Activation of 5-HT6 Receptors Modulates Sleep-Wake Activity and Hippocampal Theta Oscillation

The modulatory role of 5-HT neurons and a number of different 5-HT receptor subtypes has been well documented in the regulation of sleep-wake cycles and hippocampal activity. A high level of 5-HT6 receptor expression is present in the rat hippocampus. Further, hippocampal function has been shown to be modulated by both 5-HT6 agonists and antagonists. In the current study, the potential involvement of 5-HT6 receptors in the control of hippocampal theta rhythms and sleep-wake cycles has been investigated. Hippocampal activity was recorded by intracranial hippocampal electrodes both in anesthetized (n = 22) and in freely moving rats (n = 9). Theta rhythm was monitored in different sleep-wake states in freely moving rats and was elicited by stimulation of the brainstem reticular formation under anesthesia. Changes in theta frequency and power were analyzed before and after injection of the 5-HT6 antagonist (SAM-531) and the 5-HT6 agonist (EMD386088). In freely moving rats, EMD386088 suppressed sleep for several hours and significantly decreased theta peak frequency, while, in anesthetized rats, EMD386088 had no effect on theta power but significantly decreased theta frequency, which could be blocked by coadministration of SAM-531. SAM-531 alone did not change sleep-wake patterns and had no effect on theta parameters in both unanesthetized and anesthetized rats. Decreases in theta frequency induced by the 5-HT6 receptor agonist correspond to previously described electrophysiological patterns shared by all anxiolytic drugs, and it is in line with its behavioral anxiolytic profile. The 5-HT6 antagonist, however, failed to potentiate theta power, which is characteristic of many pro-cognitive substances, indicating that 5-HT6 receptors might not tonically modulate hippocampal oscillations and sleep-wake patterns.