Attenuation in rats of impairments of memory by scopolamine, a muscarinic receptor antagonist, by mecamylamine, a nicotinic receptor antagonist

Abstract

Rationale Scopolamine, a muscarinic antagonist, impairs learning and memory for many tasks, supporting an important role for the cholinergic system in these cognitive functions. The findings are most often interpreted to indicate that a decrease in postsynaptic muscarinic receptor activation mediates the memory impairments. However, scopolamine also results in increased release of acetylcholine in the brain as a result of blocking presynaptic muscarinic receptors. Objectives The present experiments assess whether scopolamine-induced increases in acetylcholine release may impair memory by overstimulating postsynaptic cholinergic nicotinic receptors, i.e., by reaching the high end of a nicotinic receptor activation inverted-U dose-response function. Results Rats tested in a spontaneous alternation task showed dose-dependent working memory deficits with systemic injections of mecamylamine and scopolamine. When an amnestic dose of scopolamine (0.15 mg/kg) was co-administered with a subamnestic dose of mecamylamine (0.25 mg/kg), this dose of mecamylamine significantly attenuated the scopolamine-induced memory impairments. We next assessed the levels of acetylcholine release in the hippocampus in the presence of scopolamine and mecamylamine. Mecamylamine injections resulted in decreased release of acetylcholine, while scopolamine administration caused a large increase in acetylcholine release. Conclusions These findings indicate that a nicotinic antagonist can attenuate impairments in memory produced by a muscarinic antagonist. The nicotinic antagonist may block excessive activation of nicotinic receptors postsynaptically or attenuate increases in acetylcholine release presynaptically. Either effect of a nicotinic antagonist—to decrease scopolamine-induced increases in acetylcholine output or to decrease post-synaptic acetylcholine receptor activation—may mediate the negative effects on memory of muscarinic antagonists.

Striatal cholinergic interneurons regulate cognitive and affective dysfunction in partially dopamine‐depleted mice

“…The lack of selectivity of pharmacological compounds makes the interpretation of mechanism of action unclear. Newman and Gold () showed that the cholinergic tone that is too low or too high is related to poor cognitive functions, depending on the task. In their study, scopolamine alters memory processes by acting on postsynaptic mAChRs.…”

“…In their study, scopolamine alters memory processes by acting on postsynaptic mAChRs. But it also acts on presynaptic M2 mAChRs, thus increasing the release of ACh, and accordingly improves memory processes (Newman & Gold, ). In the present study, the lack of effect of telenzepine in reversing spatial memory impairment (in comparison with social memory recognition) could result from these puzzling effects.…”

Scopolamine Impairs Appetitive But Not Aversive Trace Conditioning: Role of the Medial Prefrontal Cortex

“…However, we submit that this role is likely supported by a wider network of distributed mechanisms (Sarter et al, 2005; Egorov et al, 2006; Esclassan et al, 2009; Hasselmo and Sarter, 2011; Baysinger et al, 2012), including cholinergic projections to perirhinal cortex (Bang and Brown, 2009) and the septohippocampal system (Givens and Olton, 1995; Seeger at al., 2004; Raybuck and Gould, 2010; Newman and Gold, 2016). …”

Deciphering the scopolamine challenge rat model by preclinical functional MRI

“…An important aspect of the “SCO challenge” model is, that it could also result in an increased release of acetylcholine in the brain by blocking presynaptic muscarinic receptors. This, through the excessive activation of nicotinic receptors, may also mediate the negative effects of SCO on memory [27].…”