title: 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.
authors.affiliation: Department of Psychology, Laboratory of Integrative Neuroscience, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Ragozzino
authors.forename: Sonja
authors.initials: S
authors.lastname: Artis
authors.forename: Amritha
authors.initials: A
authors.lastname: Singh
authors.forename: Trevor M
authors.initials: TM
authors.lastname: Twose
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Beck
authors.forename: William S
authors.initials: WS
authors.lastname: Messer
mesh_terms: D000818:Animals; D003071:Cognition / Q000187:drug effects*; D003463:Cues; D004192:Discrimination, Psychological / Q000187:drug effects; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects*; D018721:Muscarinic Agonists / Q000494:pharmacology*; D018697:Nootropic Agents / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D043643:Receptor, Muscarinic M1 / Q000819:agonists*; D012472:Salivation / Q000187:drug effects
chemical_list: D018721:Muscarinic Agonists; D018697:Nootropic Agents; D010069:Oxadiazoles; D011743:Pyrimidines; D043643:Receptor, Muscarinic M1; C571284:5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine