Control of hippocampal theta rhythm by serotonin: Role of 5-HT2c receptors

The hippocampus plays an important role in learning and memory and has been implicated in a number of diseases, including epilepsy, anxiety and schizophrenia. A prominent feature of the hippocampal network is the capability to generate rhythmic oscillations. Serotonergic modulation is known to play an important role in the regulation of theta rhythm. 5-HT2c receptors represent a specific target of psychopharmacology and, in particular, the behavioral effects of the 5-HT2c receptor agonist mCPP have been thoroughly tested. The present study used this compound and the selective 5-HT2c receptor antagonist SB-242084 to elucidate the role of 5-HT2c receptors in the generation of hippocampal oscillations. Hippocampal EEG was recorded and the power in the theta frequency range was monitored in different behaviors in freely-moving rats and after brainstem stimulation in anesthetized animals. We found that in freely-moving rats, mCPP suppressed hippocampal theta rhythm and the effect was stronger during REM sleep than during waking theta states. Under urethane anesthesia, mCPP decreased the power for both spontaneous and elicited theta rhythm in a dose-dependent manner and the 5-HT2c antagonist reversed this effect. The results of this study demonstrate that 5-HT2c receptors are important element of the serotonergic modulation of hippocampal theta oscillations and thus pharmacological interactions with these receptors can modulate physiological and pathological processes associated with limbic theta activity. ⺠5-HT2cR agonist suppresses limbic theta rhythm in waking and REM sleep (by 20%, 57%). ⺠mCPP also suppressed brainstem stimulation-elicited theta rhythm under anesthesia (62%). ⺠The effect was dose-dependent and was antagonized with 5-HT2cR antagonist, SB-242084. ⺠Thus, serotonin modulation of theta activity involves 5-ht2c receptor mechanism. ⺠Drugs acting on 5-HT2cR may affect theta-associated pathological processes of cognition.