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

. 2022 Jan 11 ; 23 (2) : . [epub] 20220111

Jazyk angličtina Země Švýcarsko Médium electronic

Typ dokumentu časopisecké články, přehledy

Perzistentní odkaz   https://www.medvik.cz/link/pmid35054944

Drug addiction causes constant serious health, social, and economic burden within the human society. The current drug dependence pharmacotherapies, particularly relapse prevention, remain limited, unsatisfactory, unreliable for opioids and tobacco, and even symptomatic for stimulants and cannabinoids, thus, new more effective treatment strategies are researched. The antagonism of the growth hormone secretagogue receptor type A (GHS-R1A) has been recently proposed as a novel alcohol addiction treatment strategy, and it has been intensively studied in experimental models of other addictive drugs, such as nicotine, stimulants, opioids and cannabinoids. The role of ghrelin signaling in these drugs effects has also been investigated. The present review aims to provide a comprehensive overview of preclinical and clinical studies focused on ghrelin's/GHS-R1A possible involvement in these nonalcohol addictive drugs reinforcing effects and addiction. Although the investigation is still in its early stage, majority of the existing reviewed experimental results from rodents with the addition of few human studies, that searched correlations between the genetic variations of the ghrelin signaling or the ghrelin blood content with the addictive drugs effects, have indicated the importance of the ghrelin's/GHS-R1As involvement in the nonalcohol abused drugs pro-addictive effects. Further research is necessary to elucidate the exact involved mechanisms and to verify the future potential utilization and safety of the GHS-R1A antagonism use for these drug addiction therapies, particularly for reducing the risk of relapse.

Zobrazit více v PubMed

Pruckner N., Hinterbuchinger B., Fellinger M., König D., Waldhoer T., Lesch O.M., Gmeiner A., Vyssoki S., Vyssoki B. Alcohol-Related Mortality in the WHO European Region: Sex-Specific Trends and Predictions. Alcohol Alcohol. 2019;54:593–598. doi: 10.1093/alcalc/agz063. PubMed DOI

European Commission Tobacco—Overview. 2020. [(accessed on 1 December 2021)]. Available online: https://ec.europa.eu/health/tobacco/overview_en.

Drug-Related Deaths and Mortality in Europe. European Monitoring Centre for Drugs and Drug Addiction, Publication Office of the EU Luxemburg; Luxembourg: 2019.

UNODC World Drug Report 2021. [(accessed on 1 December 2021)]. Available online: https://www.unodc.org/unodc/data-and-analysis/wdr2021.html.

Volkow N.D., Michaelides M., Baler R. The Neuroscience of Drug Reward and Addiction. Physiol. Rev. 2019;99:2115–2140. doi: 10.1152/physrev.00014.2018. PubMed DOI PMC

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

Kelley A.E., Berridge K. The Neuroscience of Natural Rewards: Relevance to Addictive Drugs. J. Neurosci. 2002;22:3306–3311. doi: 10.1523/JNEUROSCI.22-09-03306.2002. PubMed DOI PMC

Wise R.A. Dopamine and reward: The anhedonia hypothesis 30 years on. Neurotox. Res. 2008;14:169–183. doi: 10.1007/BF03033808. PubMed DOI PMC

Wise R.A. Catecholamine theories of reward: A critical review. Brain Res. 1978;152:215–247. doi: 10.1016/0006-8993(78)90253-6. 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. Preferential stimulation of dopamine release in the nucleus accumbens by opiates, alcohol, and barbiturates: Studies with transcerebral dialysis in freely moving rats. Ann. N. Y. Acad. Sci. 1986;473:367–381. doi: 10.1111/j.1749-6632.1986.tb23629.x. 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

Di Chiara G. Nucleus accumbens shell and core dopamine: Differential role in behavior and addiction. Behav. Brain Res. 2002;137:75–114. doi: 10.1016/S0166-4328(02)00286-3. PubMed DOI

Omelchenko N., Sesack S.R. Cholinergic axons in the rat ventral tegmental area synapse preferentially onto mesoaccumbens dopamine neurons. J. Comp. Neurol. 2006;494:863–875. doi: 10.1002/cne.20852. PubMed DOI PMC

Forster G.L., Blaha C.D. Laterodorsal tegmental stimulation elicits dopamine efflux in the rat nucleus accumbens by activation of acetylcholine and glutamate receptors in the ventral tegmental area. Eur. J. Neurosci. 2000;12:3596–3604. doi: 10.1046/j.1460-9568.2000.00250.x. PubMed DOI

Larsson A., Engel J.A. Neurochemical and behavioral studies on ethanol and nicotine interactions. Neurosci. Biobehav. Rev. 2004;27:713–720. doi: 10.1016/j.neubiorev.2003.11.010. PubMed DOI

Steidl S., Wang H., Ordonez M., Zhang S., Morales M. Optogenetic excitation in the ventral tegmental area of glutamatergic or cholinergic inputs from the laterodorsal tegmental area drives reward. Eur. J. Neurosci. 2017;45:559–571. doi: 10.1111/ejn.13436. PubMed DOI

Robinson T.E., Berridge K.C. The Neural Basis of Drug Craving—An Incentive-Sensitization Theory of Addiction. Brain Res. Rev. 1993;18:247–291. doi: 10.1016/0165-0173(93)90013-P. PubMed DOI

Wise R.A. The role of reward pathways in the development of drug dependence. Pharmacol. Ther. 1987;35:227–263. doi: 10.1016/0163-7258(87)90108-2. PubMed DOI

Hnasko T.S., Sotak B.N., Palmiter R.D. Cocaine-Conditioned Place Preference by Dopamine-Deficient Mice Is Mediated by Serotonin. J. Neurosci. 2007;27:12484–12488. doi: 10.1523/JNEUROSCI.3133-07.2007. PubMed DOI PMC

Van Ree J.M., Niesink R.J., Van Wolfswinkel L., Ramsey N.F., Kornet M.M., Van Furth W.R., Vanderschuren L.J., Gerrits M.A., Van den Berg C.L. Endogenous opioids and reward. Eur. J. Pharmacol. 2000;405:89–101. doi: 10.1016/S0014-2999(00)00544-6. PubMed DOI

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

Bouarab C., Thompson B., Polter A.M. VTA GABA Neurons at the Interface of Stress and Reward. Front. Neural Circuits. 2019;13:78. doi: 10.3389/fncir.2019.00078. PubMed DOI PMC

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

Miwa J.M., Freedman R., Lester H.A. Neural Systems Governed by Nicotinic Acetylcholine Receptors: Emerging Hypotheses. Neuron. 2011;70:20–33. doi: 10.1016/j.neuron.2011.03.014. 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

Volkow N.D., Wang G.-J., Tomasi D., Baler R.D. Obesity and addiction: Neurobiological overlaps. Obes. Rev. 2013;14:2–18. doi: 10.1111/j.1467-789X.2012.01031.x. PubMed DOI PMC

Holderness C.C., Brooks-Gunn J., Warren M.P. Co-morbidity of eating disorders and substance abuse review of the literature. Int. J. Eat. Disord. 1994;16:1–34. doi: 10.1002/1098-108X(199407)16:1<1::AID-EAT2260160102>3.0.CO;2-T. PubMed DOI

Krahn D., Kurth C., Demitrack M., Drewnowski A. The relationship of dieting severity and bulimic behaviors to alcohol and other drug use in young women. J. Subst. Abus. 1992;4:341–353. doi: 10.1016/0899-3289(92)90041-U. PubMed DOI

Cabeza de Vaca S., Carr K.D. Food restriction enhances the central rewarding effect of abused drugs. J. Neurosci. 1998;18:7502–7510. doi: 10.1523/JNEUROSCI.18-18-07502.1998. PubMed DOI PMC

CCarr K.D., Kim G.-Y., De Vaca S.C. Rewarding and locomotor-activating effects of direct dopamine receptor agonists are augmented by chronic food restriction in rats. Psychopharmacology. 2001;154:420–428. doi: 10.1007/s002130000674. PubMed DOI

Carr K.D. Chronic food restriction: Enhancing effects on drug reward and striatal cell signaling. Physiol. Behav. 2007;91:459–472. doi: 10.1016/j.physbeh.2006.09.021. PubMed DOI

Kojima M., Hosoda H., Date Y., Nakazato M., Matsuo H., Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402:656–660. doi: 10.1038/45230. PubMed DOI

Egecioglu E., Jerlhag E., Salomé N., Skibicka K.P., Haage D., Bohlooly Y.M., Andersson D., Bjursell M., Perrissoud D., Engel J.A., et al. Ghrelin increases intake of rewarding food in rodents. Addict. Biol. 2010;15:304–311. doi: 10.1111/j.1369-1600.2010.00216.x. PubMed DOI PMC

Naleid A.M., Grace M.K., Cummings D.E., Levine A.S. Ghrelin induces feeding in the mesolimbic reward pathway between the ventral tegmental area and the nucleus accumbens. Peptides. 2005;26:2274–2279. doi: 10.1016/j.peptides.2005.04.025. PubMed DOI

Mason B., Wang Q., Zigman J. The Central Nervous System Sites Mediating the Orexigenic Actions of Ghrelin. Annu. Rev. Physiol. 2014;76:519–533. doi: 10.1146/annurev-physiol-021113-170310. PubMed DOI PMC

Sakata I., Nakamura K., Yamazaki M., Matsubara M., Hayashi Y., Kangawa K., Sakai T. Ghrelin-producing cells exist as two types of cells, closed- and opened-type cells, in the rat gastrointestinal tract. Peptides. 2002;23:531–536. doi: 10.1016/S0196-9781(01)00633-7. PubMed DOI

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

Cummings D.E., Frayo R.S., Marmonier C., Aubert R., Chapelot D. Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues. Am. J. Physiol. Metab. 2004;287:E297–E304. doi: 10.1152/ajpendo.00582.2003. PubMed DOI

Lu S., Guan J.-L., Wang Q.-P., Uehara K., Yamada S., Goto N., Date Y., Nakazato M., Kojima M., Kangawa K., et al. Immunocytochemical observation of ghrelin-containing neurons in the rat arcuate nucleus. Neurosci. Lett. 2002;321:157–160. doi: 10.1016/S0304-3940(01)02544-7. PubMed DOI

Mondal M.S., Date Y., Yamaguchi H., Toshinai K., Tsuruta T., Kangawa K., Nakazato M. Identification of ghrelin and its receptor in neurons of the rat arcuate nucleus. Regul. Pept. 2005;126:55–59. doi: 10.1016/j.regpep.2004.08.038. PubMed DOI

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

Cabral A., Lopez Soto E.J., Epelbaum J., Perello M. Is Ghrelin Synthesized in the Central Nervous System? Int. J. Mol. Sci. 2017;18:638. doi: 10.3390/ijms18030638. PubMed DOI PMC

Delhanty P.J., Neggers S.J., van der Lely A.J. Should We Consider Des-Acyl Ghrelin as a Separate Hormone and If So, What Does It Do? Front. Horm. Res. 2014;42:163–174. doi: 10.1159/000358345. PubMed DOI

Hopkins A.L., Nelson T.A.S., Guschina I.A., Parsons L.C., Lewis C.L., Brown R.C., Christian H., Davies J., Wells T. Unacylated ghrelin promotes adipogenesis in rodent bone marrow via ghrelin O-acyl transferase and GHS-R1a activity: Evidence for target cell-induced acylation. Sci. Rep. 2017;7:srep45541. doi: 10.1038/srep45541. PubMed DOI PMC

Delhanty P.J., Neggers S.J., van der Lely A.J. Mechanisms in endocrinology: Ghrelin: The differences between acyl- and des-acyl ghrelin. Eur. J. Endocrinol. 2012;167:601–608. doi: 10.1530/EJE-12-0456. PubMed DOI

Callaghan B., Furness J.B. Novel and Conventional Receptors for Ghrelin, Desacyl-Ghrelin, and Pharmacologically Related Compounds. Pharmacol. Rev. 2014;66:984–1001. doi: 10.1124/pr.113.008433. PubMed DOI

Heppner K.M., Piechowski C.L., Müller A., Ottaway N., Sisley S., Smiley D.L., Habegger K.M., Pfluger P.T., DiMarchi R., Biebermann H., et al. Both Acyl and Des-Acyl Ghrelin Regulate Adiposity and Glucose Metabolism via Central Nervous System Ghrelin Receptors. Diabetes. 2013;63:122–131. doi: 10.2337/db13-0414. PubMed DOI PMC

Rhea E.M., Salameh T.S., Gray S., Niu J., Banks W.A., Tong J. Ghrelin transport across the blood–brain barrier can occur independently of the growth hormone secretagogue receptor. Mol. Metab. 2018;18:88–96. doi: 10.1016/j.molmet.2018.09.007. PubMed DOI PMC

Cabral A., Valdivia S., Fernandez G., Reynaldo M., Perello M. Divergent Neuronal Circuitries Underlying Acute Orexigenic Effects of Peripheral or Central Ghrelin: Critical Role of Brain Accessibility. J. Neuroendocr. 2014;26:542–554. doi: 10.1111/jne.12168. PubMed DOI PMC

Schaeffer M., Langlet F., Lafont C., Molino F., Hodson D.J., Roux T., Lamarque L., Verdié P., Bourrier E., Dehouck B., et al. Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons. Proc. Natl. Acad. Sci. USA. 2013;110:1512–1517. doi: 10.1073/pnas.1212137110. PubMed DOI PMC

Furness J., Hunne B., Matsuda N., Yin L., Russo D., Kato I., Fujimiya M., Patterson M., McLeod J., Andrews Z., et al. Investigation of the presence of ghrelin in the central nervous system of the rat and mouse. Neuroscience. 2011;193:1–9. doi: 10.1016/j.neuroscience.2011.07.063. PubMed DOI

Perello M., Cabral A., Cornejo M.P., De Francesco P.N., Fernandez G., Uriarte M. Brain accessibility delineates the central effects of circulating ghrelin. J. Neuroendocr. 2019;31:e12677. doi: 10.1111/jne.12677. PubMed DOI

Wenthur C., Gautam R., Zhou B., Vendruscolo L.F., Leggio L., Janda K.D. Ghrelin Receptor Influence on Cocaine Reward is Not Directly Dependent on Peripheral Acyl-Ghrelin. Sci. Rep. 2019;9:1841. doi: 10.1038/s41598-019-38549-z. PubMed DOI PMC

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

Howard A.D., Feighner S.D., Cully D.F., Arena J.P., Liberator P.A., Rosenblum C.I., Hamelin M., Hreniuk D.L., Palyha O.C., Anderson J., et al. A Receptor in Pituitary and Hypothalamus That Functions in Growth Hormone Release. Science. 1996;273:974–977. doi: 10.1126/science.273.5277.974. PubMed DOI

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. Mol. Brain Res. 1997;48:23–29. doi: 10.1016/S0169-328X(97)00071-5. PubMed DOI

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

Van der Lely A.J., Tschop M., Heiman M.L., Ghigo E. Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr. Rev. 2004;25:426–457. doi: 10.1210/er.2002-0029. PubMed DOI

Abizaid A., Liu Z.-W., Andrews Z.B., Shanabrough M., Borok E., Elsworth J.D., Roth R.H., Sleeman M.W., Picciotto M., Tschöp 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

Landgren S., Engel J.A., Hyytiä P., Zetterberg H., Blennow K., Jerlhag E. Expression of the gene encoding the ghrelin receptor in rats selected for differential alcohol preference. Behav. Brain Res. 2011;221:182–188. doi: 10.1016/j.bbr.2011.03.003. PubMed DOI

Zigman J.M., Jones J.E., Lee C.E., Saper C.B., Elmquist J.K. Expression of ghrelin receptor mRNA in the rat and the mouse brain. J. Comp. Neurol. 2006;494:528–548. doi: 10.1002/cne.20823. PubMed DOI PMC

Quarta D., Di Francesco C., Melotto S., Mangiarini L., Heidbreder C., Hedou G. Systemic administration of ghrelin increases extracellular dopamine in the shell but not the core subdivision of the nucleus accumbens. Neurochem. Int. 2009;54:89–94. doi: 10.1016/j.neuint.2008.12.006. PubMed DOI

Skibicka K., Hansson C., Alvarez-Crespo M., Friberg P., Dickson S. 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

Airapetov M.I., Eresko S.O., Lebedev A.A., Bychkov E.R., Shabanov P.D. Expression of the growth hormone secretagogue receptor 1a (GHS-R1a) in the brain. Physiol. Rep. 2021;9:e15113. doi: 10.14814/phy2.15113. PubMed DOI PMC

M’Kadmi C., Leyris J.-P., Onfroy L., Gales C., Saulière A., Gagne D., Damian M., Mary S., Maingot M., Denoyelle S., et al. Agonism, Antagonism, and Inverse Agonism Bias at the Ghrelin Receptor Signaling. J. Biol. Chem. 2015;290:27021–27039. doi: 10.1074/jbc.M115.659250. PubMed DOI PMC

Holliday N.D., Holst B., Rodionova E.A., Schwartz T.W., Cox H. Importance of Constitutive Activity and Arrestin-Independent Mechanisms for Intracellular Trafficking of the Ghrelin Receptor. Mol. Endocrinol. 2007;21:3100–3112. doi: 10.1210/me.2007-0254. 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

Ribeiro L.F., Catarino T., Carvalho M., Cortes L., Santos S.D., Opazo P.O., Ribeiro L.R., Oliveiros B., Choquet D., Esteban J.A., et al. Ligand-independent activity of the ghrelin receptor modulates AMPA receptor trafficking and supports memory formation. Sci. Signal. 2021;14:eabb1953. doi: 10.1126/scisignal.abb1953. 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

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

Lim C.T., Kola B., Feltrin D., Perez-Tilve D., Tschöp 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

Schellekens H., van Oeffelen W.E.P.A., Dinan T., Cryan J.F. Promiscuous Dimerization of the Growth Hormone Secretagogue Receptor (GHS-R1a) Attenuates Ghrelin-mediated Signaling. J. Biol. Chem. 2013;288:181–191. doi: 10.1074/jbc.M112.382473. PubMed DOI PMC

Aguinaga D., Casanovas M., Rivas-Santisteban R., Reyes-Resina I., Navarro G., Franco R. The sigma-1 receptor as key common factor in cocaine and food-seeking behaviors. J. Mol. Endocrinol. 2019;63:R81–R92. doi: 10.1530/JME-19-0138. PubMed DOI

Navarro G., Rea W., Quiroz C., Moreno E., Gomez D., Wenthur C.J., Casadó V., Leggio L., Hearing M.C., Ferré S. Complexes of ghrelin GHS-R1a, GHS-R1b and dopamine D1 receptors localized in the ventral tegmental area as main mediators of the dopaminergic effects of ghrelin. J. Neurosci. 2021 doi: 10.1523/JNEUROSCI.1151-21.2021. PubMed DOI PMC

Navarro G., Aguinaga D., Angelats E., Medrano M., Moreno E., Mallol J., Cortés A., Canela E.I., Casadó V., McCormick P.J., et al. A Significant Role of the Truncated Ghrelin Receptor GHS-R1b in Ghrelin-induced Signaling in Neurons. J. Biol. Chem. 2016;291:13048–13062. doi: 10.1074/jbc.M116.715144. PubMed DOI PMC

Laviano A., Molfino A., Rianda S., Fanelli F.R. The Growth Hormone Secretagogue Receptor (Ghs-R) Curr. Pharm. Des. 2012;18:4749–4754. doi: 10.2174/138161212803216906. PubMed DOI

Muccioli G., Baragli A., Granata R., Papotti M., Ghigo E. Heterogeneity of ghrelin/growth hormone secretagogue receptors. Toward the understanding of the molecular identity of novel ghrelin/GHS receptors. Neuroendocrinology. 2007;86:147–164. doi: 10.1159/000105141. PubMed DOI

Ge X., Yang H., Bednarek M.A., Galon-Tilleman H., Chen P., Chen M., Lichtman J.S., Wang Y., Dalmas O., Yin Y., et al. LEAP2 Is an Endogenous Antagonist of the Ghrelin Receptor. Cell Metab. 2018;27:461–469.e6. doi: 10.1016/j.cmet.2017.10.016. PubMed DOI

M’kadmi C., Cabral A., Barrile F., Giribaldi J., Cantel S., Damian M., Mary S., Denoyelle S., Dutertre S., Péraldi-Roux S., et al. N-Terminal Liver-Expressed Antimicrobial Peptide 2 (LEAP2) Region Exhibits Inverse Agonist Activity toward the Ghrelin Receptor. J. Med. Chem. 2019;62:965–973. doi: 10.1021/acs.jmedchem.8b01644. 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

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

Palotai M., Bagosi Z., Jászberényi M., Csabafi K., Dochnal R., Manczinger M., Telegdy G., Szabó G. Ghrelin amplifies the nicotine-induced dopamine release in the rat striatum. Neurochem. Int. 2013;63:239–243. doi: 10.1016/j.neuint.2013.06.014. PubMed DOI

Labarthe A., Fiquet O., Hassouna R., Zizzari P., Lanfumey L., Ramoz N., Grouselle D., Epelbaum J., Tolle V. Ghrelin-Derived Peptides: A Link between Appetite/Reward, GH Axis, and Psychiatric Disorders? Front. Endocrinol. 2014;5:163. doi: 10.3389/fendo.2014.00163. PubMed DOI PMC

Wittekind D.A., Kluge M. Ghrelin in psychiatric disorders—A review. Psychoneuroendocrinology. 2015;52:176–194. doi: 10.1016/j.psyneuen.2014.11.013. PubMed DOI

Stone L.A., Harmatz E.S., Goosens K.A. Ghrelin as a Stress Hormone: Implications for Psychiatric Illness. Biol. Psychiatry. 2020;88:531–540. doi: 10.1016/j.biopsych.2020.05.013. PubMed DOI

Spencer S., Xu L., Clarke M.A., Lemus M., Reichenbach A., Geenen B., Kozicz T., Andrews Z.B. Ghrelin Regulates the Hypothalamic-Pituitary-Adrenal Axis and Restricts Anxiety After Acute Stress. Biol. Psychiatry. 2012;72:457–465. doi: 10.1016/j.biopsych.2012.03.010. PubMed DOI

Spencer S.J., Emmerzaal T.L., Kozicz T., Andrews Z.B. Ghrelin’s Role in the Hypothalamic-Pituitary-Adrenal Axis Stress Response: Implications for Mood Disorders. Biol. Psychiatry. 2015;78:19–27. doi: 10.1016/j.biopsych.2014.10.021. PubMed DOI

Bali A., Jaggi A. An Integrative Review on Role and Mechanisms of Ghrelin in Stress, Anxiety and Depression. Curr. Drug Targets. 2016;17:495–507. doi: 10.2174/1389450116666150518095650. PubMed DOI

Jerlhag E., Egecioglu E., Landgren S., Salomé N., Heilig M., Moechars D., Datta R., Perrissoud D., Dickson S., 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

Koopmann A., Schuster R., Kiefer F. The impact of the appetite-regulating, orexigenic peptide ghrelin on alcohol use disorders: A systematic review of preclinical and clinical data. Biol. Psychol. 2018;131:14–30. doi: 10.1016/j.biopsycho.2016.12.012. PubMed DOI

Farokhnia M., Browning B.D., Leggio L. Prospects for pharmacotherapies to treat alcohol use disorder: An update on recent human studies. Curr. Opin. Psychiatry. 2019;32:255–265. doi: 10.1097/YCO.0000000000000519. PubMed DOI PMC

Farokhnia M., Faulkner M.L., Piacentino D., Lee M.R., Leggio L. Ghrelin: From a gut hormone to a potential therapeutic target for alcohol use disorder. Physiol. Behav. 2019;204:49–57. doi: 10.1016/j.physbeh.2019.02.008. PubMed DOI

Denney W.S., Sonnenberg G.E., Carvajal-Gonzalez S., Tuthill T., Jackson V.M. Pharmacokinetics and pharmacodynamics of PF-05190457: The first oral ghrelin receptor inverse agonist to be profiled in healthy subjects. Br. J. Clin. Pharmacol. 2016;83:326–338. doi: 10.1111/bcp.13127. PubMed DOI PMC

Lee M.R., Farokhnia M., Cobbina E., Saravanakumar A., Li X., Battista J.T., Farinelli L.A., Akhlaghi F., Leggio L. Endocrine effects of the novel ghrelin receptor inverse agonist PF-5190457: Results from a placebo-controlled human laboratory alcohol co-administration study in heavy drinkers. Neuropharmacology. 2020;170:107788. doi: 10.1016/j.neuropharm.2019.107788. PubMed DOI PMC

Cobbina E., Lee M.R., Leggio L., Akhlaghi F. A Population Pharmacokinetic Analysis of PF-5190457, a Novel Ghrelin Receptor Inverse Agonist in Healthy Volunteers and in Heavy Alcohol Drinkers. Clin. Pharmacokinet. 2021;60:471–484. doi: 10.1007/s40262-020-00942-7. PubMed DOI PMC

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

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

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

Vanderschuren L.J., Kalivas P.W. Alterations in dopaminergic and glutamatergic transmission in the induction and ex-pression of behavioral sensitization: A critical review of preclinical studies. Psychopharmacology. 2000;151:99–120. doi: 10.1007/s002130000493. PubMed DOI

Steketee J.D., Kalivas P.W. Drug Wanting: Behavioral Sensitization and Relapse to Drug-Seeking Behavior. Pharmacol. Rev. 2011;63:348–365. doi: 10.1124/pr.109.001933. PubMed DOI PMC

Suchankova P., Engel J.A., Jerlhag E. Sub-chronic Ghrelin Receptor Blockade Attenuates Alcohol- and Amphetamine-Induced Locomotor Stimulation in Mice. Alcohol Alcohol. 2015;51:121–127. doi: 10.1093/alcalc/agv100. 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

Di Chiara G. Drug addiction as dopamine-dependent associative learning disorder. Eur. J. Pharmacol. 1999;375:13–30. doi: 10.1016/S0014-2999(99)00372-6. PubMed DOI

Spanagel R. Animal models of addiction. Dialogues Clin. Neurosci. 2017;19:247–258. PubMed PMC

Mello N.K., Negus S.S. Preclinical evaluation of pharmacotherapies for treatment of cocaine and opioid abuse using drug self-administration procedures. Neuropsychopharmacology. 1996;14:375–424. doi: 10.1016/0893-133X(95)00274-H. PubMed DOI

Pickens C., Airavaara M., Theberge F., Fanous S., Hope B.T., Shaham Y. Neurobiology of the incubation of drug craving. Trends Neurosci. 2011;34:411–420. doi: 10.1016/j.tins.2011.06.001. PubMed DOI PMC

Yin X., Li Y., Xu G., An W., Zhang W. Ghrelin fluctuation, what determines its production? Acta Biochim. Biophys. Sin. 2009;41:188–197. doi: 10.1093/abbs/gmp001. PubMed DOI

Cummings D.E., Purnell J.Q., Frayo R.S., Schmidova K., Wisse B.E., Weigle D.S. A Preprandial Rise in Plasma Ghrelin Levels Suggests a Role in Meal Initiation in Humans. Diabetes. 2001;50:1714–1719. doi: 10.2337/diabetes.50.8.1714. PubMed DOI

Gualillo O., Caminos J.E., Nogueiras R., Seoane L.M., Arvat E., Ghigo E., Casanueva F.F., Diéguez C. Effect of Food Restriction on Ghrelin in Normal-Cycling Female Rats and in Pregnancy. Obes. Res. 2002;10:682–687. doi: 10.1038/oby.2002.92. PubMed DOI

Gallus S., Lugo A., Liu X., Behrakis P., Boffi R., Bosetti C., Carreras G., Chatenoud L., Clancy L., Continente X., et al. Tack SHSPI Who Smokes in Europe? Data From 12 European Countries in the TackSHS Survey (2017–2018) J. Epidemiol. 2021;31:145–151. doi: 10.2188/jea.JE20190344. PubMed DOI PMC

Special Eurobarometer 506: Attitudes of Europeans towards Tobacco and Electronic Cigarettes. European Union Luxembourg; Luxembourg: 2021.

Farsalinos K.E., Polosa R. Safety evaluation and risk assessment of electronic cigarettes as tobacco cigarette substitutes: A systematic review. Ther. Adv. Drug Saf. 2014;5:67–86. doi: 10.1177/2042098614524430. PubMed DOI PMC

Jankowski M., Krzystanek M., Zejda J.E., Majek P., Lubanski J., Lawson J.A., Brozek G. E-Cigarettes are More Addictive than Traditional Cigarettes—A Study in Highly Educated Young People. Int. J. Environ. Res. Public Health. 2019;16:2279. doi: 10.3390/ijerph16132279. PubMed DOI PMC

Barrett S.P., Boileau I., Okker J., Pihl R.O., Dagher A. The hedonic response to cigarette smoking is proportional to dopamine release in the human striatum as measured by positron emission tomography and [11C]raclopride. Synapse. 2004;54:65–71. doi: 10.1002/syn.20066. PubMed DOI

Mansvelder H.D., Keath J.R., McGehee D.S. Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas. Neuron. 2002;33:905–919. doi: 10.1016/S0896-6273(02)00625-6. PubMed DOI

D’souza M.S., Markou A. The “Stop” and “Go” of Nicotine Dependence: Role of GABA and Glutamate. Cold Spring Harb. Perspect. Med. 2013;3:a012146. doi: 10.1101/cshperspect.a012146. PubMed DOI PMC

Aubin H.-J., Luquiens A., Bonnet N., Borgne A. From nicotine dependence to addictology. Rev. Prat. 2012;62:356–359. PubMed

Kroemer N.B., Wuttig F., Bidlingmaier M., Zimmermann U.S., Smolka M.N. Nicotine enhances modulation of food-cue reactivity by leptin and ghrelin in the ventromedial prefrontal cortex. Addict. Biol. 2014;20:832–844. doi: 10.1111/adb.12167. PubMed DOI

Kendzor D.E., Baillie L.E., Adams C.E., Stewart D.W., Copeland A.L. The effect of food deprivation on cigarette smoking in females. Addict. Behav. 2008;33:1353–1359. doi: 10.1016/j.addbeh.2008.06.008. PubMed DOI PMC

Tomoda K., Kubo K., Nishii Y., Yamamoto Y., Yoshikawa M., Kimura H. Changes of ghrelin and leptin levels in plasma by cigarette smoke in rats. J. Toxicol. Sci. 2012;37:131–138. doi: 10.2131/jts.37.131. PubMed DOI

Ypsilantis P., Politou M., Anagnostopoulos C., Tsigalou C., Kambouromiti G., Kortsaris A., Simopoulos C. Effects of cigarette smoke exposure and its cessation on body weight, food intake and circulating leptin, and ghrelin levels in the rat. Nicotine Tob. Res. 2013;15:206–212. doi: 10.1093/ntr/nts113. PubMed DOI

Ali S.S., Hamed E.A., Ayuob N.N., Ali A.S., Suliman M.I. Effects of different routes of nicotine administration on gastric morphology and hormonal secretion in rats. Exp. Physiol. 2015;100:881–895. doi: 10.1113/EP085015. PubMed DOI

Palotai M., Bagosi Z., Jászberényi M., Csabafi K., Dochnal R., Manczinger M., Telegdy G., Szabó G. Ghrelin and Nicotine Stimulate Equally the Dopamine Release in the Rat Amygdala. Neurochem. Res. 2013;38:1989–1995. doi: 10.1007/s11064-013-1105-1. 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

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

Wellman P.J., Clifford P.S., Rodriguez J., Hughes S., Eitan S., Brunel L., Fehrentz J.-A., Martinez J. Pharmacologic antagonism of ghrelin receptors attenuates development of nicotine induced locomotor sensitization in rats. Regul. Pept. 2011;172:77–80. doi: 10.1016/j.regpep.2011.08.014. PubMed DOI PMC

Landgren S., Jerlhag E., Hallman J., Oreland L., Lissner L., Strandhagen E., Thelle D.S., Zetterberg H., Blennow K., Engel J.A. Genetic Variation of the Ghrelin Signaling System in Females with Severe Alcohol Dependence. Alcohol. Clin. Exp. Res. 2010;34:1519–1524. doi: 10.1111/j.1530-0277.2010.01236.x. PubMed DOI

Suchankova P., Nilsson S., Von Der Pahlen B., Santtila P., Sandnabba K., Johansson A., Jern P., Engel J.A., Jerlhag E. Genetic variation of the growth hormone secretagogue receptor gene is associated with alcohol use disorders identification test scores and smoking. Addict. Biol. 2015;21:481–488. doi: 10.1111/adb.12277. PubMed DOI PMC

Bouros D., Tzouvelekis A., Anevlavis S., Doris M., Tryfon S., Froudarakis M., Zournatzi V., Kukuvitis A. Smoking Acutely Increases Plasma Ghrelin Concentrations. Clin. Chem. 2006;52:777–778. doi: 10.1373/clinchem.2005.065243. PubMed DOI

Kokkinos A., Tentolouris N., Kyriakaki E., Argyrakopoulou G., Doupis J., Psallas M., Kyriaki D., Katsilambros N. Differentiation in the short- and long-term effects of smoking on plasma total ghrelin concentrations between male nonsmokers and habitual smokers. Metabolism. 2007;56:523–527. doi: 10.1016/j.metabol.2006.11.012. PubMed DOI

Kaabi Y.A., Khalifa M.A. Acute One-Cigarette Smoking Decreases Ghrelin Hormone in Saliva: A Pilot Study. Int. J. Endocrinol. 2014;2014:1–4. doi: 10.1155/2014/575671. PubMed DOI PMC

Pilhatsch M., Scheuing H., Kroemer N., Kobiella A., Bidlingmaier M., Farger G., Smolka M.N., Zimmermann U.S. Nicotine administration in healthy non-smokers reduces appetite but does not alter plasma ghrelin. Hum. Psychopharmacol. Clin. Exp. 2014;29:384–387. doi: 10.1002/hup.2405. PubMed DOI

Bouhours-Nouet N., de Casson F.B., Rouleau S., Douay O., Mathieu E., Bouderlique C., Gillard P., Limal J.M., Descamps P., Coutant R. Maternal and Cord Blood Ghrelin in the Pregnancies of Smoking Mothers: Possible Markers of Nutrient Availability for the Fetus. Horm. Res. Paediatr. 2006;66:6–12. doi: 10.1159/000092807. PubMed DOI

Pöykkö S.M., Kellokoski E., Ukkola O., Kauma H., Päivänsalo M., Kesäniemi Y.A., Hörkkö S. Plasma ghrelin concentrations are positively associated with carotid artery atherosclerosis in males. J. Intern. Med. 2006;260:43–52. doi: 10.1111/j.1365-2796.2006.01661.x. PubMed DOI

Koopmann A., Bez J., LeMenager T., Hermann D., Dinter C., Reinhard I., Hoffmann H., Wiedemann K., Winterer G., Kiefer F. Effects of Cigarette Smoking on Plasma Concentration of the Appetite-Regulating Peptide Ghrelin. Ann. Nutr. Metab. 2015;66:155–161. doi: 10.1159/000381834. PubMed DOI

Fagerberg B., Hultén L.M., Hulthe J. Plasma ghrelin, body fat, insulin resistance, and smoking in clinically healthy men: The atherosclerosis and insulin resistance study. Metabolism. 2003;52:1460–1463. doi: 10.1016/S0026-0495(03)00274-9. PubMed DOI

Langenberg C., Bergstrom J., Laughlin G.A., Barrett-Connor E. Ghrelin and the Metabolic Syndrome in Older Adults. J. Clin. Endocrinol. Metab. 2005;90:6448–6453. doi: 10.1210/jc.2005-1358. PubMed DOI

Wittekind D.A., Kratzsch J., Mergl R., Enzenbach C., Witte V., Villringer A., Kluge M. Higher fasting ghrelin serum levels in active smokers than in former and never-smokers. World J. Biol. Psychiatry. 2020;21:748–756. doi: 10.1080/15622975.2019.1671610. PubMed DOI

Al’absi M., Lemieux A., Nakajima M. Peptide YY and ghrelin predict craving and risk for relapse in abstinent smokers. Psychoneuroendocrinology. 2014;49:253–259. doi: 10.1016/j.psyneuen.2014.07.018. PubMed DOI PMC

Lemieux A.M., Al’absi M. Changes in circulating peptide YY and ghrelin are associated with early smoking relapse. Biol. Psychol. 2018;131:43–48. doi: 10.1016/j.biopsycho.2017.03.007. PubMed DOI PMC

Lee H., Joe K.-H., Kim W., Park J., Lee D.-H., Sung K.-W., Kim D.-J. Increased leptin and decreased ghrelin level after smoking cessation. Neurosci. Lett. 2006;409:47–51. doi: 10.1016/j.neulet.2006.09.013. PubMed DOI

Al’absi M., DeAngelis B., Nakajima M., Hatsukami D., Allen S. Early life adversity and appetite hormones: The effects of smoking status, nicotine withdrawal, and relapse on ghrelin and peptide YY during smoking cessation. Addict. Behav. 2021;118:106866. doi: 10.1016/j.addbeh.2021.106866. PubMed DOI PMC

Yousufzai M., Harmatz E.S., Shah M., Malik M.O., Goosens K.A. Ghrelin is a persistent biomarker for chronic stress expo-sure in adolescent rats and humans. Transl. Psychiatry. 2018;8:74. doi: 10.1038/s41398-018-0135-5. PubMed DOI PMC

European Drug Report 2020: Trends and Developments. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), Publications Office of the European Union Luxembourg; Luxembourg: 2020.

Sora I., Hall F., Andrews A.M., Itokawa M., Li X.-F., Wei H.-B., Wichems C., Lesch K.-P., Murphy D.L., Uhl G.R. Molecular mechanisms of cocaine reward: Combined dopamine and serotonin transporter knockouts eliminate cocaine place preference. Proc. Natl. Acad. Sci. USA. 2001;98:5300–5305. doi: 10.1073/pnas.091039298. PubMed DOI PMC

Robertson S.D., Matthies H.J.G., Galli A. A Closer Look at Amphetamine-Induced Reverse Transport and Trafficking of the Dopamine and Norepinephrine Transporters. Mol. Neurobiol. 2009;39:73–80. doi: 10.1007/s12035-009-8053-4. PubMed DOI PMC

Partilla J.S., Dempsey A.G., Nagpal A.S., Blough B.E., Baumann M., Rothman R.B. Interaction of Amphetamines and Related Compounds at the Vesicular Monoamine Transporter. J. Pharmacol. Exp. Ther. 2006;319:237–246. doi: 10.1124/jpet.106.103622. PubMed DOI

Harris S.C., Ivy A.C., Searle L.M. The mechanism of amphetamine-induced loss of weight; a consideration of the theory of hunger and appetite. J. Am. Med. Assoc. 1947;134:1468–1475. doi: 10.1001/jama.1947.02880340022005. PubMed DOI

Halford J.C.G., Blundell J.E. Pharmacology of appetite suppression. Prog. Drug Res. 2000;54:25–58. doi: 10.1007/978-3-0348-8391-7_2. PubMed DOI

Carroll M.E. The role of food deprivation in the maintenance and reinstatement of cocaine-seeking behavior in rats. Drug Alcohol Depend. 1985;16:95–109. doi: 10.1016/0376-8716(85)90109-7. PubMed DOI

Carroll E.M., Stotz D.C. Oral d-amphetamine and ketamine self-administration by rhesus monkeys: Effects of food deprivation. J. Pharmacol. Exp. Ther. 1983;227:28–34. PubMed

Crowley W., Ramoz G., Keefe K., Torto R., Kalra S., Hanson G. Differential effects of methamphetamine on expression of neuropeptide Y mRNA in hypothalamus and on serum leptin and ghrelin concentrations in ad libitum-fed and schedule-fed rats. Neuroscience. 2005;132:167–173. doi: 10.1016/j.neuroscience.2004.11.037. PubMed DOI

Kobeissy F.H., Jeung J.A., Warren M.W., Geier J.E., Gold M.S. Changes in leptin, ghrelin, growth hormone and neuropeptide-Y after an acute model of MDMA and methamphetamine exposure in rats. Addict. Biol. 2007;13:15–25. doi: 10.1111/j.1369-1600.2007.00083.x. PubMed DOI

Tessari M., Catalano A., Pellitteri M., Di Francesco C., Marini F., Gerrard P.A., Heidbreder C.A., Melotto S. Correlation between serum ghrelin levels and cocaine-seeking behaviour triggered by cocaine-associated conditioned stimuli in rats. Addict. Biol. 2007;12:22–29. doi: 10.1111/j.1369-1600.2007.00052.x. PubMed DOI

You Z.-B., Wang B., Gardner E.L., Wise R.A. Cocaine and cocaine expectancy increase growth hormone, ghrelin, GLP-1, IGF-1, adiponectin, and corticosterone while decreasing leptin, insulin, GIP, and prolactin. Pharmacol. Biochem. Behav. 2019;176:53–56. doi: 10.1016/j.pbb.2018.11.001. PubMed DOI

You Z.B., Galaj E., Alen F., Wang B., Bi G.H., Moore A.R., Buck T., Crissman M., Pari S., Xi Z.X., et al. Involvement of the ghrelin system in the maintenance and reinstatement of cocaine-motivated behaviors: A role of adrenergic action at peripheral beta1 receptors. Neuropsychopharmacology. 2021 doi: 10.1038/s41386-021-01249-2. PubMed DOI PMC

Hosoda H., Kangawa K. The autonomic nervous system regulates gastric ghrelin secretion in rats. Regul. Pept. 2008;146:12–18. doi: 10.1016/j.regpep.2007.07.005. 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

Wellman P.J., Hollas C.N., Elliott A.E. Systemic ghrelin sensitizes cocaine-induced hyperlocomotion in rats. Regul. Pept. 2008;146:33–37. doi: 10.1016/j.regpep.2007.07.007. PubMed DOI PMC

Wellman P.J., Clifford P.S., Rodriguez J.A. Ghrelin and ghrelin receptor modulation of psychostimulant action. Front. Neurosci. 2013;7:171. doi: 10.3389/fnins.2013.00171. PubMed DOI PMC

Wren A.M., Small C.J., Fribbens C.V., Neary N.M., Ward H.L., Seal L.J., Ghatei M.A., Bloom S.R. The hypothalamic mecha-nisms of the hypophysiotropic action of ghrelin. Neuroendocrinology. 2002;76:316–324. doi: 10.1159/000066629. PubMed DOI

Li Y., Acerbo M.J., Robinson T.E. The induction of behavioural sensitization is associated with cocaine-induced structural plasticity in the core (but not shell) of the nucleus accumbens. Eur. J. Neurosci. 2004;20:1647–1654. doi: 10.1111/j.1460-9568.2004.03612.x. PubMed DOI

Sellings L.H.L., Clarke P.B.S. Segregation of Amphetamine Reward and Locomotor Stimulation between Nucleus Accumbens Medial Shell and Core. J. Neurosci. 2003;23:6295–6303. doi: 10.1523/JNEUROSCI.23-15-06295.2003. PubMed DOI PMC

Jang J.K., Kim W.Y., Cho B.R., Lee J.W., Kim J.-H. Microinjection of ghrelin in the nucleus accumbens core enhances locomotor activity induced by cocaine. Behav. Brain Res. 2013;248:7–11. doi: 10.1016/j.bbr.2013.03.049. PubMed DOI

Jang J.K., Kim W.Y., Cho B.R., Lee J.W., Kim J.-H. Locomotor sensitization is expressed by ghrelin and D1 dopamine receptor agonist in the nucleus accumbens core in amphetamine pre-exposed rat. Addict. Biol. 2017;23:849–856. doi: 10.1111/adb.12533. PubMed DOI

Davis K.W., Wellman P.J., Clifford P.S. Augmented cocaine conditioned place preference in rats pretreated with systemic ghrelin. Regul. Pept. 2007;140:148–152. doi: 10.1016/j.regpep.2006.12.003. PubMed DOI PMC

Schuette L.M., Gray C.C., Currie P.J. Microinjection of Ghrelin into the Ventral Tegmental Area Potentiates Cocaine-Induced Conditioned Place Preference. J. Behav. Brain Sci. 2013;3:576–580. doi: 10.4236/jbbs.2013.38060. PubMed DOI PMC

Dunn D.P., Bastacky J.M., Gray C.C., Abtahi S., Currie P.J. Role of mesolimbic ghrelin in the acquisition of cocaine reward. Neurosci. Lett. 2019;709:134367. doi: 10.1016/j.neulet.2019.134367. 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

Currie P.J., Khelemsky R., Rigsbee E.M., Dono L.M., Coiro C.D., Chapman C.D., Hinchcliff K. Ghrelin is an orexigenic peptide and elicits anxiety-like behaviors following administration into discrete regions of the hypothalamus. Behav. Brain Res. 2012;226:96–105. doi: 10.1016/j.bbr.2011.08.037. PubMed DOI PMC

Carlini V.P., Varas M.M., Cragnolini A.B., Schiöth H.B., Scimonelli T.N., de Barioglio S.R. Differential role of the hippocampus, amygdala, and dorsal raphe nucleus in regulating feeding, memory, and anxiety-like behavioral responses to ghrelin. Biochem. Biophys. Res. Commun. 2004;313:635–641. doi: 10.1016/j.bbrc.2003.11.150. 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

Clifford P.S., Rodriguez J., Schul D., Hughes S., Kniffin T., Hart N., Eitan S., Brunel L., Fehrentz J.-A., Martinez J., et al. Attenuation of cocaine-induced locomotor sensitization in rats sustaining genetic or pharmacologic antagonism of ghrelin receptors. Addict. Biol. 2012;17:956–963. doi: 10.1111/j.1369-1600.2011.00339.x. PubMed DOI PMC

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

Edvardsson C.E., Vestlund J., Jerlhag E. A ghrelin receptor antagonist reduces the ability of ghrelin, alcohol or amphetamine to induce a dopamine release in the ventral tegmental area and in nucleus accumbens shell in rats. Eur. J. Pharmacol. 2021;899:174039. doi: 10.1016/j.ejphar.2021.174039. PubMed DOI

Yoshida M., Yokoo H., Mizoguchi K., Kawahara H., Tsuda A., Nishikawa T., Tanaka M. Eating and drinking cause in-creased dopamine release in the nucleus accumbens and ventral tegmental area in the rat: Measurement by in vivo microdi-alysis. Neurosci. Lett. 1992;139:73–76. doi: 10.1016/0304-3940(92)90861-Z. PubMed DOI

Bradberry C.W., Roth R.H. Cocaine increases extracellular dopamine in rat nucleus accumbens and ventral tegmental area as shown by in vivo microdialysis. Neurosci. Lett. 1989;103:97–102. doi: 10.1016/0304-3940(89)90492-8. PubMed DOI

Kalivas P., Bourdelais A., Abhold R., Abbott L. Somatodendritic release of endogenous dopamine: In vivo dialysis in the A10 dopamine region. Neurosci. Lett. 1989;100:215–220. doi: 10.1016/0304-3940(89)90687-3. PubMed DOI

Yoon S.-J., Pae C.-U., Lee H., Choi B., Kim T.-S., Lyoo I.K., Kwon D.-H., Kim D.-J. Ghrelin precursor gene polymorphism and methamphetamine dependence in the Korean population. Neurosci. Res. 2005;53:391–395. doi: 10.1016/j.neures.2005.08.013. PubMed DOI

Suchankova P., Jerlhag E., Jayaram-Lindstrom N., Nilsson S., Torén K., Rosengren A., Engel J.A., Franck J. Genetic Variation of the Ghrelin Signalling System in Individuals with Amphetamine Dependence. PLoS ONE. 2013;8:e61242. doi: 10.1371/journal.pone.0061242. PubMed DOI PMC

Bouhlal S., Ellefsen K.N., Sheskier M.B., Singley E., Pirard S., Gorelick D.A., Huestis M.A., Leggio L. Acute effects of intravenous cocaine administration on serum concentrations of ghrelin, amylin, glucagon-like peptide-1, insulin, leptin and peptide YY and relationships with cardiorespiratory and subjective responses. Drug Alcohol Depend. 2017;180:68–75. doi: 10.1016/j.drugalcdep.2017.07.033. PubMed DOI PMC

Sahin S., Yuce M., Alacam H., Karabekiroglu K., Say G.N., Salıs O. Effect of methylphenidate treatment on appetite and levels of leptin, ghrelin, adiponectin, and brain-derived neurotrophic factor in children and adolescents with attention deficit and hyperactivity disorder. Int. J. Psychiatry Clin. Pract. 2014;18:280–287. doi: 10.3109/13651501.2014.940054. PubMed DOI

Abizaid A., Mineur Y., Roth R., Elsworth J., Sleeman M., Picciotto M., Horvath T. Reduced locomotor responses to cocaine in ghrelin-deficient mice. Neuroscience. 2011;192:500–506. doi: 10.1016/j.neuroscience.2011.06.001. PubMed DOI

Solimini R., Pichini S., Pacifici R., Busardò F.P., Giorgetti R. Pharmacotoxicology of Non-fentanyl Derived New Synthetic Opioids. Front. Pharmacol. 2018;9:654. doi: 10.3389/fphar.2018.00654. PubMed DOI PMC

De Vries T.J., Shippenberg T.S. Neural systems underlying opiate addiction. J. Neurosci. 2002;22:3321–3325. doi: 10.1523/JNEUROSCI.22-09-03321.2002. PubMed DOI PMC

Fields H.L., Margolis E.B. Understanding opioid reward. Trends Neurosci. 2015;38:217–225. doi: 10.1016/j.tins.2015.01.002. PubMed DOI PMC

Klitenick M., Deutch A., Churchill L., Kalivas P. Topography and functional role of dopaminergic projections from the ventral mesencephalic tegmentum to the ventral pallidum. Neuroscience. 1992;50:371–386. doi: 10.1016/0306-4522(92)90430-A. PubMed DOI

Xi Z.X., Stein E.A. Increased mesolimbic GABA concentration blocks heroin self-administration in the rat. J. Pharmacol. Exp. Ther. 2000;294:613–619. PubMed

Fattore L., Deiana S., Spano S.M., Cossu G., Fadda P., Scherma M., Fratta W. Endocannabinoid system and opioid addiction: Behavioural aspects. Pharmacol. Biochem. Behav. 2005;81:343–359. doi: 10.1016/j.pbb.2005.01.031. 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

Navarro M., Carrera M.R.A., Fratta W., Valverde O., Cossu G., Fattore L., Chowen J.A., Gomez R., Del Arco I., Villanúa M.A., et al. Functional Interaction between Opioid and Cannabinoid Receptors in Drug Self-Administration. J. Neurosci. 2001;21:5344–5350. doi: 10.1523/JNEUROSCI.21-14-05344.2001. PubMed DOI PMC

Caille S., Alvarez-Jaimes L., Polis I., Stouffer D.G., Parsons L.H. Specific alterations of extracellular endocannabinoid levels in the nucleus accumbens by ethanol, heroin, and cocaine self-administration. J. Neurosci. 2007;27:3695–3702. doi: 10.1523/JNEUROSCI.4403-06.2007. PubMed DOI PMC

Grigson P.S. Like drugs for chocolate: Separate rewards modulated by common mechanisms? Physiol. Behav. 2002;76:389–395. doi: 10.1016/S0031-9384(02)00758-8. PubMed DOI

Skibicka K.P., Dickson S.L. Ghrelin and food reward: The story of potential underlying substrates. Peptides. 2011;32:2265–2273. doi: 10.1016/j.peptides.2011.05.016. 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. 2012;17:95–107. doi: 10.1111/j.1369-1600.2010.00294.x. PubMed DOI PMC

Kawahara Y., Kaneko F., Yamada M., Kishikawa Y., Kawahara H., Nishi A. Food reward-sensitive interaction of ghrelin and opioid receptor pathways in mesolimbic dopamine system. Neuropharmacology. 2013;67:395–402. doi: 10.1016/j.neuropharm.2012.11.022. 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

Shalev U., Highfield D., Yap J., Shaham Y. Stress and relapse to drug seeking in rats: Studies on the generality of the effect. Psychopharmacology. 2000;150:337–346. doi: 10.1007/s002130000441. PubMed DOI

D’cunha T.M., Sedki F., Macri J., Casola C., Shalev U. The effects of chronic food restriction on cue-induced heroin seeking in abstinent male rats. Psychopharmacology. 2013;225:241–250. doi: 10.1007/s00213-012-2810-1. 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. 2012;17:613–622. doi: 10.1111/j.1369-1600.2011.00396.x. PubMed DOI

D’cunha T.M., Chisholm A., Hryhorczuk C., Fulton S., Shalev U. A role for leptin and ghrelin in the augmentation of heroin seeking induced by chronic food restriction. Psychopharmacology. 2019;237:787–800. doi: 10.1007/s00213-019-05415-9. 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., 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

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

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

Zhao J., Du X., Chen M., Zhu S. Growth Hormone Secretagogue Receptor 1A Antagonist JMV2959 Effectively Prevents Morphine Memory Reconsolidation and Relapse. Front. Pharmacol. 2021;12:718615. doi: 10.3389/fphar.2021.718615. PubMed DOI PMC

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

Kara H., Erdogan A., Akbas H., Kuloglu M.M. The Relationship of Serum Leptin and Ghrelin Levels with Craving and Withdrawal in Opioid Use Disorder. Alpha Psychiatry. 2021;22:200–205. doi: 10.5152/alphapsychiatry.2021.2056. 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

Charalambous C., Havlickova T., Lapka M., Puskina N., Šlamberová R., Kuchar M., Sustkova-Fiserova M. Cannabinoid-Induced Conditioned Place Preference, Intravenous Self-Administration, and Behavioral Stimulation Influenced by Ghrelin Receptor Antagonism in Rats. Int. J. Mol. Sci. 2021;22:2397. doi: 10.3390/ijms22052397. 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

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

Farokhnia M., Grodin E.N., Lee M.R., Oot E.N., Blackburn A.N., Stangl B.L., Schwandt M.L., Farinelli L.A., Momenan R., Ramchandani V.A. Exogenous Ghrelin Administration Increases Alcohol Self-Administration and Modulates Brain Functional Activity in Heavy-Drinking Alcohol-Dependent Individuals. Mol. Psychiatry. 2018;23:2029–2038. doi: 10.1038/mp.2017.226. PubMed DOI

Farokhnia M., McDiarmid G.R., Newmeyer M., 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;10:71. doi: 10.1038/s41398-020-0756-3. PubMed DOI PMC

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

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., Morasco B.J., Nugent S., Ayers C., O’neil M.E., Freeman M., Paynter R., Kansagara D. Pharmacotherapy for the Treatment of Cannabis Use Disorder: A Systematic Review. Ann. Intern. Med. 2019;172:398–412. doi: 10.7326/M19-1105. PubMed DOI

Manzanares J., Cabañero D., Puente N., García-Gutiérrez 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

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

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

Alen F., Crespo I., Ramírez-López M.T., Jagerovic N., Goya P., De Fonseca F.R., De Heras R.G., Orio L. Ghrelin-Induced Orexigenic Effect in Rats Depends on the Metabolic Status and Is Counteracted by Peripheral CB1 Receptor Antagonism. PLoS ONE. 2013;8:e60918. doi: 10.1371/journal.pone.0060918. 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

Tong J., Dave N., Mugundu G.M., Davis H.W., Gaylinn B.D., Thorner M.O., Tschop M.H., D’Alessio D., Desai P.B. The phar-macokinetics of acyl, des-acyl, and total ghrelin in healthy human subjects. Eur. J. Endocrinol. 2013;168:821–828. doi: 10.1530/EJE-13-0072. PubMed DOI PMC

St-Onge V., Watts A., Abizaid A. Ghrelin enhances cue-induced bar pressing for high fat food. Horm. Behav. 2016;78:141–149. doi: 10.1016/j.yhbeh.2015.11.005. PubMed DOI

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

Cruz C.R., Smith R.G. The growth hormone secretagogue receptor. Vitam. Horm. 2008;77:47–88. PubMed

Van Amsterdam J., Talhout R., Vleeming W., Opperhuizen A. Contribution of monoamine oxidase (MAO) inhibition to tobacco and alcohol addiction. Life Sci. 2006;79:1969–1973. doi: 10.1016/j.lfs.2006.06.010. PubMed DOI

Sadakierska-Chudy A., Frankowska M., Filip M. Mitoepigenetics and drug addiction. Pharmacol. Ther. 2014;144:226–233. doi: 10.1016/j.pharmthera.2014.06.002. PubMed DOI

Schnaitman C., Erwin V.G., Greenawalt J.W. The submitochondrial localization of monoamine oxidase. An enzymatic marker for the outer membrane of rat liver mitochondria. J. Cell Biol. 1967;32:719–735. doi: 10.1083/jcb.32.3.719. PubMed DOI PMC

Cohen G., Kesler N. Monoamine Oxidase and Mitochondrial Respiration. J. Neurochem. 2002;73:2310–2315. doi: 10.1046/j.1471-4159.1999.0732310.x. PubMed DOI

Angelova P.R., Abramov A.Y. Role of mitochondrial ROS in the brain: From physiology to neurodegeneration. FEBS Lett. 2018;592:692–702. doi: 10.1002/1873-3468.12964. PubMed DOI

Xu H., Li Y., Liu R., Wu L., Zhang C., Ding N., Ma A., Zhang J., Xie X. Protective effects of ghrelin on brain mitochondria after cardiac arrest and resuscitation. Neuropeptides. 2019;76:101936. doi: 10.1016/j.npep.2019.05.007. PubMed DOI

Najít záznam

Citační ukazatele

Nahrávání dat ...

Možnosti archivace

Nahrávání dat ...