Influence of the 5-HT<sub>6</sub>Receptor on Acetylcholine Release in the Cortex:  Pharmacological Characterization of 4-(2-Bromo-6-pyrrolidin-1-ylpyridine-4-sulfonyl)phenylamine, a Potent and Selective 5-HT<sub>6</sub>Receptor Antagonist

133

Antagonists at serotonin type 6 (5-HT 6 ) receptors show activity in models of learning and memory. Although the underlying mechanism(s) are not well understood, these effects may involve an increase in acetylcholine (ACh) levels. The present study sought to characterize the cognitive-enhancing effects of the 5-HT 6 antagonist Ro4368554 (3-benzenesulfonyl-7-(4-methyl-piperazin-1-yl)1H-indole) in a rat object recognition task employing a cholinergic (scopolamine pretreatment) and a serotonergic-(tryptophan (TRP) depletion) deficient model, and compared its pattern of action with that of the acetylcholinesterase inhibitor metrifonate. Initial testing in a time-dependent forgetting task employing a 24-h delay between training and testing showed that metrifonate improved object recognition (at 10 and 30 mg/kg, p.o.), whereas Ro4368554 was inactive. Both, Ro4368554 (3 and 10 mg/kg, intraperitoneally (i.p.)) and metrifonate (10 mg/kg, p.o., respectively) reversed memory deficits induced by scopolamine and TRP depletion (10 mg/kg, i.p., and 3 mg/kg, p.o., respectively). In conclusion, although Ro4368554 did not improve a time-related retention deficit, it reversed a cholinergic and a serotonergic memory deficit, suggesting that both mechanisms may be involved in the facilitation of object memory by Ro4368554 and, possibly, other 5-HT 6 receptor antagonists.

Section: Neurochemical Mechanisms Involved In the Effects Of 5-ht 6 Asupporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

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

Lieben

Blokland

Şık

et al. 2005

133

“…With regard to cognition, rats acutely treated with 5-HT 6 R antagonists demonstrated improved spatial memory retention 1 week after Morris maze training (Woolley et al, 2001;Stean et al, 2002). 5-HT 6 R antagonists also enhanced acquisition and reversed a scopolamine-evoked deficit in rat operant autoshaping and passive avoidance tasks (Bos et al, 2001;Meneses, 2001;Riemer et al, 2003). Pretreatment with a 5-HT 6 R antagonist also improved rat performance of an attentional set-shifting task, a rodent analog of the Wisconsin card sorting test, a commonly used assay of cognitive-guided sorting (Hatcher et al, 2005).…”

Section: -Ht 6 R-influenced Behaviorsmentioning

confidence: 99%

“…Thus, the expression pattern and pharmacological properties of Rs indicate that they may contribute to serotonergic modulation of clinically relevant neuropsychological processes and psychopharmacological responses. Administration of 5-HT 6 R antagonists and antisense oligonucleotides have been reported to produce several behavioral effects in rodents, including feeding suppression (Svartengren et al, 2004), yawning and stretching (Bourson et al, 1995;Sleight et al, 1996;Sleight et al, 1998;Bentley et al, 1999), decreased anxiety-related behaviors (Hamon et al, 1999), and improved performance in learning and memory tasks (Meneses, 2001;Rogers and Hagan, 2001;Woolley et al, 2001;Russell and Dias, 2002;Lindner et al, 2003;Riemer et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

A Null Mutation of the Serotonin 6 Receptor Alters Acute Responses to Ethanol

Bonasera

Chu

Brennan

et al. 2006

The anatomical distribution and pharmacology of serotonin 6 receptors (5-HT 6 Rs) implicate them as contributors to the serotonergic regulation of complex behavior. To complement the limited range of pharmacological tools available to examine 5-HT 6 R function, we have generated a mouse line bearing a constitutive null mutation of the 5-HT 6 R gene. No perturbations of baseline behavior were noted in a wide array of assays pertinent to multiple neurobehavioral processes. However, 5-HT 6 R mutant mice demonstrated reduced responses to the ataxic and sedative effects of ethanol. No differences in ethanol metabolism were evident between wild-type and 5-HT 6 R mutant mice. These findings implicate 5-HT 6 Rs in the serotonergic modulation of responses to ethanol.

“…The mechanism of enhanced consolidation is not completely understood; however, microdialysis studies have shown that 5-HT 6 inhibition increases acetylcholine and glutamate release in the cortex and hippocampus (Dawson et al, 2001;Riemer et al, 2003). Although a number of different antagonists have been tested, 5-HT 6 receptor activation in learning has not been investigated, and the anatomical basis for 5-HT 6 receptor effects on memory and learning have not been examined.…”

Section: Introductionmentioning

confidence: 99%

Increased Expression of 5-HT6 Receptors in the Rat Dorsomedial Striatum Impairs Instrumental Learning

Mitchell

Sexton

Neumaier

2006

A number of studies have shown that systemic 5-HT 6 receptor antagonists can improve learning and memory, but the mechanism for these observations is not known. As striatum normally expresses 5-HT 6 receptors abundantly and is important in consolidating stimulusresponse learning, we used targeted gene delivery to further increase the expression of 5-HT 6 receptors in rat striatum and then examined learning. Increased 5-HT 6 expression had no effect on performance in the Morris water maze, a hippocampal-dependent learning paradigm, and did not alter the latency to approach or consume sucrose tablets. However, rats with increased 5-HT 6 expression failed to acquire a reward-based instrumental learning task, a striatum-dependent learning model, during 3 days of successive sessions as compared to sham surgery or GFP-expressing control rats. This behavioral deficit was observed in rats overexpressing 5-HT 6 receptors in the dorsomedial striatum, but not in rats with increased dorsocentral striatal expression. The 5-HT 6 receptor-associated deficit was reversed by administration of a 5-HT 6 antagonist, SB-258585, before each training session. When animals learned the instrumental learning task before gene transfer, increased 5-HT 6 receptor expression had no effect on long-term recall or performance of the task or on extinction of operant responding. Thus, 5-HT 6 receptor activity in rat striatum disrupts acquisition of new instrumental learning but does not impair memory or performance of reward-motivated behavior once established.