Naltrexone Reverses Ethanol Preference and Protein Kinase C Activation in

Overview

Journal Front Physiol

Date 2018 Mar 30

PMID 29593550

Citations 4

Authors

Rajeswari Koyyada

Nilesh Latchooman

Julius Jonaitis

Samir S Ayoub

Olivia Corcoran

Stefano O Casalotti

Affiliations

Soon will be listed here.

Abstract

Alcohol use disorder (AUD) is a major health, social and economic problem for which there are few effective treatments. The opiate antagonist naltrexone is currently prescribed clinically with mixed success. We have used naltrexone in an established behavioral assay (CAFE) in that measures the flies' preference for ethanol-containing food. We have confirmed that exposed to ethanol develop a preference toward this drug and we demonstrate that naltrexone, in a dose dependant manner, reverses the ethanol-induced ethanol preference. This effect is not permanent, as preference for alcohol returns after discontinuing naltrexone. Additionally, naltrexone reduced the alcohol-induced increase in protein kinase C activity. These findings are of interest because they confirm that is a useful model for studying human responses to addictive drugs. Additionally because of the lack of a closely conserved opiate system in insects, our results could either indicate that a functionally related system does exist in insects or that in insects, and potentially also in mammals, naltrexone binds to alternative sites. Identifying such sites could lead to improved treatment strategies for AUD.

Citing Articles

Voluntary intake of psychoactive substances is regulated by the dopamine receptor Dop1R1 in Drosophila.

Kanno M, Hiramatsu S, Kondo S, Tanimoto H, Ichinose T Sci Rep. 2021; 11(1):3432.

PMID: 33564023 PMC: 7873259. DOI: 10.1038/s41598-021-82813-0.

Flying Together: as a Tool to Understand the Genetics of Human Alcoholism.

Lathen D, Merrill C, Rothenfluh A Int J Mol Sci. 2020; 21(18).

PMID: 32932795 PMC: 7555299. DOI: 10.3390/ijms21186649.

G-protein αq gene expression plays a role in alcohol tolerance in .

Aleyakpo B, Umukoro O, Kavlie R, Ranson D, Thompsett A, Corcoran O Brain Neurosci Adv. 2020; 3:2398212819883081.

PMID: 32166184 PMC: 7058197. DOI: 10.1177/2398212819883081.

Studying alcohol use disorder using Drosophila melanogaster in the era of 'Big Data'.

Engel G, Taber K, Vinton E, Crocker A Behav Brain Funct. 2019; 15(1):7.

PMID: 30992041 PMC: 6469124. DOI: 10.1186/s12993-019-0159-x.

References

Lenz C, Williamson M, Grimmelikhuijzen C . Molecular cloning and genomic organization of a second probable allatostatin receptor from Drosophila melanogaster. Biochem Biophys Res Commun. 2000; 273(2):571-7. DOI: 10.1006/bbrc.2000.2964. View

Kreienkamp H, Larusson H, Witte I, Roeder T, Birgul N, Honck H . Functional annotation of two orphan G-protein-coupled receptors, Drostar1 and -2, from Drosophila melanogaster and their ligands by reverse pharmacology. J Biol Chem. 2002; 277(42):39937-43. DOI: 10.1074/jbc.M206931200. View

Oh D, Jung K, Yang B, Lee J, Choi I, Chai Y . Naltrexone influences protein kinase Ce and integrin alpha7 activity in SH-SY5Y neuroblastoma cells. Exp Mol Med. 2006; 38(1):100-6. DOI: 10.1038/emm.2006.12. View

Kumar S, Lane B, Morrow A . Differential effects of systemic ethanol administration on protein kinase cepsilon, gamma, and beta isoform expression, membrane translocation, and target phosphorylation: reversal by chronic ethanol exposure. J Pharmacol Exp Ther. 2006; 319(3):1366-75. DOI: 10.1124/jpet.106.110890. View

Ja W, Carvalho G, Mak E, de la Rosa N, Fang A, Liong J . Prandiology of Drosophila and the CAFE assay. Proc Natl Acad Sci U S A. 2007; 104(20):8253-6. PMC: 1899109. DOI: 10.1073/pnas.0702726104. View

Wilkie M, Besheer J, Kelley S, Kumar S, OBuckley T, Morrow A . Acute ethanol administration rapidly increases phosphorylation of conventional protein kinase C in specific mammalian brain regions in vivo. Alcohol Clin Exp Res. 2007; 31(7):1259-67. PMC: 2861774. DOI: 10.1111/j.1530-0277.2007.00423.x. View

Yang C, Belawat P, Hafen E, Jan L, Jan Y . Drosophila egg-laying site selection as a system to study simple decision-making processes. Science. 2008; 319(5870):1679-83. PMC: 2581776. DOI: 10.1126/science.1151842. View

Gilpin N, Koob G . Neurobiology of alcohol dependence: focus on motivational mechanisms. Alcohol Res Health. 2009; 31(3):185-95. PMC: 2770186. View

Flatscher-Bader T, Wilce P . The effect of alcohol and nicotine abuse on gene expression in the brain. Nutr Res Rev. 2009; 22(2):148-62. DOI: 10.1017/S0954422409990114. View

10.

Chen J, Zhang Y, Shen P . Protein kinase C deficiency-induced alcohol insensitivity and underlying cellular targets in Drosophila. Neuroscience. 2009; 166(1):34-9. PMC: 2849016. DOI: 10.1016/j.neuroscience.2009.12.009. View

11.

Yu J, Halder D, Baek M, Das N, Choi M, Oh D . Changes in the expression of transthyretin and protein kinase Cγ genes in the prefrontal cortex in response to naltrexone. Neurosci Lett. 2010; 488(3):288-93. DOI: 10.1016/j.neulet.2010.11.049. View

12.

Huber R, Panksepp J, Nathaniel T, Alcaro A, Panksepp J . Drug-sensitive reward in crayfish: an invertebrate model system for the study of SEEKING, reward, addiction, and withdrawal. Neurosci Biobehav Rev. 2010; 35(9):1847-53. PMC: 4803470. DOI: 10.1016/j.neubiorev.2010.12.008. View

13.

Arias A, Sewell R . Pharmacogenetically driven treatments for alcoholism: are we there yet?. CNS Drugs. 2012; 26(6):461-76. PMC: 5759971. DOI: 10.2165/11633180-000000000-00000. View

14.

Devineni A, Heberlein U . The evolution of Drosophila melanogaster as a model for alcohol research. Annu Rev Neurosci. 2013; 36:121-38. DOI: 10.1146/annurev-neuro-062012-170256. View

15.

Nestler E . Epigenetic mechanisms of drug addiction. Neuropharmacology. 2013; 76 Pt B:259-68. PMC: 3766384. DOI: 10.1016/j.neuropharm.2013.04.004. View

16.

Peru Y Colon De Portugal R, Ojelade S, Penninti P, Dove R, Nye M, Acevedo S . Long-lasting, experience-dependent alcohol preference in Drosophila. Addict Biol. 2013; 19(3):392-401. PMC: 3991769. DOI: 10.1111/adb.12105. View

17.

Azanchi R, Kaun K, Heberlein U . Competing dopamine neurons drive oviposition choice for ethanol in Drosophila. Proc Natl Acad Sci U S A. 2013; 110(52):21153-8. PMC: 3876210. DOI: 10.1073/pnas.1320208110. View

18.

Liang J, Olsen R . Alcohol use disorders and current pharmacological therapies: the role of GABA(A) receptors. Acta Pharmacol Sin. 2014; 35(8):981-93. PMC: 4125717. DOI: 10.1038/aps.2014.50. View

19.

Kufahl P, Watterson L, Olive M . The development of acamprosate as a treatment against alcohol relapse. Expert Opin Drug Discov. 2014; 9(11):1355-69. PMC: 4578640. DOI: 10.1517/17460441.2014.960840. View

20.

Crabbe J . Use of animal models of alcohol-related behavior. Handb Clin Neurol. 2014; 125:71-86. DOI: 10.1016/B978-0-444-62619-6.00005-7. View