The Effects of L-NAME and Agmatine in The Nucleus Accumbens Core Regıon on Morphine Withdrawal Syndrome

Aim:The mesocorticolimbic dopaminergic system, especially the nucleus accumbens, 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 the nucleus accumbens subregions on withdrawal signs and locomotor activity behavior during naloxone-induced withdrawal in morphine-dependent rats.Materials and Methods: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, control group) microinjections morphine withdrawal was induced by naloxone.Results:Local administration of agmatine and L-NAME into the NAcc significantly suppressed the jumping number during naloxone induced withdrawal. 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 increased stereotypic movements, but did not change locomotor activity behaviors such as ambulatory activity and total covered distance. Local administration of L-NAME into the NAcc did not increase 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

Nukleus Akumbens Core Bölgesinde L-NAME ve Agmatinin Morfin Yoksunluğuna Etkileri

Aim: The mesocorticolimbic dopaminergic system, especially the nucleus accumbens, 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 the nucleus accumbens subregions on withdrawal signs and locomotor activity behavior during naloxone-induced withdrawal in morphine-dependent rats. Materials and Methods: 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, control group) microinjections morphine withdrawal was induced by naloxone. Results: Local administration of agmatine and L-NAME into the NAcc significantly suppressed the jumping number during naloxone induced withdrawal. 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 increased stereotypic movements, but did not change locomotor activity behaviors such as ambulatory activity and total covered distance. Local administration of L-NAME into the NAcc did not increase 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.Amaç: Mezokortikolimbik dopaminerjik sistem, özellikle de nukleus akumbens bölgesi opioid bağımlılığı ve yoksunluğunda önemli bölgelerdendir. Yapılan çalışmalara göre nitrik oksit sentaz inhibitörleri opioidlere karşı tolerans gelişimini, opioid bağımlılığı ve yoksunluğunu değiştirmektedir. Biz bu çalışmada L-NAME ve agmatinin nukleus akumbens alt-bölgelerinden biri olan nukleus akumbens çekirdek (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 grubu) 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 silkinmesi ve defekasyon gibi yoksunluk bulgularında anlamlı farklılık saptanmadı. NAcc bölgesine lokal enjekte edilen agmatin stereotipik hareketleri artırdığı 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 hareketlerde, ambulatuvar hareketlerde ve toplam kat edilen mesafede artışa yol açmadı. Sonuç: Bu bulgular nitrik oksit üretiminin NAcc bölgesinde baskılanmasının morfin yoksunluk sendromunda rol oynadığını, fakat tek başına sorumlu olmadığını göstermektedir