Role of serotonin in epilepsy : focus on 5-HT2 receptors

Abstract

Studies in experimental models have showed a potential role for serotonergic transmission in epilepsy, suggesting serotonin receptors (5-HTRs) as promising candidates as a target for new antiepileptic drugs. Indeed, 5-HT is known to regulate a wide variety of focal and generalized seizures, including absence epilepsy both in human and in animal models. In particular, agents that elevate extracellular 5-HT levels, such as 5-hydroxytryptophan and 5-HT reuptake blockers, inhibit both focal (limbic) and generalized seizures. Conversely, depletion of brain 5-HT lowers the threshold to audiogenically, chemically and electrically evoked convulsions. More recently, increased threshold to kainic acid-induced seizures was observed in mice with genetically increased 5-HT levels. The serotonergic system is very complex and several receptor subtypes may be relevant to epilepsy. At least 14 distinct G protein-coupled 5-HTR and one ligand-gated ion channel receptor (5-HT3) are divided into seven distinct classes (5-HT1 to 5-HT7). 5-HT2A/2CRs are the major focus of this talk. Early findings showing that mice lacking the 5-HT2CR are extremely susceptible to audiogenic seizures and are prone to spontaneous death from seizures will be presented together with new experimental evidence in different animal models of epilepsy. Thus, serotonergic neurotransmission mediated by 5-HT2CR subtype suppresses neuronal network hyperexcitability and seizure activity.