2009;7:37–49. doi: 10.2174/157015909787602779. PubMed DOI PMC

Guan X.M., Yu H., Palyha O.C., McKee K.K., Feighner S.D., Sirinathsinghji D.J., Smith R.G., Van der Ploeg L.H., Howard A.D. Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Res. Mol. Brain Res. 1997;48:23–29. doi: 10.1016/S0169-328X(97)00071-5. 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

Jerlhag E., Egecioglu E., Dickson S.L., Engel J.A. Glutamatergic regulation of ghrelin-induced activation of the mesolimbic dopamine system. Addict. Biol. 2011;16:82–91. doi: 10.1111/j.1369-1600.2010.00231.x. 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

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

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

Kalafateli A.L., Vallof D., Jornulf 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

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

Zangen A., Solinas M., Ikemoto S., Goldberg S.R., Wise R.A. Two brain sites for cannabinoid reward. J. Neurosci. 2006;26:4901–4907. doi: 10.1523/JNEUROSCI.3554-05.2006. PubMed DOI PMC

Wise R.A., Bozarth M.A. A psychomotor stimulant theory of addiction. Psychol. Rev. 1987;94:469–492. doi: 10.1037/0033-295X.94.4.469. PubMed DOI

Polissidis A., Chouliara O., Galanopoulos A., Marselos M., Papadopoulou-Daifoti Z., Antoniou K. Behavioural and dopaminergic alterations induced by a low dose of WIN 55,212-2 in a conditioned place preference procedure. Life Sci. 2009;85:248–254. doi: 10.1016/j.lfs.2009.05.015. PubMed DOI

Polissidis A., Galanopoulos A., Naxakis G., Papahatjis D., Papadopoulou-Daifoti Z., Antoniou K. The cannabinoid CB1 receptor biphasically modulates motor activity and regulates dopamine and glutamate release region dependently. Int. J. Neuropsychopharmacol. 2013;16:393–403. doi: 10.1017/S1461145712000156. PubMed DOI

Koob G.F., Volkow N.D. Neurobiology of addiction: A neurocircuitry analysis. Lancet Psychiatry. 2016;3:760–773. doi: 10.1016/S2215-0366(16)00104-8. PubMed DOI PMC

Jerlhag E., Egecioglu E., Landgren S., Salome 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

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

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

Engel J.A., Nylander I., Jerlhag E. A ghrelin receptor (GHS-R1A) antagonist attenuates the rewarding properties 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

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

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

Vlachou S., Panagis G. Regulation of brain reward by the endocannabinoid system: A critical review of behavioral studies in animals. Curr. Pharm. Des. 2014;20:2072–2088. doi: 10.2174/13816128113199990433. PubMed DOI

Hoffman A.F., Lupica C.R. Synaptic targets of Delta9-tetrahydrocannabinol in the central nervous system. Cold Spring Harb. Perspect. Med. 2013;3 doi: 10.1101/cshperspect.a012237. PubMed DOI PMC

Covey D.P., Wenzel J.M., Cheer J.F. Cannabinoid modulation of drug reward and the implications of marijuana legalization. Brain Res. 2015;1628:233–243. doi: 10.1016/j.brainres.2014.11.034. PubMed DOI PMC

Chen J.P., Paredes W., Lowinson J.H., Gardner E.L. Strain-specific facilitation of dopamine efflux by delta 9-tetrahydrocannabinol in the nucleus accumbens of rat: An in vivo microdialysis study. Neurosci. Lett. 1991;129:136–180. doi: 10.1016/0304-3940(91)90739-G. PubMed DOI

Chen J., Marmur R., Pulles A., Paredes W., Gardner E.L. Ventral tegmental microinjection of delta 9-tetrahydrocannabinol enhances ventral tegmental somatodendritic dopamine levels but not forebrain dopamine levels: Evidence for local neural action by marijuana’s psychoactive ingredient. Brain Res. 1993;621:65–70. doi: 10.1016/0006-8993(93)90298-2. PubMed DOI

Navarro M., Fernandez-Ruiz J.J., de Miguel R., Hernandez M.L., Cebeira M., Ramos J.A. An acute dose of delta 9-tetrahydrocannabinol affects behavioral and neurochemical indices of mesolimbic dopaminergic activity. Behav. Brain Res. 1993;57:37–46. doi: 10.1016/0166-4328(93)90059-Y. PubMed DOI

Polissidis A., Chouliara O., Galanopoulos A., Rentesi G., Dosi M., Hyphantis T., Marselos M., Papadopoulou-Daifoti Z., Nomikos G.G., Spyraki C., et al. Individual differences in the effects of cannabinoids on motor activity, dopaminergic activity and DARPP-32 phosphorylation in distinct regions of the brain. Int. J. Neuropsychopharmacol. 2010;13:1175–1191. doi: 10.1017/S1461145709991003. 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. 2019;25:e12845. doi: 10.1111/adb.12845. PubMed DOI

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

Jiang H., Betancourt L., Smith R.G. Ghrelin amplifies dopamine signaling by cross talk involving formation of growth hormone secretagogue receptor/dopamine receptor subtype 1 heterodimers. Mol. Endocrinol. 2006;20:1772–1785. doi: 10.1210/me.2005-0084. PubMed DOI

Jerlhag E., Janson A.C., Waters S., Engel J.A. Concomitant release of ventral tegmental acetylcholine and accumbal dopamine by ghrelin in rats. PLoS ONE. 2012;7:e49557. doi: 10.1371/journal.pone.0049557. PubMed DOI PMC

Serrenho D., Santos S.D., Carvalho A.L. The Role of Ghrelin in Regulating Synaptic Function and Plasticity of Feeding-Associated Circuits. Front. Cell. Neurosci. 2019;13:205. doi: 10.3389/fncel.2019.00205. PubMed DOI PMC

Castaneda T.R., Tong J., Datta R., Culler M., Tschop M.H. Ghrelin in the regulation of body weight and metabolism. Front Neuroendocr. 2010;31:44–60. doi: 10.1016/j.yfrne.2009.10.008. PubMed DOI

Lopez Soto E.J., Agosti F., Cabral A., Mustafa E.R., Damonte V.M., Gandini M.A., Rodriguez S., Castrogiovanni D., Felix R., Perello M., et al. Constitutive and ghrelin-dependent GHSR1a activation impairs CaV2.1 and CaV2.2 currents in hypothalamic neurons. J. Gen. Physiol. 2015;146:205–219. doi: 10.1085/jgp.201511383. PubMed DOI PMC

Friend L., Weed J., Sandoval P., Nufer T., Ostlund I., Edwards J.G. CB1-Dependent Long-Term Depression in Ventral Tegmental Area GABA Neurons: A Novel Target for Marijuana. J. Neurosci. 2017;37:10943–10954. doi: 10.1523/JNEUROSCI.0190-17.2017. PubMed DOI PMC

Kern A., Albarran-Zeckler R., Walsh H.E., Smith R.G. Apo-ghrelin receptor forms heteromers with DRD2 in hypothalamic neurons and is essential for anorexigenic effects of DRD2 agonism. Neuron. 2012;73:317–332. doi: 10.1016/j.neuron.2011.10.038. PubMed DOI PMC

Manzoni O.J., Bockaert J. Cannabinoids inhibit GABAergic synaptic transmission in mice nucleus accumbens. Eur. J. Pharmacol. 2001;412:R3–R5. doi: 10.1016/S0014-2999(01)00723-3. PubMed DOI

Aono Y., Saigusa T., Mizoguchi N., Iwakami T., Takada K., Gionhaku N., Oi Y., Ueda K., Koshikawa N., Cools A.R. Role of GABAA receptors in the endomorphin-1-, but not endomorphin-2-, induced dopamine efflux in the nucleus accumbens of freely moving rats. Eur. J. Pharmacol. 2008;580:87–94. doi: 10.1016/j.ejphar.2007.10.020. PubMed DOI

Saigusa T., Aono Y., Mizoguchi N., Iwakami T., Takada K., Oi Y., Ueda K., Koshikawa N., Cools A.R. Role of GABAB receptors in the endomorphin-1-, but not endomorphin-2-, induced dopamine efflux in the nucleus accumbens of freely moving rats. Eur. J. Pharmacol. 2008;581:276–282. doi: 10.1016/j.ejphar.2007.12.008. PubMed DOI

Cruz M.T., Herman M.A., Cote D.M., Ryabinin A.E., Roberto M. Ghrelin increases GABAergic transmission and interacts with ethanol actions in the rat central nucleus of the amygdala. Neuropsychopharmacology. 2013;38:364–375. doi: 10.1038/npp.2012.190. PubMed DOI PMC

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

Paxinos G., Watson C. The rat brain in stereotaxic coordinates. 6th ed. Academic Press/Elsevier; Amsterdam, The Netherlands: 2006.

Skibicka K.P., Hansson C., Alvarez-Crespo M., Friberg P.A., Dickson S.L. Ghrelin directly targets the ventral tegmental area to increase food motivation. Neuroscience. 2011;180:129–137. doi: 10.1016/j.neuroscience.2011.02.016. PubMed DOI

Syslova K., Rambousek L., Kuzma M., Najmanova V., Bubenikova-Valesova V., Slamberova R., Kacer P. Monitoring of dopamine and its metabolites in brain microdialysates: Method combining freeze-drying with liquid chromatography-tandem mass spectrometry. J. Chromatogr. A. 2011;1218:3382–3391. doi: 10.1016/j.chroma.2011.02.006. PubMed DOI

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

Cannabinoid-Induced Conditioned Place Preference, Intravenous Self-Administration, and Behavioral Stimulation Influenced by Ghrelin Receptor Antagonism in Rats