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5-HT2A/2C Receptor Modulation of Absence Seizures and Characterization of the GHB-Model

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5-HT2A/2C receptor modulation of absence seizures and characterization of the GHB-model A thesis submitted to Cardiff University for the degree of Doctor of Philosophy by Marcello Venzi (MSc) School of Biosciences, Cardiff University, October 2014 Chapter 1 Declaration and Statements This work has not been submitted in substance for any other degree or award at this or any other university or place of learning, nor is being submitted concurrently in candidature for any degree or other award. Signed ………………………………………… (candidate) Date ………………………… STATEMENT 1 This thesis is being submitted in partial fulfillment of the requirements for the degree of PhD . Signed ………………………………………… (candidate) Date ………………………… STATEMENT 2 This thesis is the result of my own independent work/investigation, except where otherwise stated. Other sources are acknowledged by explicit references. The views expressed are my own. Signed ………………………………………… (candidate) Date ………………………… STATEMENT 3 I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter- library loan, and for the title and summary to be made available to outside organisations. Signed ………………………………………… (candidate) Date ………………………… STATEMENT 4: PREVIOUSLY APPROVED BAR ON ACCESS I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter- library loans after expiry of a bar on access previously approved by the Academic Standards & Quality Committee. Signed ………………………………………… (candidate) Date ………………………… II Chapter 1 Summary Absence seizures (ASs) are non-convulsive epileptic events which are common in pediatric and juvenile epilepsies. They consist of EEG generalized spike-and-wave-discharges (SWDs) accompanied by an impairment of consciousness and are expressed within the thalamocortical network. This thesis initially focused on investigating the modulation of ASs by two serotonin receptors (5-HTRs), 5-HT2A and 5-HT2C, in a polygenic (i.e. Genetic Absence Epilepsy Rats from Strasbourg, GAERS) and a pharmacological (i.e. γ-hydroxybutyrate, GHB) model of ASs. It was found that, in GAERS, pharmacological activation of 5-HT2A/CRs blocked ASs, whereas 5-HT2AR antagonists increased seizure length. However, experiments on the GHB-model revealed that GHB induced not only ASs but also a period of sedation/hypnosis, a behavioural state that had been neglected in the literature. Thus, the rest of this thesis was devoted to further characterizing the GHB-model. The main result was that GHB-elicited ASs can be distinguished at the level of both EEG and behaviour. In vivo characterization of thalamic firing during GHB- elicited ASs and hypnosis via silicon probes in freely moving animals revealed that both states were accompanied by a decrease in firing rate. In particular, contrary to what was predicted by in vitro and in vivo experiments under neurolept anaesthesia, T-type Ca2+ channel-dependent burst firing in thalamic neurons was found in <10% of spike-and-wave complexes of SWDs. The prevalent activity of nucleus reticularis thalami neurons during ASs was either silence or tonic firing. Indeed, thalamic application of the potent T-type channel antagonist, TTAP-2, by reverse microdialysis did not affect GHB-elicited ASs. Finally, the development of an algorithm to classify GHB-elicited ASs demonstrated that the spectral properties of SWDs can be used to discriminate hypnosis and SWDs. Moreover, spectral coherence can be used in different experimental models of ASs to characterize SWDs according to their waveform regularity. III Chapter 1 Collaborations Animal implantations and data collection in Chapter 5 were performed together with Dr. François David. IV Chapter 1 Acknowledgements First and foremost I would like to thank my supervisor, Vincenzo for his support throughout my PhD and for always having time for me no matter how busy he was. Secondly, I am grateful to all members of the Crunelli lab, in particular Cian and François: Cian for his help in teaching me surgery and for our discussions, which helped to keep alive my interest in science and Francois, for honing my matlab skills and teaching me spike sorting, and for showing me what it takes to stay at the top of the food chain. Also, Bill, for the chats about pharmacology, statistics, electrophysiology, and all the other areas of science in which my knowledge is sorely lacking, Tim, for his help with histological analysis, and Hannah, for giving me motivational treats whilst I was writing this thesis! Thirdly, I would like to thank Cristiano, for his expertise in 5-HT immunohistochemistry, and Giuseppe for helping me to find a serotinergic drug. V Chapter 1 Table of contents Chapter 1 INTRODUCTION............................................................................................................... 4 1.1 Classification of epileptic seizures and epilepsies ........................................................................................ 4 1.2 Typical absence seizures .......................................................................................................................................... 7 1.2.1 Childhood absence epilepsy (CAE) ................................................................................................. 10 1.2.2 Summary ................................................................................................................................................... 14 1.3 Thalamocortical Network ..................................................................................................................................... 15 1.3.1 General features of the TC network ............................................................................................... 15 1.3.2 Electrophysiological properties of TC and NRT neurons ...................................................... 21 1.4 Experimental models of absence seizures ..................................................................................................... 31 1.4.1 Genetic models of absence seizures ............................................................................................... 32 1.4.2 Pharmacological models of absence seizures ............................................................................ 37 1.5 Mechanism of ASs: evidence from genetic and pharmacological models ....................................... 44 1.5.1 Cortex .......................................................................................................................................................... 44 1.5.2 Thalamus ................................................................................................................................................... 47 1.6 Serotonin and absence seizures ......................................................................................................................... 51 1.6.1 General aspect of the serotoninergic system ............................................................................. 51 1.6.2 5-HT receptors subtypes .................................................................................................................... 51 1.6.3 Serotonin and ASs: focus on 5-HT2 receptors ........................................................................... 61 1.7 Thesis Aims ................................................................................................................................................................... 63 Chapter 2 METHODS ........................................................................................................................ 64 2.1 Animals and ethical statement ........................................................................................................................... 64 2.2 Recovery Surgeries ................................................................................................................................................... 64 2.2.1 Anaesthesia, analgesia and post-operative care ....................................................................... 64 2.2.2 Epidural EEG electrodes implantation .......................................................................................... 66 2.2.3 Epidural EEG electrodes and microdialysis probes implantation ..................................... 66 2.2.4 Epidural EEG electrodes and thalamic silicon probe implantation .................................. 68 2.2.5 Conclusion of recovery surgeries .................................................................................................... 69 2.3 Experimental protocols for in vivo recordings ............................................................................................ 70 2.3.1 Freely-moving EEG recordings ........................................................................................................ 70 2.3.2 Freely-moving EEG recordings and reverse microdialysis .................................................. 71 2.3.3 Freely-moving EEG and thalamic silicon probe recordings ................................................. 74 VI Chapter 1 2.4 Data analysis for in vivo recordings ................................................................................................................. 77 2.4.1 Visual detection of behavioural states in the GHB-model of ASs ....................................... 77 2.4.2 Automatic detection of ASs in GAERS ............................................................................................ 77 2.4.3 ASs quantification .................................................................................................................................
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  • (12) Patent Application Publication (10) Pub. No.: US 2009/0053329 A1 Peters Et Al

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    US 2009.0053329A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0053329 A1 Peters et al. (43) Pub. Date: Feb. 26, 2009 (54) COMBINATIONS OF 5-HT2A INVERSE 61/012,771, filed on Dec. 10, 2007, provisional appli AGONSTS AND ANTAGONSTS WITH cation No. 61/026,092, filed on Feb. 4, 2008. ANTIPSYCHOTICS Publication Classification (75) Inventors: Perry Peters, San Diego, CA (US); (51) Int. Cl. David Furlano, San Diego, CA A633/00 (2006.01) (US); Daun Bahr, San Diego, CA A6II 3/445 (2006.01) (US); Daniel Van Kammen, San A 6LX 3/59 (2006.01) Diego, CA (US); Mark Brann, A6II 3/438 (2006.01) Rye, NH (US) A6IP 25/18 (2006.01) Correspondence Address: A 6LX 3L/2197 (2006.01) KNOBBE MARTENS OLSON & BEAR LLP A6II 3/54 (2006.01) 2040 MAINSTREET, FOURTEENTH FLOOR A6II 3/55 (2006.01) IRVINE, CA 92.614 (US) (52) U.S. Cl. .................... 424/722:514/329; 514/259.41: 514/278; 514/254.06; 514/222.2: 514/212.01 (73) Assignee: Acadia Pharmaceuticals, Inc., San Diego, CA (US) (57) ABSTRACT Combinations of 5-HT2A inverse agonists or antagonists (21) Appl. No.: 12/051,807 Such as pimavanserin with antipsychotics Such as risperidone are shown to induce a rapid onset of antipsychotic action and (22) Filed: Mar. 19, 2008 increase the number of responders when compared to therapy with the antipsychotic alone. These effects can be achieved at Related U.S. Application Data a low dose of the antipsychotic, thereby reducing the inci (60) Provisional application No.