Nukleus akumbens core bölgesinde L-NAME ve agmatinin morfin yoksunluğuna etkileri

Year 2020, , 65 - 72, 20.04.2020

Mahluga Jafarova Demirkapu , Hasan Yananlı , Elmar Mammadov , İna Dervishi , Ali Kırbaş , Şafak Yaşar , Tzemal Sali , Mansur Kurbanoğlu , Merve Çağlar , Öykü Uslu , Halil Sakallı , Betilay Topkara

https://doi.org/10.37696/nkmj.654542

Abstract

Amaç: Mezokortikolimbik dopaminerjik sistem, özellikle de nukleus akumbens (NAc) opioid bağımlılığı ve yoksunluğında önemli bölgelerdir. Yapılan çalışmalar nitrik oksid sentaz inhibitorlerinin opioidlere karşı tolerans gelişimini, opioid bağımlılığı ve yoksunluğunu modüle ettiğini göstermektedir. Biz bu çalışmada L-NAME ve agmatinin nukleus akumbens alt-bölgelerinden biri olan nukleus akumbens core (NAcc) bölgesine lokal enjeksiyonlarının morfin bağımlısı sıçanlarda naloksonla tetiklenen yoksunluk sırasında yoksunluk bulguları ve lokomotor aktivite davranışı üzerine etkilerini araştırmayı amaçladık.
Materyal ve Metot: Çalışmada yirmi dört yetişkin Sprague-Dawley sıçanı kullanıldı. Tüm hayvanlarda morfin bağımlılığı NAcc bölgelerine kılavuz kanüller yerleştirildikten sonra geliştirildi. Deneyin son gününde bilateral L-NAME, agmatin veya aCSF (yapay beyin omurilik sıvısı; kontrol grup) mikroenjeksiyonlarını takiben nalokson uygulanarak morfin yoksunluğu tetiklendi.
Bulgular: NAcc bölgesine lokal uygulanan agmatin ve L-NAME morfin bağımlısı hayvanlarda nalokson sonrası sıçrama sayısını anlamlı olarak baskıladı. Lokal L-NAME tedavisi diş gıcırdatma skorunu değiştirmediği halde agmatin tedavisi anlamlı düzeyde baskıladı. Lokal L-NAME ve agmatin tedavisinden sonra ıslak köpek sılkınmesi ve defekasyon gibi yoksunluk bulgularında anlamlı farklılık saptanmadı. NAcc bölgesine lokal enjekte edilen agmatin stereotipik hareketleri arttırdığı halde ambulatuvar ve toplam kat edilen mesafe gibi lokomotor aktivite davranışlarında anlamlı değişiklik yapmadı. NAcc bölgesine lokal enjekte edilen L-NAME naloksonla tetiklenen yoksunluk sendromunda stereotipik ve ambulatuvar hareketlerde ve toplam kat edilen mesafede artışa neden olmadı.
Sonuç: Bu bulgular nitrik oksit üretiminin NAcc'de baskılanmasının morfin yoksunluk sendromunda rol oynadığını, fakat tek başına sorumlu olmadığını göstermektedir.

Keywords

nukleus akumbens, L-NAME, agmatin, morfin, yoksunluk

The effects of L-NAME and agmatine in the nucleus accumbens core region on morphine withdrawal syndrome

Abstract

Objective: The mesocorticolimbic dopaminergic system, especially the nucleus accumbens (NAc), is an important region in opioid dependence and withdrawal. Studies have shown that nitric oxide synthase inhibitors modulate the development of tolerance to opioids, opioid dependence, and withdrawal. In this study, we aimed to investigate the effects of local injections of L-NAME and agmatine into the nucleus accumbens core (NAcc), one of nucleus accumbens subregions on withdrawal signs and locomotor activity behavior during naloxone-induced withdrawal in morphine-dependent rats.
Material and Method: Twenty-four adult Sprague-Dawley rats were used in the study. Morphine dependence was developed in all animals after guide cannula implantation into the NAcc region. On the last day of experiment, following bilateral L-NAME, agmatine or artificial cerebrospinal fluid (aCSF) microinjections (control group) morphine withdrawal was induced by naloxone.
Results: Local administration of agmatine and L-NAME into the NAcc significantly suppressed the jumping number in morphine-dependent rats induced by naloxone. Local agmatine treatment significantly suppressed the score of teeth chattering, although the L-NAME did not change. No significant difference was observed in withdrawal symptoms such as wet dog shakes and defecation after local agmatine and L-NAME treatment. Agmatine, locally injected into the NAcc increased stereotypic movements, but did not make significant changes in locomotor activity behaviors such as ambulatory and total covered distance. Local administration of L-NAME into the NAcc caused no increase in stereotypic, and ambulatory movements, and total covered distance during naloxone-induced withdrawal.
Conclusion: These results suggest that inhibition of nitric oxide synthesis in NAcc plays a role in morphine withdrawal symptoms, but it is not responsible alone.

Keywords

nucleus accumbens, L-NAME, agmatine, morphine, withdrawal

Supporting Institution

The study was funded by researchers.

Thanks

We would like to thank Merve Özegel, due to the contribution of the experiment (rip).

References

• Koob GF. Drugs of abuse: anatomy, pharmacology and function of reward pathways. Trends Pharmacol Sci. 1992 May;13(5):177-84.
• Gysling K, Wang RY. Morphine-induced activation of A10 dopamine neurons in the rat. Brain Res. 1983 Oct; 277(1):119-27.
• Kelley AE. Neural integrative activities of nucleus accumbens subregions in relation to learning and motivation. Psychobiology 1999 June;27(2):198-213.
• Lowenstein CJ, Dinerman JL, Snyder SH. Nitric Oxide: A Physiologic Messenger. Ann. Intern. Med. 1994 Feb;120(3):227-37.
• Snyder SH. Nitricoxide: First in a New Class of Neurotransmitters. Science. 1992 Jul;257(5069):494-6.
• Javadi S, Ejtemaeimehr S, Keyvanfar HR, Moghaddas P, Aminian A, Rajabzadeh A, Mani AR, Dehpour AR. Pioglitazone potentiates development of morphine-dependence in mice: possible role of NO/cGMP pathway. Brain Res. 2013 May;1510:22-37.
• Buccafusco JJ, Terry AV Jr, Shuster L. Spinal NMDA receptor--nitric oxide mediation of the expression of morphine withdrawal symptoms in the rat. Brain Res. 1995 May;679(2):189-99.
• Cappendijk SL, Duval SY, de Vries R, Dzoljic MR. Comparative study of normotensive and hypertensive nitric oxide synthase inhibitors on morphine withdrawal syndrome in rats. Neurosci Lett. 1995 Jan;183(1-2):67-70.
• Vaupel DB, Kimes AS, London ED. Comparison of 7-nitroindazole with other nitric oxide synthase inhibitors as attenuators of opioid withdrawal. Psychopharmacology (Berl). 1995;118(4):361-8.
• Reis DJ, Regunathan S. Agmatine: a novel neurotransmitter? Adv. Pharmacol. 1998; 42:645–9.
• Uzbay TI. The pharmacological importance of agmatine in the brain. Neuroscience and Biobehavioral Reviews 2012 January;36(1):502-19.
• Raasch W, Schäfer U, Chun J, Dominiak P. Biological significance of agmatine, an endogenous ligand at imidazoline binding sites. Br J Pharmacol. 2001 Jul;133(6):755–80.
• Auguet M, Viossat I, Marin JG, Chabrier PE. Selective inhibition of inducible nitric oxide synthase by agmatine. Jpn J Pharmacol. 1995 Nov;69(3):285-7.
• Galea E, Regunathan S, Eliopoulos V, Feinstein DL, Reis DJ. Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine. Biochem J. 1996 May;316(Pt 1):247-9.
• Rawls SM, Gerber K, Ding Z, Roth C, Raffa RB. Agmatine: identification and inhibition of methamphetamine, kappa opioid, and cannabinoid withdrawal in planarians. Synapse. 2008 Dec; 62(12):927-34.
• Su RB, Lu XQ, Huang Y, Liu Y, Gong ZH, Wei XL, Wu N, Li J. Effects of intragastric agmatine on morphine-induced physiological dependence in beagle dogs and rhesus monkeys. Eur J Pharmacol. 2008 Jun;587(1-3):155-62.
• Aricioglu F, Means A, Regunathan S. Effect of agmatine on the development of morphine dependence in rats: potential role of cAMP system. Eur J Pharmacol. 2004 Nov;504(3):191-7.
• Yananli H, Gören MZ, Berkman K, Aricioğlu F. Effect of agmatine on brain L-citrulline production during morphine withdrawal in rats: a microdialysis study in nucleus accumbens. Brain Res. 2007 Feb;1132(1):51-8.
• Paxinos G, Watson C: The Rat Brain in Stereotaxic Coordinates (fourth edition).Academic press, San Diego, California, 1998.
• Topkara B, Yananli HR, Sakallı E, Demirkapu MJ. Effects of Injection of Gamma-Aminobutyric Acid Agonists into the Nucleus Accumbens on Naloxone-Induced Morphine Withdrawal. Pharmacology 2017;100:131-8.
• Trujillo KA, Akil H. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science. 1991 Jan;251(4989):85-7.
• Jones KL, Zhu H, Jenab S, Du T, Inturrisi CE, Barr GA. Attenuation of acute morphine withdrawal in the neonatal rat by the competitive NMDA receptor antagonist LY235959. Neuropsychopharmacology. 2002 Mar;26(3):301-10.
• Koyuncuoğlu H, Dizdar Y, Aricioğlu F, Sayin U. Effects of MK 801 on morphine physical dependence: attenuation and intensification. Pharmacol Biochem Behav. 1992 Oct;43(2):487-90.
• Koob GF, Volkow ND. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry. 2016 Aug; 3(8):760-73.
• Herman BH, Vocci F, Bridge P. The effects of NMDA receptor antagonists and nitric oxide synthase inhibitors on opioid tolerance and withdrawal. Neuropsychopharmacology 1995 Dec;13(4):269-93.
• Parvardeh S, Moghimi M, Eslami P, Masoudi A. α-Terpineol attenuates morphine-induced physical dependence and tolerance in mice: role of nitric oxide. Iran J Basic Med Sci. 2016 Feb; 19(2):201-8.
• Yang XC, Reis DJ. Agmatine selectively blocks the N-methyl-D-aspartate subclass of glutamate receptor channels in rat hippocampal neurons. J Pharmacol Exp Ther. 1999 Feb; 288(2):544-9.
• Peng SY, Li B, Xi K, Wang JJ, Zhu JN. Presynaptic α2-adrenoceptor modulates glutamatergic synaptic transmission in rat nucleus accumbens in vitro. Neurosci Lett. 2018 Feb;665:117-22.
• Pinelli A, Trivulzio S. Quantitative evaluation of opioid withdrawal signs in rats repeatedly treated with morphine and injected with naloxone, in the absence or presence of the antiabstinence agent clonidine. J PharmacolToxicol Methods. 1997 Nov;38(3):117-31.
• Moayeri A, Azimi M, Karimi E, Aidy A, Abbasi N. Attenuation of Morphine Withdrawal Syndrome by ProsopisFarcta Extract and Its Bioactive Component Luteolin in Comparison with Clonidine in Rats. Med SciMonit Basic Res. 2018 Oct;24:151-158.
• Kolik LG, Konstantinopolsky MA. Comparative Assessment of the Effectiveness of Noncompetitive NMDA Receptor Antagonists Amantadine and Hemantane in Morphine Withdrawal Syndrome Model. Bull ExpBiol Med. 2019 Apr;166(6):739-43.