Acquisition, Retention, and Recall of Memory After Injection of RS67333, a 5-HT4 Receptor Agonist, Into the Nucleus Basalis Magnocellularis of the Rat

Abstract

The serotonin 5-HT4 subtype receptor is predominantly localized into anatomical structures linked to memory and cognition. A few experimental studies report that the acute systemic administration of selective 5-HT4 agonists has ameliorative effects on memory performance, and that these effects are reversed by contemporary administration of 5-HT4 receptor antagonists. To verify whether this procognitive action occurs via the activation of the cholinergic nucleus basalis magnocellularis (NBM)-cortical pathways, we examined the effects of RS67333, a selective partial agonist of the 5-HT4 receptor, on rat performance in a place recognition task upon local administration of the drug into the NBM area. The intra-NBM administration of RS67333 enhances the acquisition (200-500 ng/0.5 µL) and the consolidation (40-200 ng/0.5 µL) of the place recognition memory. These effects are reversed by pretreatment with the selective 5-HT4 receptor antagonist RS39604 (300 ng/0.5µL). Conversely, the recall of memory is not affected by the 5-HT4 agonist. Our results indicate that 5-HT4 receptors located within the NBM may play a role in spatial memory and that the procognitive effect of RS67333 is due, at least in part, to the potentiation of the activity of cholinergic NBM-cortical pathways.The putative role of the serotonergic system in memory improvement or recovery from impaired cognitive performance has received considerable attention over the last years. In this context, radioligand binding and autoradiography studies performed in different animal species revealed that the serotonin 5-HT4 subtype receptor, a G-protein-coupled receptor activating the adenylate cyclase system, is predominantly localized in anatomical structures linked to memory and cognition (Eglen et al. 1995b;Waeber et al. 1996). In addition, direct evidence of the physiological relevance of 5-HT4 subtype receptors in learning and memory processes has been reported by several authors (Fontana et

The Promnesic Effect of G-protein-Coupled 5-HT4 Receptors Activation Is Mediated by a Potentiation of Learning-Induced Spine Growth in the Mouse Hippocampus

“…The 5-HT 4 Rs specificity of this effect is confirmed by the fact that injecting the 5-HT 4 antagonist RS39604 prior to SL65.0155 prevented the increase in performance and the potentiation of learning-induced spines, with mice receiving the two compounds or the double injection of saline showing comparable levels of performance and of dendritic spines. The lack of effect of the 5-HT 4 antagonist on discrimination performance is consistent with previous studies showing that RS39604 did not affect the performance of rats in a place recognition task (Orsetti et al, 2003) nor interfered with basal synaptic transmission, LTP, or depotentiation in rat hippocampal slices (Kulla and Manahan-Vaughan, 2002). These findings support the view that the increment in OTM performance does not crucially depend on the endogenous activity of serotonin but, rather, on 5-HT 4 Rs activation enhancing excitability in central nervous system neurons (Dumuis et al, 1988;Torres et al, 1996).…”

Kinetic Modeling of 11C-SB207145 Binding to 5-HT4 Receptors in the Human Brain In Vivo

“…We estimated 2 different binding potentials (BP ND 5 V T /V ND -1 and BP P 5 V T 2 V ND, V T and V ND being the distribution volumes in the target and in the reference regions, respectively) (25) using the 1-and 2-tissue-compartment models with blood volume fixed at 0.05 mL/ cm 3 . As a noninvasive reference tissue method, we explored SRTM (26) to derive estimates of BP ND .…”

“…Theserot onin 4 receptor (5-HT 4 receptor) is a G-proteincoupled serotonin receptor with its highest cerebral density in the basal ganglia and medium density in the hippocampus (1). Animal studies have found 5-HT 4 partial agonists to have procognitive and memory-enhancing effects (2)(3)(4), possibly mediated by a modulation of other neurotransmitter systems (5) such as the dopaminergic (6), GABAergic (7), and acetylcholinergic systems. Thus, 5-HT 4 agonists are shown to facilitate at least in part the release of the neurotransmitter acetylcholine in the frontal cortex (8) and hippocampus (2).…”

Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment

“…With respect to the potential therapeutic modulation of 5-HT 4 R with RS67333 and excluding its putative antidepressant-like activity (2-4), most studies focused on the promnesic or antiamnesic actions of this compound. These effects on cognitive functions that concern learning and memory are probably, in part, because of the fact that the pharmacological stimulation of these receptors increases the release of ACh in the hippocampus and cortex, and it also increases serotonin, dopamine, and GABA release (5)(6)(7)(8)(9)(10)(11)(12)(13). Concerning the selective aspects of memory functions, RS67333 has been shown to improve object recognition in adult (14,15) and aged animals (16,17) and place recognition (10) in rodents.…”