Selective 5-HT1A Antagonists WAY 100635 and NAD-299 Attenuate the Impairment of Passive Avoidance Caused by Scopolamine in the Rat

Abstract

Systemic administration of the muscarinic-receptor antagonists atropine and scopolamine produces cognitive deficits in humans, nonhuman primates and rodents. In humans, these deficits resemble symptoms of dementia seen in Alzheimer's disease. The passive avoidance (PA) task has been one of the most frequently used animal models for studying cholinergic mechanisms in learning and memory. The present study examined the ability of two selective 5-HT 1A receptor antagonists WAY 100635 and NAD-299 (robalzotan) and two acetylcholinesterase (AChE) inhibitors tacrine and donepezil to attenuate the impairment of PA retention caused by the nonselective muscarinic receptor antagonist scopolamine in the rat. Although demonstrating differences in their temporal kinetics, both WAY 100635 and NAD-299 attenuated the impairment of PA caused by scopolamine (0.3 mg/kg s.c.). Donepezil did not block the PA deficit caused by the 0.3 mg/kg dose of scopolamine, but it prevented the inhibitory effects of the 0.2 mg/kg dose of scopolamine. In contrast, tacrine was effective vs both the 0.2 and 0.3 mg/kg doses of scopolamine. These results indicate that (1) a functional 5-HT 1A receptor antagonism can attenuate the anterograde amnesia produced by muscarinic-receptor blockade, and (2) the AChE inhibitors tacrine and donepezil differ in their ability to modify muscarinic-receptor-mediated function in vivo. These results suggest that 5-HT 1A receptor antagonists may have a potential in the treatment of cognitive symptoms in psychopathologies characterized by reduced ACh transmission such as Alzheimer's disease.

Analysis of the Role of the 5-HT1B Receptor in Spatial and Aversive Learning in the Rat

“…This contrasts with the WM task, in which young, unimpaired rats acquire the task very rapidly, making it difficult to demonstrate druginduced facilitation of performance. This conclusion is also supported by the failure of acetylcholinesterase inhibitors such as donepezil to facilitate WM acquisition and retention in young, unimpaired rats, while a facilitatory effect on memory retention is observed in the PA task (Misane and Ö gren, 2003;Rogers and Hagan, 2001;Van der Staay et al, 1996). Acetylcholinesterase inhibitors are usually able to attenuate memory deficits induced pharmacologically, for example by scopolamine, in the WM and PA tasks (Braida et al, 1996;Cheng et al, 1996;Misane and Ö gren, 2003).…”

“…This indicates that the facilitatory effects of NAS-181 on PA retention may involve enhancement of cholinergic transmission. Unlike the effects of acetylcholinesterase inhibitors (Braida et al, 1996;Cheng et al, 1996;Misane and Ö gren, 2003), the effects of 5-HT 1B receptor blockade on cholinergic transmission does not appear to be sufficient to attenuate the deficit induced by a high dose of scopolamine in the PA task. The conclusion based on the studies with a subthreshold dose of scopolamine, that the facilitatory effects of NAS-181 in the PA task is mediated by enhanced cholinergic transmission, is supported by recent microdialysis results.…”

“…It also seems likely that performance in the two learning tasks is differentially regulated neurochemically, as indicated by studies with acetylcholinesterase inhibitors. Recent results with the selective 5-HT 1A antagonist, robalzotan, suggest that an increase of extracellular acetylcholine with about 200% in the hippocampus is sufficient to enhance PA retention but not WM performance in young, unimpaired rats (Misane and Ö gren, 2003). There are also possible differences in the degree of tonic stimulation of the 5-HT 1B receptor in different brain areas that might contribute to the differential effects of NAS-181 on PA and WM performance.…”

The scopolamine-reversal paradigm in rats and monkeys: the importance of computer-assisted operant-conditioning memory tasks for screening drug candidates

“…More recent studies with the currently prescribed AD drugs rivastigmine, donepezil, and galantamine have reported similar scopolamine-reversal properties in the rat (Bejar et al 1999;Takahata et al 2005;van der Staay and Bouger 2005;de Bruin and Pouzet 2006;Lindner et al 2006). However, cholinomimetic drugs are not the only pharmacological class to reverse scopolamine-induced memory deficits (Misane and Ogren 2003;Van Kampen et al 2004;Lieben et al 2005) attesting perhaps to the greater than expected versatility of the model.…”

Big Dynorphin, a Prodynorphin-Derived Peptide Produces NMDA Receptor-Mediated Effects on Memory, Anxiolytic-Like and Locomotor Behavior in Mice

“…PA is an aversive learning task based on classical (Pavlovian) fear conditioning that allows analysis of both facilitation and impairment of memory function (Bammer, 1982;Misane and Ogren, 2003). PA testing was performed during the light cycle between 1000 and 1300.…”