Akut ketamin uygulamasının kognitif fonksiyonlar üzerine etkilerinin araştırılması
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Tarih
2018
Yazarlar
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Cilt Başlığı
Yayıncı
Dicle Üniversitesi, Sağlık Bilimleri Enstitüsü
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Amaç: Major Depresif Bozukluk tedavisinde kullanılan klasik ajanların etkilerinin belli bir periyod sonrasında ba?laması ve vakaların önemli bir kısmında etkisiz kalmaları, yeni ve hızlı-etkili terapötik yakla?ımlara ihtiyaç duyulmasına sebep olmaktadır. Literatürde, subanestezik tek-doz ketamin uygulamasının, hızlı ve güçlü antidepresan-benzeri etkiler olu?turduğu, tekrarlanan yüksek-doz uygulamaların ise kognitif fonksiyon bozukluklarına neden olduğu belirtilmektedir. Antidepresan etki olu?umuna, serotonerjik a?ırımda güçlenme ve AMPA reseptör aktivasyonunu içeren çe?itli mekanizmaların katkı sağladığı vurgulanmaktadır. Bu çalı?mada, subanestezik dozda ketamin'in tekrarlanan uygulamaları ile emosyonel bellek süreçleri (edinme, peki?tirme ve geri çağırma) üzerine olu?an etkilerin incelenmesi; akut ketamin uygulamasının antidepresan etkinliğinde serotonerjik sistemin ve AMPA reseptörlerinin rollerinin ara?tırılması planlanmı?tır. Gereç ve Yöntem: Bu amaçla deneklerin, methiothepin ile serotonin reseptör antagonizması veya p-klorofenil alanin ile serotonin deplesyonu suretiyle serotonerjik aktiviteleri, GYKI-52466 ile de AMPA reseptörleri baskılanmı?ır. Antidepresan kontrol grubu olarak fluoksetin kullanılmı? ve ketamin ile kombinasyonunun etkileri değerlendirilmi?tir. Psikofarmakolojik incelemeler; zorunlu yüzme, açık alan, yükseltilmi? artı labirenti ve pasif sakınma test düzenekleriyle gerçekle?tirilmi?tir. Lipid peroksidasyonları, beyin malondialdehit seviyeleri incelenerek değerlendirilmi?tir. Ek-4 xvi Beyin kesitlerinde kaspaz-3 ekspresyon seviyeleri incelenmi? ve histopatolojik değerlendirmeler yapılmı?tır. Bulgular: Tekrarlanan ketamin uygulamalarıyla emosyonel bellek süreç performanslarında, kaspaz-3 ekspresyon ve malondialdehit seviyelerinde anlamlı farklılık gözlemlenmemi?tir. Buna kar?ın, ketamin uygulanan grupların beyin kesitlerinde gerçekle?tirilen histopatolojik incelemelerde kısmi nörodejeneratif bulgular tespit edilmi?tir. Subanestezik tek-doz ketamin uygulaması ile lokomotor aktivite etkilenmeksizin hızlı antidepresan-benzeri etkiler olu?tuğu gözlemlenmi?tir. Serotonerjik aktivitenin baskılanması ve AMPA reseptörlerinin antagonize edilmesi durumlarında ketamin'in antidepresan-benzeri etki olu?turmakta ba?arısız olduğu anla?ılmı?tır. Sonuç: Kullandığımız subanestezik dozda ketamin'in tekrarlanan uygulamalarıyla beyinde kısmi nörodejenerasyonu i?aret eden bulgular saptanmı?, olu?an bu dejenerasyonun davranı? deneyleri ile incelenen emosyonel bellek süreçlerini etkileyecek boyutta olmadığı anla?ılmı?tır. Gerçekle?tirilecek ileri çalı?malar, ketamin'in antidepresan etki mekanizmasının ve glutamaterjik sistemin depresyondaki rolünün aydınlatılmasına olanak sağlayacaktır.
Aim: Current antidepressant therapies to treat Major Depressive Disorder are being insufficient for a significant part of the patients and with a delayed onset of action. This lack of success and suspended effect are causing a vital problem especially in treatment-resistant and suicidal MDD patients. Finding new and fast-acting strategies in depression treatment is, therefore, essential. In numerous preclinical and clinical studies, it is reported that a single low-dose ketamine administration produces robust and prolonged antidepressant-like effects. Current literature implies that various mechanisms may contribute antidepressant effects of ketamine including an increment in serotonergic transmission and increased activity of non-NMDA ionotropic AMPA receptors. In the present study, we aimed to investigate the involvement of serotonergic system and AMPA receptors in antidepressant-like effects of low-dose ketamine and its effects on emotional memory processes. Material and Method: In this outcome, we either blocked the serotonin receptors with methiothepin or depleted serotonin with p-chlorophenyl alanine, and AMPA receptors were blocked with GYKI-52466. Fluoxetine was used as the antidepressant control, and effects of its combination with ketamine were evaluated. We used a forced swimming test to measure depression, an open field test to measure locomotion and an elevated plus maze test to measure anxiety. A passive avoidance test was used to assess effects on emotional learning and memory processes (i.e., acquisition, consolidation, and retrieval). Brain prefrontal cortex and hippocampi tissues were isolated to measure malondialdehyde (MDA) levels as an Ek-5 xviii indicator of lipid peroxidation. Caspase-3 expressions in PFK slices and histopathological assessment of a wide range of brain areas were practiced. Results: Our data demonstrated that single-dose ketamine produces robust antidepressant-like effects and even one week after drug injection it was still effective, yet insignificantly. Furthermore, ketamine failed to produce antidepressant-like effects if serotonin was depleted or its receptors were blocked. Ketamine with an AMPA receptor antagonist also made a similar failure in reducing depression symptoms. Ketamine did not cause a defect in emotional memory when used alone, yet it reduced memory acquisition and consolidation when combined with fluoxetine. Moreover, antiserotonergic drugs as pCPA and methiothepin were improved memory consolidation process. No significant difference was observed in malondialdehyde levels in brain PFK and hippocampi tissues with the drugs applied during the test procedure. Similarly, PFK caspase-3 expression level analyze has shown no significant difference between test groups. Yet, histopathological assessment has shown a variety of neurodegenerative symptoms including; perineural edema in pyramidal neurons, loss of cerebellar Purkinje cells, necrosis in hippocampal neurons and thrombosis in the subpial vascular area. Furthermore, proliferation in oligodendria cells was observed. Conclusion: Repetitive administrations of subanesthetic-dose ketamine did cause neurodegenerative symptoms. Still, the dosage we used was unable to affect emotional memory processes in behavioral tests. A single low-dose ketamine administration produced rapid antidepressant-like effects, and it is understood that the activity of serotonergic system and AMPA receptors are necessary for ketamine to exhibit this effect. Prescribing ketamine a role in depression treatment may be possible with extensive research; to enlighten its mechanism of action, to reduce its side-effects and to prevent its abusive use. In the light of the latest research, an increment in indications of ketamine doesn't seem a distant possibility.
Aim: Current antidepressant therapies to treat Major Depressive Disorder are being insufficient for a significant part of the patients and with a delayed onset of action. This lack of success and suspended effect are causing a vital problem especially in treatment-resistant and suicidal MDD patients. Finding new and fast-acting strategies in depression treatment is, therefore, essential. In numerous preclinical and clinical studies, it is reported that a single low-dose ketamine administration produces robust and prolonged antidepressant-like effects. Current literature implies that various mechanisms may contribute antidepressant effects of ketamine including an increment in serotonergic transmission and increased activity of non-NMDA ionotropic AMPA receptors. In the present study, we aimed to investigate the involvement of serotonergic system and AMPA receptors in antidepressant-like effects of low-dose ketamine and its effects on emotional memory processes. Material and Method: In this outcome, we either blocked the serotonin receptors with methiothepin or depleted serotonin with p-chlorophenyl alanine, and AMPA receptors were blocked with GYKI-52466. Fluoxetine was used as the antidepressant control, and effects of its combination with ketamine were evaluated. We used a forced swimming test to measure depression, an open field test to measure locomotion and an elevated plus maze test to measure anxiety. A passive avoidance test was used to assess effects on emotional learning and memory processes (i.e., acquisition, consolidation, and retrieval). Brain prefrontal cortex and hippocampi tissues were isolated to measure malondialdehyde (MDA) levels as an Ek-5 xviii indicator of lipid peroxidation. Caspase-3 expressions in PFK slices and histopathological assessment of a wide range of brain areas were practiced. Results: Our data demonstrated that single-dose ketamine produces robust antidepressant-like effects and even one week after drug injection it was still effective, yet insignificantly. Furthermore, ketamine failed to produce antidepressant-like effects if serotonin was depleted or its receptors were blocked. Ketamine with an AMPA receptor antagonist also made a similar failure in reducing depression symptoms. Ketamine did not cause a defect in emotional memory when used alone, yet it reduced memory acquisition and consolidation when combined with fluoxetine. Moreover, antiserotonergic drugs as pCPA and methiothepin were improved memory consolidation process. No significant difference was observed in malondialdehyde levels in brain PFK and hippocampi tissues with the drugs applied during the test procedure. Similarly, PFK caspase-3 expression level analyze has shown no significant difference between test groups. Yet, histopathological assessment has shown a variety of neurodegenerative symptoms including; perineural edema in pyramidal neurons, loss of cerebellar Purkinje cells, necrosis in hippocampal neurons and thrombosis in the subpial vascular area. Furthermore, proliferation in oligodendria cells was observed. Conclusion: Repetitive administrations of subanesthetic-dose ketamine did cause neurodegenerative symptoms. Still, the dosage we used was unable to affect emotional memory processes in behavioral tests. A single low-dose ketamine administration produced rapid antidepressant-like effects, and it is understood that the activity of serotonergic system and AMPA receptors are necessary for ketamine to exhibit this effect. Prescribing ketamine a role in depression treatment may be possible with extensive research; to enlighten its mechanism of action, to reduce its side-effects and to prevent its abusive use. In the light of the latest research, an increment in indications of ketamine doesn't seem a distant possibility.
Açıklama
Anahtar Kelimeler
Ketamin, Kognitif fonksiyonlar, Major depresif bozukluk, NMDA reseptörleri, AMPA reseptörleri, Ketamine, Cognitive functions, Major depressive disorder, NMDA receptors, AMPA receptors
Kaynak
WoS Q Değeri
Scopus Q Değeri
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Sayı
Künye
Uyar, E. (2018). Akut ketamin uygulamasının kognitif fonksiyonlar üzerine etkilerinin araştırılması. Doktora tezi, Dicle Üniversitesi, Diyarbakır.
