Serotonergic 5-HT2C Receptors as a Potential Therapeutic Target for the Design Antiepileptic Drugs

A variety of clinical observations suggest that certain forms of epilepsy are due to long-term, progressive changes in neural networks that eventually provoke spontaneous and recurring seizures. Recently, there has been growing evidence that serotonergic neurotransmission modulates experimentally induced seizures and is involved in the enhanced seizure susceptibility observed in some genetically epilepsy-prone animals. Generally, agents that elevate extracellular serotonin (5-Hydroxytryptamine, 5-HT) levels, such as 5-hydroxytryptophan, and 5-HT reuptake blockers inhibit both limbic and generalized seizures. Conversely, depletion of brain 5-HT lowers the threshold to audiogenically, chemically and electrically-evoked convulsions. More specifically, the recent finding that the 5-HT2B/2C receptor agonist, 1-(m-chlorophenyl)-piperazine (mCPP) is anticonvulsant has kindled an interest into the investigation of the serotonergic 5-HT2C receptor subtype as a potential target for the treatment of epilepsy. Further pharmacological evaluation of selective activation or inactivation of the 5-HT2C receptor subtype with selective agonist/positive modulators and antagonists will provide important information about the therapeutic contribution of this receptor to the epileptic circuitry in the brain. Future development of serotonergic antiepileptic drugs will be a significant addition to the therapeutic armamentarium against epilepsy.