The Selective M₁ Muscarinic Cholinergic Agonist CDD-0102A Enhances Working Memory and Cognitive Flexibility

Abstract

Various neurodegenerative diseases and psychiatric disorders are marked by alterations in brain cholinergic function and cognitive deficits. Efforts to alleviate such deficits have been limited by a lack of selective M 1 muscarinic agonists. 5-(3-Ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine hydrochloride (CDD-0102A) is a partial agonist at M 1 muscarinic receptors with limited activity at other muscarinic receptor subtypes. The present studies investigated the effects of CDD-0102A on working memory and strategy shifting in rats. CDD-0102A administered intraperitoneally 30 min before testing at 0.1, 0.3, and 1 mg/kg significantly enhanced delayed spontaneous alternation performance in a four-arm cross maze, suggesting improvement in working memory. In separate experiments, CDD-0102A had potent enhancing effects on learning and switching between a place and visual cue discrimination.Treatment with CDD-0102A did not affect acquisition of either a place or visual cue discrimination. In contrast, CDD-0102A at 0.03 and 0.1 mg/kg significantly enhanced a shift between a place and visual cue discrimination. Analysis of the errors in the shift to the place or shift to the visual cue strategy revealed that in both cases CDD-0102A significantly increased the ability to initially inhibit a previously relevant strategy and maintain a new, relevant strategy once selected. In anesthetized rats, the minimum dose required to induce salivation was approximately 0.3 mg/kg i.p. Salivation increased with dose, and the estimated ED 50 was 2.0 mg/kg. The data suggest that CDD-0102A has unique memory and cognitive enhancing properties that might be useful in the treatment of neurological disorders at doses that do not produce adverse effects such as salivation.

Knockdown of phospholipase C-β1 in the medial prefrontal cortex of male mice impairs working memory among multiple schizophrenia endophenotypes

“…62 Sabcomeline (CDD0102A), a selective agonist of M1 mAchRs, enhances working memory in the mPFC, but not in the anterior cingulate cortex. 63,64 Moreover, benzylqui nolone carboxylic acid, a selective positive allosteric modula tor of rat M1 mAchRs, has robust effects on M1mediated re sponses in mPFC pyramidal cells, increases the firing of mPFC neurons in vivo, and improves mPFCdependent forms of cognitive function. 65 Thus, it is expected that modu lation of cholinergic θ rhythms by the M1PLCβ1 pathway in the mPFC may be involved in the functional connections among brain regions related to working memory.…”

Central Executive Dysfunction and Deferred Prefrontal Processing in Veterans With Gulf War Illness

“…Muscarinic Ch transmission has been robustly linked to cognitive processes (see Bartus, 2000; Bentley et al, 2000; Hasselmo and Sarter, 2011). Specifically, selective action of acetylcholine on the M1 receptor has been shown to mediate working memory (WM) performance (Ragozzino et al, 2012). …”

Cognitive flexibility impairment and reduced frontal cortex BDNF expression in the ouabain model of mania

“…As in past studies (Amodeo et al, 2014; Ragozzino et al, 2012), perseverative errors measured the ability to initially inhibit a previously learned choice pattern and/or generate a new choice pattern. Regressive errors only occurred after a rat made a correct choice in reversal learning and measured the ability to maintain the new, correct choice pattern.…”

“…The spontaneous alternation test in a Y-maze was used as a short-term or working memory test as in past studies (Mohler et al, 2012; Ragozzino et al, 1995; 2012; Walker et al, 1991). One possibility is that ouabain treatment does not affect working memory in rats.…”

“…Another possibility is that ouabain-treated rats under different test conditions may have exhibited a working memory deficit. For example, past studies have shown that when a delay is inserted between choices in the spontaneous alternation test there can be pharmacological effects on memory (Mohler et al, 2012; Ragozzino et al, 2012). Still other studies report with greater interference, i.e.…”