Comparison of the effects of four cholinomimetic agents on cognition in primates following disruption by scopolamine or by lists of objects

Abstract

The ability of four central cholinomimetics to reverse a scopolamine-induced spatial memory impairment or to improve visual recognition memory in primates was examined. Physostigmine (0.04-0.08 mg/kg IM) fully reversed the effects of scopolamine (0.03 mg/kg). Coadministration of pilocarpine (3.0-5.0 mg/kg) caused partial reversal of the scopolamine impairment after intermediate or long retention intervals (10 or 20 s). Treatment with arecoline (0.1-1.8 mg/kg) or nicotine (1.0-2.0 mg/kg) generally did not reverse the effects of scopolamine. A task in which memory could be taxed by increasing the number of visual stimuli presented appeared more sensitive to the effects of cholinomimetics on cognition than the scopolamine reversal model. In this paradigm treatment with physostigmine (0.001, 0.01 or 0.03 mg/kg) increased choice accuracy from about 55 to 70% correct. Arecoline improved performance at one dose only (0.1 mg/kg) which also induced marked adverse side-effects (salivation and tremor). Pilocarpine improved performance in the dose range 0.125-0.35 mg/kg, but not at higher doses which also induced marked salivation. Treatment with nicotine (0.001-2.0 mg/kg tended to improve performance but this did not reach statistical significance. The relevance of these findings for studies in man and for animal models of dementia is discussed.

Muscarinic and Nicotinic Acetylcholine Receptor Agonists and Allosteric Modulators for the Treatment of Schizophrenia

“…Early validation came from extensive preclinical and clinical studies with non-selective mAChR ligands. Non-selective mAChR antagonists (eg, scopolamine) robustly impaired multiple cognitive functions, such as sensory information processing, attention, learning, working and short-term memory, and executive tasks, whereas direct-and indirectacting (eg, AChEIs) mAChR agonists enhanced aspects of normal cognition and/or reversed cognitive impairments induced by mAChR antagonists or cholinergic circuit lesions (Aigner and Mishkin, 1986;Rusted and Warburton, 1988;Rupniak et al, 1989;Matsuoka et al, 1991;Decker and Majchrzak, 1992). Moreover, mAChR antagonists induced psychotic-like symptoms and cognitive impairments in healthy subjects and/or exacerbated existing positive and cognitive symptomatology in schizophrenic patients (Osterholm and Camoriano, 1982;Hamborg-Petersen et al, 1984;Tandon et al, 1991).…”

“…For example, mAChR and nAChR antagonists, such as scopolamine and mecamylamine, have shown potent amnesiac properties in animals and humans (Domer and Schuller, 1960;Pazzagli and Pepeu, 1965;Rusted and Warburton, 1988;Decker and Majchrzak, 1992;Newhouse et al, 1992Newhouse et al, , 1994Terry et al, 1996), whereas mAChR and nAChR agonists and acetylcholinesterase inhibitors (AChEIs) have augmented normal cognition and/or ameliorated impairments induced by lesions of cholinergic circuitry or antagonism of cholinergic receptors (Aigner and Mishkin, 1986;Elrod et al, 1988;Rupniak et al, 1989;Matsuoka et al, 1991;Levin et al, 1998Levin et al, , 2006Newhouse et al, 2004;Sarter et al, 2009). Furthermore, mAChR and nAChR antagonists have exacerbated existing positive and cognitive symptoms in schizophrenic patients and/or induced psychosis in normal human volunteers (Harington and Kincaid-Smith, 1958;Osterholm and Camoriano, 1982;Hamborg-Petersen et al, 1984;Tandon et al, 1991), whereas mAChR and nAChR agonists and AChEIs have improved certain aspects of the positive and/or negative symptoms, and attentional and memoryrelated deficits (Janowsky et al, 1973;Smith et al, 2006;Harris et al, 2004;Edelstein et al, 1981;Kirrane et al, 2001;Shekhar et al, 2008).…”

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

“…Systemic administration of the nonselective muscarinic receptor antagonists atropine and scopolamine causes cognitive deficits in humans (Christensen et al, 1992;Ebert and Kirch, 1998;Wesnes et al, 1991), nonhuman primates (Rupniak et al, 1989) and rodents (Patel and Tariot, 1991;Sunderland et al, 1986). In human volunteers, the pattern of cognitive impairment caused by scopolamine mimics in some aspects the cognitive symptomology seen in Alzheimer's disease (AD) (Ebert and Kirch, 1998) which is associated with the degeneration of cholinergic neurons in the basal forebrain resulting in a reduction of cholinergic neurotransmission in the forebrain (Araujo et al, 1988;DeKosky et al, 1996;Kuhl et al, 1999;Shinotoh et al, 2000;Shiozaki et al, 1999;Whitehouse et al, 1982).…”

Ameliorating effect of lyophilized extract ofButea frondosaleaves on scopolamine-induced amnesia in rats

“…Scopolamine, a muscarinic antagonist, induces central cholinergic blockade and produces a reversible impairment of learning and memory. Moreover, the cognitive impairment produced following scopolamine administration resembles the memory impairment seen in AD (Rupniak et al, 1989).…”