The 5-HT6 Receptor Antagonist SB-271046 Selectively Enhances Excitatory Neurotransmission in the Rat Frontal Cortex and Hippocampus

Abstract

Preclinical evidence has suggested a possible role for the 5-HTThe 5-hydroxytryptamine (5-HT, serotonin) receptor superfamily currently consists of 14 members divided into seven classes (5-HT 1-7 ) according to structural and functional homologies (for review see Barnes and Sharp 1999). One of the most recently identified of these is the 5-HT 6 receptor. Initially cloned from rat striatum (Monsma et al. 1993;Ruat et al. 1993), the 5-HT 6 receptor, like 5-HT 4 and 5-HT 7 , is a G protein-linked receptor, which stimulates adenylate cyclase via G s -coupling. In situ hybridization and Northern blot studies have revealed that 5-HT 6 receptor mRNA appears to be almost exclusively expressed within the brain (Monsma et al. 1993;Ruat et al. 1993;Ward et al. 1995). Regional analysis of expression reveals that the highest levels of mRNA are found within the olfactory tubercle, striatum, nucleus accumbens, cerebral cortex and subfields of the hippocampus (Monsma et

The Selective 5-HT6 Receptor Antagonist Ro4368554 Restores Memory Performance in Cholinergic and Serotonergic Models of Memory Deficiency in the Rat

“…Since long-term potentiation is assumed to represent a physiological model for learning and memory (Lynch, 2004), this might be a potential mechanism underlying cognitive deficits in a TRP deficiency model. As mentioned earlier, 5-HT 6 antagonists seem to increase excitatory neurotransmission (Dawson et al, 2001). Consequently, if the effects of TRP depletion were mediated via a nitric oxide mechanism, the effects of Ro4368554 in the TRP depletion model might be mediated via the nitric oxide-glutamatergic pathway.…”

“…However, microdialysis experiments showed that 5-HT 6 antagonism did not change 5-HT levels in various brain areas (Dawson et al, 2001;Lacroix et al, 2004). At least two possible alternative explanations can be offered to explain the effects of Ro4368554 in the TRP model.…”

“…Although the effects seem to involve a cholinergic mechanism, microdialysis studies have shown that the 5-HT 6 antagonist SB-271046 increases levels of glutamate and aspartate in the frontal cortex and hippocampus (Dawson et al, 2001). It was suggested that this effect may be mediated via an indirect effect of blockade of 5-HT 6 receptors on GABAergic interneurons (see also Woolley et al, 2004).…”

Reversal of Subchronic PCP-Induced Deficits in Attentional Set Shifting in Rats by Sertindole and a 5-HT6 Receptor Antagonist: Comparison Among Antipsychotics

“…Combined 5-HT 2A /DA D 2 antagonism can increase extracellular levels of DA and acetylcholine in frontal cortex (Liegeois et al, 2002); whereas, 5-HT 6 receptor antagonists also increase levels of glutamate (Dawson et al, 2001;Lacroix et al, 2004;Mitchell and Neumaier, 2005;Li et al, 2007) as well as DA and norepinephrine (Lacroix et al, 2004) in the frontal cortex without impacting 5-HT transmission. Sertindole and SB271046, but not risperidone, were recently found to significantly increase extracellular glutamate and acetylcholine in the frontal cortex (Mork et al, 2007).…”

A preliminary investigation into the effects of antipsychotics on sub-chronic phencyclidine-induced deficits in attentional set-shifting in female rats

“…Clozapine has affinity at a wide range of receptors including 5-HT 6 receptors. A selective 5-HT 6 receptor antagonist has been shown to improve set-shifting ability [26], this may be via facilitation of cortical and hippocampal glutamatergic activity [12].…”