Role for serotonin2A (5-HT2A) and 2C (5-HT2C) receptors in experimental absence seizures

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-HT(2)Rs) 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-HT(2A)R and 5-HT(2C)R 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-HT(2A)R and 5-HT(2C)R ligands. The 5-HT(2A) agonist TCB-2 dose-dependently decreased the total time spent in ASs, an effect that was blocked by the selective 5-HT(2A) antagonist MDL11,939. Both MDL11,939 and another selective 5-HT(2A) antagonist (M100,907) increased the length of individual seizures when injected alone. The 5-HT(2C) agonists lorcaserin and CP-809,101 dose-dependently suppressed ASs, an effect blocked by the selective 5-HT(2C) antagonist SB 242984. In summary, 5-HT(2A)Rs and 5-HT(2C)Rs negatively control the expression of experimental ASs, indicating that selective agonists at these 5-HT(2)R subtypes might be potential novel anti-absence drugs.