SummaryAimsSubstantial evidence indicates that 5‐HT2Creceptors are involved in the control of neuronal network excitability and in seizure pathophysiology. Here, we have addressed the relatively unexplored relationship between temporal lobe epilepsy (TLE), the most frequent type of intractable epilepsy, and 5‐HT2CRs.MethodsIn this study, we investigated this issue using a model of partial complex (limbic) seizures in urethane‐anesthetized rat, based on the phenomenon of maximal dentate activation (MDA) using 5‐HT2Ccompounds, electrophysiology, immunohistochemistry, and western blotting techniques.ResultsThe 5‐HT2CagonistsmCPP(1 mg/kg, i.p) and lorcaserin (3 mg/kg, i.p), but not RO60‐0175 (1–3 mg/kg i.p.), were antiepileptogenic reducing the MDA response duration. The selective 5‐HT2Cantagonist SB242084 (2 mg/kg, i.p) unveiled antiepileptogenic effects of RO60‐0175 (3 mg/kg, i.p) but did not alter those induced bymCPPand lorcaserin. Compared with control rats, electrically stimulated rats showed an increase in glutamic acid decarboxylase levels and a heterogeneous decrease in 5‐HT2CR immunoreactivity in different hippocampal areas.ConclusionsIn our animal model of TLE,mCPPand lorcaserin were anticonvulsant; likely acting on receptor subtypes other than 5‐HT2C. Epileptogenesis induced early adaptive changes and reorganization in the 5‐HT2CR and GABA systems.