Comparison of the effects of the 5-HT3 receptor antagonists WAY-100579 and ondansetron on spatial learning in the water maze in rats with excitotoxic lesions of the forebrain cholinergic projection system

Hodges, Helen; Sowiński, P.; Turner, JP; Fletcher, Allan

doi:10.1007/bf02249414

Cited by 42 publications

(17 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Antagonism of the 5-HT 3 R has been shown to improve cognitive performance in some animal paradigms (e.g., pharmacologically induced hypocholinergic models) (Hodges et al, 1996), but not in all in vivo experimental systems tested (Pitsikas and Borsini, 1997). Using the selective, competitive 5-HT 3 R antagonist ondansetron, no improvement in recognition memory was observed in the present study.…”

Section: Discussioncontrasting

confidence: 73%

RG3487, a Novel Nicotinic α7 Receptor Partial Agonist, Improves Cognition and Sensorimotor Gating in Rodents

Wallace¹,

Callahan²,

Tehim³

et al. 2010

J Pharmacol Exp Ther

111

View full text Add to dashboard Cite

Neuronal nicotinic ␣7 acetylcholine receptors (␣7nAChRs) are expressed primarily in the brain and are implicated in modulating many cognitive functions (e.g., attention, working and episodic memory). Not surprisingly, much effort has been committed to the development of molecules acting at ␣7nAChRs as potential therapies for a variety of central nervous system diseases (e.g., Alzheimer's). N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide hydrochloride (RG3487) binds potently to the human ␣7nAChR (K i ϭ 6 nM), in which it acts as a partial agonist (63-69% of acetylcholine) as assessed by whole-cell patch-clamp recordings in both oocytes and QM7 cell lines. RG3487 activates human ␣7nAChRs with an EC 50 of 0.8 M (oocytes) and 7.7 M (QM7 cells). RG3487 also exhibits antagonist properties at the serotonin 3 receptor [IC 50 ϭ 2.8 nM (oocytes), 32.7 nM (N1E-115 cells)]. In vivo, RG3487 improved object recognition memory in rats after acute [minimally effective dose (MED) 1.0 mg/kg p.o.] or repeated (10 day) administration at brain and plasma concentrations in the low-nanomolar range. Spatial learning deficits in age-impaired rats were reversed after RG3487 administration (MED: 0.03 mg/kg i.p.) as evaluated in the Morris water maze task. In the prepulse inhibition (PPI) of startle model of sensorimotor gating, RG3487 improved apomorphine-induced deficits in PPI performance (MED: 0.03 mg/kg i.p.) and reversed phencyclidine-induced impairments in an attentional set-shifting model of executive function (MED: Յ0.03 mg/kg i.p.). Cumulative evidence from these studies indicates RG3487 is a novel and potent ␣7nAChR partial agonist that improves cognitive performance and sensorimotor gating.

show abstract

Section: Discussioncontrasting

confidence: 73%

RG3487, a Novel Nicotinic α7 Receptor Partial Agonist, Improves Cognition and Sensorimotor Gating in Rodents

Wallace¹,

Callahan²,

Tehim³

et al. 2010

J Pharmacol Exp Ther

111

View full text Add to dashboard Cite

show abstract

“…The antagonism of 5-HT3 receptors by memantine may account for, at least partially, the observed behavioral (cognitionenhancing) effects of memantine. Although it is not clear how 5-HT3 receptor antagonists offer beneficial effects to cognition, 5-HT3 receptor antagonists can improve water maze learning in aged rats (Pitsikas et al, 1993) and in rats with neurotoxic lesions of the basal forebrain (Hodges et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Memantine Improves Spatial Learning in a Transgenic Mouse Model of Alzheimer's Disease

Minkeviciene

Banerjee²,

Tanila

2004

J Pharmacol Exp Ther

169

122

View full text Add to dashboard Cite

Memantine, a low-to moderate-affinity uncompetitive N-methyl-D-aspartate receptor antagonist, has been shown to improve learning and memory in several pharmacological models of Alzheimer's disease (AD). In the present study, the effect of memantine on locomotor activity, social behavior, and spatial learning was assessed in a transgenic mouse model of AD. Eight-month-old male C57BL/6J mice carrying mutated human APP and PS1 genes (APP/PS1) and their nontransgenic (NT) litter mates were administered a therapeutic dose of memantine (30 mg/kg/day p.o.) for 2 to 3 weeks. At this age, APP/PS1 mice show elevated levels of ␤-amyloid peptides in several brain regions. APP/PS1 mice exhibited less exploratory rearing and increased aggressive behavior compared with NT mice. In the water maze test for spatial learning, APP/PS1 mice had longer escape latencies to both hidden and visible platforms, but they did not differ from NT mice in their swimming speed. Memantine significantly improved the acquisition of the water maze in APP/PS1 mice without affecting swimming speed. Memantine did not affect either locomotor activity or aggressive behavior in either genotype. These data indicate that memantine improves hippocampus-based spatial learning in a transgenic mouse model of AD without producing nonspecific effects on locomotion/exploratory activity.In the mammalian brain, NMDA receptors are involved in important physiological functions such as synaptic plasticity and synapse formation, which play important roles in memory, learning, and the formation of neural networks during development (Mayer and Westbrook, 1987). NMDA receptors are also thought to be involved in a variety of neuropathological states caused by excitotoxic neuronal injury such as ischemia, epilepsy, and several neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, and Huntington's disease). In fact, any central nervous system disorder in which neuronal loss is caused by glutamate-induced excitotoxicity has the potential to be treated by NMDA receptor antagonists. However, given the critical role of NMDA receptors in learning and memory (Morris, 1989;Tsien et al., 1996), it may appear counterintuitive that an NMDA receptor antagonist could improve the symptomatology of Alzheimer's disease (AD).Several NMDA receptor antagonists possessing high affinity for NMDA receptors [e.g., (ϩ)MK-801] have been found to cause neurobehavioral adverse effects such as hallucination and cognitive impairment (Benvenga and Spaulding, 1988;Abi-Saab et al., 1998). These adverse events have largely limited the clinical development of high-affinity NMDA receptor antagonists. An alternative approach to avoid such side effects is to produce a partial rather than complete blockade of the NMDA receptor. Partial receptor blockade can be achieved, for example, by low-affinity NMDA receptor antagonists, which typically possess a better therapeutic window than high-affinity NMDA receptor antagonists (Rogawski, 2000). Memantine, a low-to moderate-affinity NMDA r...

show abstract

“…41 Indeed, 5-HT 3 receptor antagonists facilitate cognitive processes 1 and seem to have procognitive effects during ageing. 7,42,43 The inhibitory effects of neuroleptics at 5-HT 3 receptors might contribute to the antipsychotic potential of these compounds, as 5-HT 3 receptor antagonists reduce dopaminergic neurotransmission (see, for review, Costall et al ). Indeed, first clinical investigations suggested an anxiolytic and antipsychotic potency of specific 5-HT 3 receptor antagonists.…”

Section: Discussionmentioning

confidence: 99%

Antipsychotic drugs antagonize human serotonin type 3 receptor currents in a noncompetitive manner

et al. 2004

View full text Add to dashboard Cite

The serotonin type 3 (5-HT 3 ) receptor is the only ligand-gated ion channel receptor for serotonin (5-HT). 5-HT 3 receptors play an important role in modulating the inhibitory action of dopamine in mesocorticolimbic brain regions. Neuroleptic drugs are commonly thought to exert their psychopharmacological action mainly through dopamine and serotonin type 2 (5-HT 2 ) receptors. Except for clozapine, a direct pharmacological interaction of neuroleptics with 5-HT 3 receptors has not yet been described. Using the concentration-clamp technique, we investigated the effects of flupentixol, various phenothiazines, haloperidol, clozapine and risperidone on Na þ -inward currents through 5-HT 3 receptors stably expressed in human embryonic kidney 293 cells, and through endogenous 5-HT 3 receptors of murine N1E-115 neuroblastoma cells. In addition, we studied their effects on Ca 2 þ influx, measured as a change in intracellular Ca 2 þ concentrations ([Ca 2 þ ] i ). All neuroleptic drugs, but not risperidone, antagonized Na þ -and Ca 2 þ -inward currents evoked by 5-HT (10 lM for 2 s and 1 lM, respectively) in a voltage-independent manner. Only clozapine was a competitive antagonist, while all other compounds turned out to be noncompetitive. Fluphenazine and haloperidol affected membrane anisotropy at concentrations below their IC 50 values, indicating that a change in membrane anisotropy might contribute to their antagonistic effect at the 5-HT 3 receptor. Only structure analogues of flupentixol and fluphenazine with a lipophilic side chain were potent antagonists against 5-HT-evoked Na þ and Ca 2 þ currents. Since 5-HT 3 receptors modulate mesolimbic and mesocortical dopaminergic activity, the functional antagonism of neuroleptics at 5-HT 3 receptors may contribute to their antipsychotic efficacy and may constitute a not yet recognized pharmacological principle of these drugs.

show abstract

Comparison of the effects of the 5-HT3 receptor antagonists WAY-100579 and ondansetron on spatial learning in the water maze in rats with excitotoxic lesions of the forebrain cholinergic projection system

Cited by 42 publications

References 48 publications

RG3487, a Novel Nicotinic α7 Receptor Partial Agonist, Improves Cognition and Sensorimotor Gating in Rodents

RG3487, a Novel Nicotinic α7 Receptor Partial Agonist, Improves Cognition and Sensorimotor Gating in Rodents

Memantine Improves Spatial Learning in a Transgenic Mouse Model of Alzheimer's Disease

Antipsychotic drugs antagonize human serotonin type 3 receptor currents in a noncompetitive manner

Contact Info

Product

Resources

About