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The Effects of Acute and Chronic Diphenhydramine and Cetirizine Use on Learning and Memory in Rats

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The Effects of Acute and Chronic Diphenhydramine and Cetirizine Use on Learning and Memory in Rats T.C. REPUBLIC OF TURKEY HACETTEPE UNIVERSITY INSTITUTE OF HEALTH SCIENCES THE EFFECTS OF ACUTE AND CHRONIC DIPHENHYDRAMINE AND CETIRIZINE USE ON LEARNING AND MEMORY IN RATS Sadık Taşkın TAŞ, MD Medical Pharmacology Program DOCTOR OF PHILOSOPHY THESIS ANKARA 2018 T.C. REPUBLIC OF TURKEY HACETTEPE UNIVERSITY INSTITUTE OF HEALTH SCIENCES THE EFFECTS OF ACUTE AND CHRONIC DIPHENHYDRAMINE AND CETIRIZINE USE ON LEARNING AND MEMORY IN RATS Sadık Taşkın TAŞ, MD Medical Pharmacology Program DOCTOR OF PHILOSOPHY THESIS ADVISOR OF THE THESIS Prof. Mehmet Yıldırım SARA, MD, PhD ANKARA 2018 iii The Effects of Acute and Chronic Diphenhydramine and Cetirizine Use on Learning and Memory in Rats Sadık Taşkın Taş, MD This study has been approved and accepted as a PhD dissertation in the program of “Medical Pharmacology” by the examining committee, whose members are listed below, on 18.01.2018. Chairman of the Committee : Prof. Dr. Alper Bektaş İskit Hacettepe University Advisor of the Dissertation : Prof. Dr. Mehmet Yıldırım Sara Hacettepe University Member : Prof. Dr. Emine Demirel Yılmaz Ankara University Member : Doç. Dr. Güray Soydan Hacettepe University Member : Doç. Dr. Ergin Dileköz Gazi University This dissertation has been approved by the committee above in conformity to the regulations and by laws of Hacettepe University Graduate Programs. Prof. Dr. Diclehan Orhan Institute Director iv YAYIMLAMA VE FİKRİ MÜLKİYET HAKLARI BEYANI Enstitü tarafından onaylanan lisansüstü tezimin/raporumun tamamını veya herhangi bir kısmını, basılı (kağıt) ve elektronik formatta arşivleme ve aşağıda verilen koşullarla kullanıma açma iznini Hacettepe Üniversitesine verdiğimi bildiririm. Bu izinle Üniversiteye verilen kullanım hakları dışındaki tüm fikri mülkiyet haklarım bende kalacak, tezimin tamamının ya da bir bölümünün gelecekteki çalışmalarda (makale, kitap, lisans ve patent vb.) kullanım hakları bana ait olacaktır. Tezin kendi orijinal çalışmam olduğunu, başkalarının haklarını ihlal etmediğimi ve tezimin tek yetkili sahibi olduğumu beyan ve taahhüt ederim. Tezimde yer alan telif hakkı bulunan ve sahiplerinden yazılı izin alınarak kullanılması zorunlu metinlerin yazılı izin alınarak kullandığımı ve istenildiğinde suretlerini üniversiteye teslim etmeyi taahhüt ederim. ● Tezimin/Raporumun tamamı dünya çapında erişime açılabilir ve bir kısmı veya tamamının fotokopisi alınabilir. (Bu seçenekle teziniz arama motorlarında indekslenebilecek, daha sonra tezinizin erişim statüsünün değiştirilmesini talep etseniz ve kütüphane bu talebinizi yerine getirse bile, teziniz arama motorlarının önbelleklerinde kalmaya devam edebilecektir) o Tezimin/Raporumun ……………. tarihine kadar erişime açılmasını ve fotokopi alınmasını (İç kapak, Özet, İçindekiler ve Kaynakça hariç) istemiyorum. (Bu sürenin sonunda uzatma için başvuruda bulunmadığım takdirde, tezimin/raporumun tamamı her yerden erişime açılabilir, kaynak gösterilmek şartıyla bir kısmı veya tamamının fotokopisi alınabilir.) o Tezimin/Raporumun ……………. tarihine kadar erişime açılmasını istemiyorum ancak kaynak gösterilmek şartıyla bir kısmı veya tamamının fotokopisinin alınmasını onaylıyorum. o Serbest Seçenek/Yazarın Seçimi 18/01/2018 Dr. Sadık Taşkın Taş v ETHICAL DECLARATION I declare that all the information and documents have been obtained within the academic rules and all audio-visual and written information and results in this thesis study have been presented according to the rules of scientific ethics. I did not do any distortions in the data set. In the case of using other works, related studies have been fully cited in accordance with the scientific standards. I also declare that my thesis study is original except the cited references. It was produced by myself in consultation with my supervisor Prof. Mehmet Yıldırım SARA, MD, PhD and written according to the thesis guidelines of Hacettepe University Institute of Health Sciences. Sadık Taşkın Taş, MD vi ACKNOWLEDGEMENTS I would like to thank… … Prof. Dr. Mehmet Yıldırım SARA, MD, PhD for his supervision and guidance throughout my time in the Department of Medical Pharmacology; …the members of my thesis committee for their helpful advices given during my thesis studies; …the members of my dissertation defense committee for their time and consideration for evaluating my dissertation; …all the current and former professors of my department, especially Prof. Alper Bektaş İskit, MD, PhD, and my first supervisor Prof. Emin Rüştü Onur, MD, PhD—for their contributions to my academic development; …all assistants, PhD students, technicians and staff of my department for their companionship and cooperation, especially my lab colleagues Canan Kurşungöz, PhD, Metin Yeşiltepe, MD, Arwa Al Bayrakdar, MS and Barış Alten; …all my friends, especially Daniel Kastner, Winston Ellis and Ekim Gümeler for their support and society; …my father, my mother, my brother, my sister and all my family for their devotion and understanding. This work is dedicated to my wife, Güneş. vii ÖZET Taş, S. T., Akut ve Kronik Difenhidramin ve Setirizin İlaç Kullanımının Sıçanlarda Öğrenme ve Bellek Üzerine Etkileri, Hacettepe Üniversitesi Sağlık Bilimleri Enstitüsü Tıbbi Farmakoloji Programı Doktora Tezi, Ankara, 2018. Antihistaminik ilaçlar alerji, nezle ve uykusuzluk gibi birçok endikasyonu olan ve çok yaygın olarak kullanılan bir ilaç grubudur. Bu ilaçların santral sinir sistemi yan etkileri yaptığı bilinmesine rağmen öğrenme ve bellek gibi bilişsel fonksiyonlar üzerine etkileri tam olarak aydınlatılamamıştır. Bu çalışmada in vivo hipokampal alan potansiyeli kayıtları kullanılarak akut ve kronik setirizin ve difenhidramin tedavisi ile gelişen nöroplastisite değişikliği etkileri incelendi. Difenhidraminin antimuskarinik etkilerini değerlendirmek için ise skopolamin kullanıldı. Ayrıca, setirizinin kognitif performans üzerinde etkilerini araştırmak için davranış deneyleri yapıldı. Setirizinin patofizyolojik koşullardaki etkilerini araştırmak için de bir REM uyku yoksunluğu modeli kullanıldı. Difenhidramin ve setirizin akut kullanımı kısa dönem plastisitenin potansiyasyon fazlarını engelledi ancak kronik kullanımda bu etkiye tolerans gelişti. Uzun dönem plastisite deneylerinde setirizin tüm gruplarda LTD’yi ve kronik tedavi grubunda LTP’yi inhibe etti. Akut ve kronik setirizin tedavisi sonrası yapılan davranış deneylerinde anlamlı bir sonuç alınamadı. Bu sonuçlar setirizinin uzun dönem plastisite üzerine difenhidraminin oluşturamadığı etkileri olduğunu göstermektedir. Bu bulgulara göre, setirizin hipokampal devreleri H1 reseptör blokajı dışında daha önce bilinmeyen bir mekanizma ile etkiliyor olabilir. Uyku yoksunluğu sırasında setirizin kullanımı kognitif bozukluklara karşı koruyucu olabilir. Anahtar Kelimeler: Antihistaminik ilaçlar, öğrenme, bellek, setirizin, difenhidramin, REM uyku yoksunluğu Destekleyen Kurumlar: Hacettepe Üniversitesi Bilimsel Araştırma Projeleri Koordinasyon Birimi, Proje Numarası: THD-2017-16553 viii ABSTRACT Taş, S. T., The Effects of Acute and Chronic Diphenhydramine and Cetirizine Use on Learning and Memory in Rats, Hacettepe University Institute of Health Sciences Medical Pharmacology Doctor of Philosophy Thesis, Ankara, 2018. Antihistamines are one of the most widely used drug groups in various indications such as allergy, common cold and insomnia. Although these drugs are known to cause central nervous system side effects, their effects on cognitive functions such as learning and memory are not fully elucidated. We used in vivo hippocampal field potential recordings to assess the neuroplasticity changes caused by acute and chronic diphenhydramine and cetirizine treatment. Scopolamine is also used to assess the antimuscarinic effects of diphenhydramine. Furthermore, behavioral experiments were conducted to investigate the effect of cetirizine on cognitive performance. An REM sleep deprivation model was used to assess the effects of cetirizine in pathophysiological conditions. Acute use of diphenhydramine and cetirizine affected the potentiation phases of short-term plasticity while chronic treatment caused a tolerance to this effect. In long-term plasticity experiments, cetirizine blocked LTD in all groups and inhibited LTP in chronic treatment. Cetirizine prevented REM sleep deprivation-induced inhibition of LTP. Behavioral experiments with acute and chronic cetirizine treatment yielded no significant results. Our data showed that cetirizine has a significant effect in long-term plasticity that diphenhydramine failed to elicit. Therefore, cetirizine might be affecting the hippocampal circuitry independent of H1 receptor blockage through a previously unknown mechanism. Cetirizine use during sleep deprivation could be protective against cognitive dysfunction. Key Words: Antihistamines, learning, memory, cetirizine, diphenhydramine, REM sleep deprivation Supporting Organizations: Hacettepe University Scientific Research Projects Coordination Unit, Project Number: THD-2017-16553 ix TABLE OF CONTENTS APPROVAL PAGE iii YAYIMLAMA VE FİKRİ MÜLKİYET HAKLARI BEYANI iii ETHICAL DECLARATION v ACKNOWLEDGEMENTS vi ÖZET vii ABSTRACT viii TABLE OF CONTENTS ix SYMBOLS AND ABBREVIATIONS xiii LIST OF FIGURES xv LIST OF TABLES xvii 1. INTRODUCTION 1 2. GENERAL INFORMATION 6 Histamine 6 Chemical Properties of Histamine 6 Synthesis of Histamine 7 Histamine Receptors 8 Histamine H1 Receptor 8 Histamine H2 Receptor 10 Histamine H3 Receptor 11 Histamine H4 Receptor 12 Role of Histamine in Homeostatic Brain Functions 12 Role of Histamine in Higher Brain Functions 15 Antihistamines 19 First
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