title: Role for serotonin2A (5-HT2A) and 2C (5-HT2C) receptors in experimental absence seizures.
abstract: Absence seizures (ASs) are the hallmark of childhood/juvenile absence epilepsy. Monotherapy with first-line anti-absence drugs only controls ASs in 50% of patients, indicating the need for novel therapeutic targets. Since serotonin family-2 receptors (5-HT2Rs) are known to modulate neuronal activity in the cortico-thalamo-cortical loop, the main network involved in AS generation, we investigated the effect of selective 5-HT2AR and 5-HT2CR ligands on ASs in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a well established polygenic rat model of these non-convulsive seizures. GAERS rats were implanted with fronto-parietal EEG electrodes under general anesthesia, and their ASs were later recorded under freely moving conditions before and after intraperitoneal administration of various 5-HT2AR and 5-HT2CR ligands. The 5-HT2A agonist TCB-2 dose-dependently decreased the total time spent in ASs, an effect that was blocked by the selective 5-HT2A antagonist MDL11,939. Both MDL11,939 and another selective 5-HT2A antagonist (M100,907) increased the length of individual seizures when injected alone. The 5-HT2C agonists lorcaserin and CP-809,101 dose-dependently suppressed ASs, an effect blocked by the selective 5-HT2C antagonist SB 242984. In summary, 5-HT2ARs and 5-HT2CRs negatively control the expression of experimental ASs, indicating that selective agonists at these 5-HT2R subtypes might be potential novel anti-absence drugs.
authors.affiliation: Neuroscience Division, School of Bioscience, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK.
authors.forename: Marcello
authors.initials: M
authors.lastname: Venzi
authors.affiliation: Neuroscience Division, School of Bioscience, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK.
authors.forename: François
authors.initials: F
authors.lastname: David
authors.affiliation: Werner Reichardt Centre for Integrative Neuroscience, Tuebingen University, Tuebingen, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Bellet
authors.affiliation: Neuroscience Division, School of Bioscience, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Cavaccini
authors.affiliation: University of Bologna, Department of Veterinary Medical Sciences, Bologna, Italy.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Bombardi
authors.affiliation: Neuroscience Division, School of Bioscience, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK; Department of Physiology and Biochemistry, University of Malta, Malta. Electronic address: crunelli@cardiff.ac.uk.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Crunelli
authors.affiliation: Neuroscience Division, School of Bioscience, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK; Department of Physiology and Biochemistry, University of Malta, Malta. Electronic address: giuseppe.digiovanni@um.edu.mt.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Giovanni
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D004832:Epilepsy, Absence / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D055647:Rats, Transgenic; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology*; D044405:Receptor, Serotonin, 5-HT2C / Q000502:physiology*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology
chemical_list: C518685:CP-809,101; D010879:Piperazines; D011719:Pyrazines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists
keywords: Absence epilepsy; EEG; Selective serotonin 2 receptor drugs