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

Abstract

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-HT 6 receptor expression is present in the rat hippocampus. Further, hippocampal function has been shown to be modulated by both 5-HT 6 agonists and antagonists. In the current study, the potential involvement of 5-HT 6 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-HT 6 antagonist (SAM-531) and the 5-HT 6 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-HT 6 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-HT 6 antagonist, however, failed to potentiate theta power, which is characteristic of many pro-cognitive substances, indicating that 5-HT 6 receptors might not tonically modulate hippocampal oscillations and sleep−wake patterns.

Neurotransmitters and Memory

“…The regulation of AMPAR trafficking, focusing on the roles of several key intracellular AMPAR interacting proteins (Anggono and Huganir, 2012;see also Lynch, 2006). Lynch (2006) informs us that ampakines are a structurally diverse family of small molecules that positively modulate AMPA-type glutamate receptors, and thereby enhance fast, excitatory transmission throughout the brain. Surprisingly, ampakines have discrete effects on brain activity and behavior.…”

“…Because their excitatory synaptic targets mediate communication between cortical regions, serve as sites of memory encoding, and regulate the production of growth factors, ampakines have a broad range of potential therapeutic applications. Several of these possibilities have been tested with positive results in preclinical models; preliminary clinical work has also been encouraging (Lynch, 2006). Jane et al (2009) highlight that compared to the other glutamate receptors, progress in the understanding of the functions of kainate receptors (KARs) has lagged behind, due mainly to the relative lack of specific pharmacological tools.…”

“…The MWM alone significantly increased pERK1/2 levels and further increases were seen when treating with SB-271046 during the MWM. Ly et al (2013) had recently noted that the 5-HT 6 antagonist SAM-531, failed to potentiate theta power, which is characteristic of many procognitive substances, indicating that 5-HT 6 receptors might not tonically modulate hippocampal oscillations and sleep2wake patterns. Together this evidence offers us the following picture, which allows illustrating the useful of 5-HT systems.…”

“…Considering a genuine need to treat cognitive deficits associated with many neuropsychiatric conditions as well as an increasingly aging population; including diverse neurotransmission systems cell surface receptors and intracellular drug targets. Vincent, 1989;Lynch, 2004;Gupta et al, 2012;McGaugh, 1989;Myhrer, 2003;Sarter et al, 1992;Talpos et al, 2013;Tomi et al, 2012). Perhaps, among the more popular behavioral tasks are passive avoidance, the Morris water maze, radial maze, spontaneous alternation, and NOR.…”

“…Importantly, Stern and Alberini (2012) (see also Lynch et al, 2011) mention that in addition to pharmacological approaches, there are a number of behavioral manipulations that have been found to be effective in promoting memory enhancement. First, repetition has long been known to enhance memory performance, and it has been consistently shown that repeated training trials and/or learning events are associated with better memory.…”