1. Koob GF, Volkow ND. Neurobiology of addiction: a
neurocircuitry analysis. Lancet Psychiatry. 2016;3(8):760-73.
doi: 10.1016/s2215-0366(16)00104-8.
2. Koob GF, Volkow ND. Neurocircuitry of addiction.
Neuropsychopharmacology. 2010;35(1):217-38. doi:
10.1038/npp.2009.110.
3. Belzeaux R, Lalanne L, Kieffer BL, Lutz PE. Focusing on
the opioid system for addiction biomarker discovery.
Trends Mol Med. 2018;24(2):206-20. doi: 10.1016/j.
molmed.2017.12.004.
4. Wise RA, Jordan CJ. Dopamine, behavior, and addiction.
J Biomed Sci. 2021;28(1):83. doi: 10.1186/s12929-021-
00779-7.
5. Tzschentke TM, Schmidt WJ. Glutamatergic mechanisms in
addiction. Mol Psychiatry. 2003;8(4):373-82. doi: 10.1038/
sj.mp.4001269.
6. Falcão-Pires I, Leite-Moreira AF. Apelin: a novel neurohumoral
modulator of the cardiovascular system. Pathophysiologic
importance and potential use as a therapeutic target. Rev Port
Cardiol. 2005;24(10):1263-76.
7. Gurzu B, Petrescu BC, Costuleanu M, Petrescu G. Interactions
between apelin and angiotensin II on rat portal vein. J Renin
Angiotensin Aldosterone Syst. 2006;7(4):212-6. doi: 10.3317/
jraas.2006.040.
8. Tatemoto K, Hosoya M, Habata Y, Fujii R, Kakegawa T,
Zou MX, et al. Isolation and characterization of a novel
endogenous peptide ligand for the human APJ receptor.
Biochem Biophys Res Commun. 1998;251(2):471-6. doi:
10.1006/bbrc.1998.9489.
9. Charles CJ. Putative role for apelin in pressure/volume
homeostasis and cardiovascular disease. Cardiovasc
Hematol Agents Med Chem. 2007;5(1):1-10. doi:
10.2174/187152507779315804.
10. Ladeiras-Lopes R, Ferreira-Martins J, Leite-Moreira AF. The
apelinergic system: the role played in human physiology
and pathology and potential therapeutic applications.
Arq Bras Cardiol. 2008;90(5):343-9. doi: 10.1590/s0066-
782x2008000500012.
11. Zhen EY, Higgs RE, Gutierrez JA. Pyroglutamyl apelin-13
identified as the major apelin isoform in human plasma. Anal
Biochem. 2013;442(1):1-9. doi: 10.1016/j.ab.2013.07.006.
12. Kleinz MJ, Davenport AP. Emerging roles of apelin in biology
and medicine. Pharmacol Ther. 2005;107(2):198-211. doi:
10.1016/j.pharmthera.2005.04.001.
13. Wang G, Anini Y, Wei W, Qi X, O’Carroll AM, Mochizuki
T, et al. Apelin, a new enteric peptide: localization in the
gastrointestinal tract, ontogeny, and stimulation of gastric cell
proliferation and of cholecystokinin secretion. Endocrinology.
2004;145(3):1342-8. doi: 10.1210/en.2003-1116.
14. Folino A, Montarolo PG, Samaja M, Rastaldo R. Effects
of apelin on the cardiovascular system. Heart Fail Rev.
2015;20(4):505-18. doi: 10.1007/s10741-015-9475-x.
15. Masri B, van den Berghe L, Sorli C, Knibiehler B, Audigier
Y. [Apelin signalisation and vascular physiopathology]. J
Soc Biol. 2009;203(2):171-9. doi: 10.1051/jbio/2009021.
[French].
16. Nishida M, Hamaoka K. The apelin-APJ system: its role in
renal physiology and potential therapeutic applications for
renal disease. OA Nephrol. 2013;1(7):1-5.
17. Hu G, Wang Z, Zhang R, Sun W, Chen X. The role of
apelin/apelin receptor in energy metabolism and water
homeostasis: a comprehensive narrative review. Front
Physiol. 2021;12:632886. doi: 10.3389/fphys.2021.632886.
18. Li A, Zhao Q, Chen L, Li Z. Apelin/APJ system: an emerging
therapeutic target for neurological diseases. Mol Biol Rep.
2023;50(2):1639-53. doi: 10.1007/s11033-022-08075-9.
19. Zhang Y, Jiang W, Sun W, Guo W, Xia B, Shen X, et al.
Neuroprotective roles of apelin-13 in neurological diseases.
Neurochem Res. 2023;48(6):1648-62. doi: 10.1007/s11064-
023-03869-0.
20. Khaksari M, Aboutaleb N, Nasirinezhad F, Vakili A, Madjd
Z. Apelin-13 protects the brain against ischemic reperfusion
injury and cerebral edema in a transient model of focal
cerebral ischemia. J Mol Neurosci. 2012;48(1):201-8. doi:
10.1007/s12031-012-9808-3.
21. Zhou JX, Shuai NN, Wang B, Jin X, Kuang X, Tian SW.
Neuroprotective gain of apelin/APJ system. Neuropeptides.
2021;87:102131. doi: 10.1016/j.npep.2021.102131.
22. Pouresmaeili-Babaki E, Esmaeili-Mahani S, Abbasnejad M,
Ravan H. Protective effect of neuropeptide apelin-13 on
6-hydroxydopamine-induced neurotoxicity in SH-SY5Y
dopaminergic cells: involvement of its antioxidant and
antiapoptotic properties. Rejuvenation Res. 2018;21(2):162-
7. doi: 10.1089/rej.2017.1951. 23. Haghparast E, Sheibani V, Abbasnejad M, Esmaeili-Mahani
S. Apelin-13 attenuates motor impairments and prevents
the changes in synaptic plasticity-related molecules in the
striatum of Parkinsonism rats. Peptides. 2019;117:170091.
doi: 10.1016/j.peptides.2019.05.003.
24. Haghparast E, Esmaeili-Mahani S, Abbasnejad M,
Sheibani V. Apelin-13 ameliorates cognitive impairments
in 6-hydroxydopamine-induced substantia nigra lesion
in rats. Neuropeptides. 2018;68:28-35. doi: 10.1016/j.
npep.2018.01.001.
25. Aminyavari S, Zahmatkesh M, Farahmandfar M,
Khodagholi F, Dargahi L, Zarrindast MR. Protective role
of apelin-13 on amyloid β25-35-induced memory deficit;
involvement of autophagy and apoptosis process. Prog
Neuropsychopharmacol Biol Psychiatry. 2019;89:322-34.
doi: 10.1016/j.pnpbp.2018.10.005.
26. Masoumi J, Abbasloui M, Parvan R, Mohammadnejad
D, Pavon-Djavid G, Barzegari A, et al. Apelin, a
promising target for Alzheimer disease prevention and
treatment. Neuropeptides. 2018;70:76-86. doi: 10.1016/j.
npep.2018.05.008.
27. Reaux A, Gallatz K, Palkovits M, Llorens-Cortes C.
Distribution of apelin-synthesizing neurons in the adult rat
brain. Neuroscience. 2002;113(3):653-62. doi: 10.1016/
s0306-4522(02)00192-6.
28. Lee DK, Cheng R, Nguyen T, Fan T, Kariyawasam AP, Liu Y, et
al. Characterization of apelin, the ligand for the APJ receptor.
J Neurochem. 2000;74(1):34-41. doi: 10.1046/j.1471-
4159.2000.0740034.x.
29. Dai TT, Wang B, Xiao ZY, You Y, Tian SW. Apelin-13
upregulates BDNF against chronic stress-induced depressionlike phenotypes by ameliorating HPA axis and hippocampal
glucocorticoid receptor dysfunctions. Neuroscience.
2018;390:151-9. doi: 10.1016/j.neuroscience.2018.08.018.
30. Tian SW, Xu F, Gui SJ. Apelin-13 reverses memory
impairment and depression-like behavior in chronic social
defeat stressed rats. Peptides. 2018;108:1-6. doi: 10.1016/j.
peptides.2018.08.009.
31. Foroughi K, Khaksari M, Rahmati M, Bitaraf FS, Shayannia
A. Apelin-13 protects PC12 cells against methamphetamineinduced oxidative stress, autophagy and apoptosis.
Neurochem Res. 2019;44(9):2103-12. doi: 10.1007/s11064-
019-02847-9.
32. Yildiz I, Çimen YA, Eroğlu Güneş C, Özkürkçüler A, Kurar E,
Kutlu S. Effect of morphine dependency on apelinergic system
in rat hippocampus. Acta Physiol. 2022;234(Suppl 724):45.
33. Zarrinkalam E, Heidarianpour A. The effect of different training
modes on serum apelin and pain threshold in morphinedependent rats. Avicenna J Neuro Psycho Physiology.
2015;2(3):60-5. doi: 10.17795/ajnpp-34440.
34. Mohseni F, Khaksari M, Rafaiee R, Rahimi K, Norouzi P,
Garmabi B. Apelin-13 improves anxiety and cognition via
hippocampal increases BDNF expression and reduction cell
death in neonatal alcohol exposed rats. Int J Pept Res Ther.
2021;27(2):1351-62. doi: 10.1007/s10989-021-10173-4.
35. Mohseni F, Garmabi B, Khaksari M. Apelin-13 attenuates
spatial memory impairment by anti-oxidative, antiapoptosis, and anti-inflammatory mechanism against ethanol
neurotoxicity in the neonatal rat hippocampus. Neuropeptides.
2021;87:102130. doi: 10.1016/j.npep.2021.102130.
36. Tavanai A, Asadikaram G, Masoumi M. Opium addiction
is associated with increased damage to cardiomyocytes:
protective roles played by apelins. Iran Heart J. 2020;21(3):6-
14.
37. Darcq E, Kieffer BL. Opioid receptors: drivers to addiction?
Nat Rev Neurosci. 2018;19(8):499-514. doi: 10.1038/
s41583-018-0028-x.
38. Stuber GD, Wise RA. Lateral hypothalamic circuits for
feeding and reward. Nat Neurosci. 2016;19(2):198-205. doi:
10.1038/nn.4220.
39. Tyree SM, de Lecea L. Lateral hypothalamic control of the
ventral tegmental area: reward evaluation and the driving of
motivated behavior. Front Syst Neurosci. 2017;11:50. doi:
10.3389/fnsys.2017.00050.
40. Nieh EH, Vander Weele CM, Matthews GA, Presbrey
KN, Wichmann R, Leppla CA, et al. Inhibitory input from
the lateral hypothalamus to the ventral tegmental area
disinhibits dopamine neurons and promotes behavioral
activation. Neuron. 2016;90(6):1286-98. doi: 10.1016/j.
neuron.2016.04.035.
41. Castro DC, Cole SL, Berridge KC. Lateral hypothalamus,
nucleus accumbens, and ventral pallidum roles in eating
and hunger: interactions between homeostatic and reward
circuitry. Front Syst Neurosci. 2015;9:90. doi: 10.3389/
fnsys.2015.00090.
42. DiLeone RJ, Georgescu D, Nestler EJ. Lateral hypothalamic
neuropeptides in reward and drug addiction. Life Sci.
2003;73(6):759-68. doi: 10.1016/s0024-3205(03)00408-9.
43. Harris GC, Wimmer M, Randall-Thompson JF, Aston-Jones G.
Lateral hypothalamic orexin neurons are critically involved
in learning to associate an environment with morphine
reward. Behav Brain Res. 2007;183(1):43-51. doi: 10.1016/j.
bbr.2007.05.025.
44. Aston-Jones G, Smith RJ, Sartor GC, Moorman DE,
Massi L, Tahsili-Fahadan P, et al. Lateral hypothalamic
orexin/hypocretin neurons: a role in reward-seeking and
addiction. Brain Res. 2010;1314:74-90. doi: 10.1016/j.
brainres.2009.09.106.
45. Ghozland S, Matthes HW, Simonin F, Filliol D, Kieffer
BL, Maldonado R. Motivational effects of cannabinoids
are mediated by mu-opioid and kappa-opioid receptors.
J Neurosci. 2002;22(3):1146-54. doi: 10.1523/
jneurosci.22-03-01146.2002.
46. Berrendero F, Kieffer BL, Maldonado R. Attenuation of
nicotine-induced antinociception, rewarding effects,
and dependence in mu-opioid receptor knock-out
mice. J Neurosci. 2002;22(24):10935-40. doi: 10.1523/
jneurosci.22-24-10935.2002.
47. Berrettini W. Alcohol addiction and the mu-opioid receptor.
Prog Neuropsychopharmacol Biol Psychiatry. 2016;65:228-
33. doi: 10.1016/j.pnpbp.2015.07.011.
48. Zubieta JK, Gorelick DA, Stauffer R, Ravert HT, Dannals RF,
Frost JJ. Increased mu opioid receptor binding detected by
PET in cocaine-dependent men is associated with cocaine
craving. Nat Med. 1996;2(11):1225-9. doi: 10.1038/nm1196-
1225.
49. Moles A, Kieffer BL, D’Amato FR. Deficit in attachment
behavior in mice lacking the mu-opioid receptor gene. Science.
2004;304(5679):1983-6. doi: 10.1126/science.1095943.
50. Befort K, Filliol D, Darcq E, Ghate A, Matifas A, Lardenois A,
et al. Gene expression is altered in the lateral hypothalamus
upon activation of the mu opioid receptor. Ann N Y Acad Sci.
2008;1129:175-84. doi: 10.1196/annals.1417.028.
51. Mollereau C, Roumy M, Zajac JM. Opioid-modulating
peptides: mechanisms of action. Curr Top Med Chem.
2005;5(3):341-55. doi: 10.2174/1568026053544515.
52. Mansour A, Fox CA, Meng F, Akil H, Watson SJ. Kappa 1
receptor mRNA distribution in the rat CNS: comparison to
kappa receptor binding and prodynorphin mRNA. Mol Cell
Neurosci. 1994;5(2):124-44. doi: 10.1006/mcne.1994.1015.
53. Tejeda HA, Shippenberg TS, Henriksson R. The dynorphin/κopioid receptor system and its role in psychiatric disorders. Cell Mol Life Sci. 2012;69(6):857-96. doi: 10.1007/s00018-
011-0844-x.
54. Glick SD, Maisonneuve IM, Raucci J, Archer S. Kappa opioid
inhibition of morphine and cocaine self-administration in
rats. Brain Res. 1995;681(1-2):147-52. doi: 10.1016/0006-
8993(95)00306-b.
55. Schenk S, Partridge B, Shippenberg TS. U69593, a kappa-opioid
agonist, decreases cocaine self-administration and decreases
cocaine-produced drug-seeking. Psychopharmacology (Berl).
1999;144(4):339-46. doi: 10.1007/s002130051016.
56. Negus SS, Mello NK, Portoghese PS, Lin CE. Effects of kappa
opioids on cocaine self-administration by rhesus monkeys. J
Pharmacol Exp Ther. 1997;282(1):44-55.
57. Khan MI, Sawyer BJ, Akins NS, Le HV. A systematic review
on the kappa opioid receptor and its ligands: new directions
for the treatment of pain, anxiety, depression, and drug
abuse. Eur J Med Chem. 2022;243:114785. doi: 10.1016/j.
ejmech.2022.114785.
58. Li Y, Chen J, Bai B, Du H, Liu Y, Liu H. Heterodimerization
of human apelin and kappa opioid receptors: roles in
signal transduction. Cell Signal. 2012;24(5):991-1001. doi:
10.1016/j.cellsig.2011.12.012.
59. Ilaghi M, Soltanizadeh A, Amiri S, Kohlmeier KA, Shabani
M. The apelin/APJ signaling system and cytoprotection: role
of its cross-talk with kappa opioid receptor. Eur J Pharmacol.
2022;936:175353. doi: 10.1016/j.ejphar.2022.175353.
60. Lv S, Zhang X, Feng Y, Zhou Y, Cui B, Yang Y, et al. Intravenous
administration of pyroglutamyl apelin-13 alleviates murine
inflammatory pain via the kappa opioid receptor. Front
Neurosci. 2020;14:929. doi: 10.3389/fnins.2020.00929.
61. Mansour A, Fox CA, Burke S, Meng F, Thompson RC, Akil H,
et al. Mu, delta, and kappa opioid receptor mRNA expression
in the rat CNS: an in-situ hybridization study. J Comp Neurol.
1994;350(3):412-38. doi: 10.1002/cne.903500307.
62. Medhurst AD, Jennings CA, Robbins MJ, Davis RP, Ellis C,
Winborn KY, et al. Pharmacological and immunohistochemical
characterization of the APJ receptor and its endogenous
ligand apelin. J Neurochem. 2003;84(5):1162-72. doi:
10.1046/j.1471-4159.2003.01587.x.