TY - JOUR T1 - The selective M<sub>1</sub> muscarinic cholinergic agonist CDD-0102A enhances working memory and cognitive flexibility JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.111.187625 SP - jpet.111.187625 AU - Michael E Ragozzino AU - Sonja Artis AU - Amritha Singh AU - Trevor M Twose AU - Joseph E Beck AU - William S Messer Y1 - 2011/01/01 UR - http://jpet.aspetjournals.org/content/early/2011/12/01/jpet.111.187625.abstract N2 - 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 M1 muscarinic agonists. CDD-0102A is a partial agonist at M1 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 Long Evans rats. CDD-0102A administered i.p. 30 minutes 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 was found to have 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 ED50 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. ER -