AF-DX 116, a Presynaptic Muscarinic Receptor Antagonist, Potentiates the Effects of Glucose and Reverses the Effects of Insulin on Memory Silvia R. Kopf, Mariano M. Boccia, and Carlos M. Baratti Laboratorio de Neurofarmacologı ´a de Procesos de Memoria, Ca ´tedra de Farmacologı´a–Facultad de Farmacia y Bioquı ´mica, Universidad de Buenos Aires, Junı ´n 956 –5° Piso, 1113 Buenos Aires, Argentina Male Swiss mice were tested 24 h after training in a one-trial step-through inhibitory avoidance task. Low subeffective doses of D-(+)-glucose (10 mg/kg, ip), but not its stereoisomer L-(-)-glucose (30 mg/kg, ip), administered immediately after training, and AF-DX 116 (0.3 mg/kg, ip), a presynaptic muscarinic receptor antagonist, given 10 min after training, interact to improve retention. Insulin (8 IU/kg, ip) impaired retention when injected immediately after training, and the effects were reversed, in a dose- related manner, by AF-DX 116 (0.3, 1.0, or 3.0 mg/kg, ip) administered 10 min following insulin. Since AF-DX 116 possibly blocks autoreceptors mediating the inhibition of acetylcholine release from cholinergic nerve terminals, the present data support the view that changes in the central nervous system glucose availability, subsequent to modification of circulating glucose levels, influence the activity of central cholinergic mechanisms involved in memory storage of an inhibitory avoidance response in mice. © 1998 Academic Press Key Words: glucose; insulin; acetylcholine; AF-DX 116; muscarinic autoreceptors; glucoregulation; memory; inhibitory avoidance; retention; acetylcholine release; M 2 -antagonists. INTRODUCTION There is now clear evidence that posttraining injections of glucose can facilitate retention of various types of appetitive and aversive-motivated learn- ing tasks, both in rats and in mice (Gold, 1992; Messier & Gagnon, 1996). Glucose can also influence learning and memory processes in young adults (Benton, Owens & Parker, 1993) and aged humans (Manning, Parsons & Gold, 1992) and in patients suffering from mild Alzheimer’s disease (Messier & Gagnon, 1996). The mechanisms underlying the effects of glucose on memory are not clear. However, evidence has been gathered in support of a relationship between brain glucose avilability and acetylcholine synthesis under conditions of in- creased cholinergic activity (Gibson & Blass, 1976). One of these conditions is observed during the posttraining period that follows a learning experience (Jaffard, Galey, Micheau & Durking, 1985; Matthies, Rauca & Liebman, 1974; This research was partially supported by a grant from FONCYT (PMT-PICT 0390). S.R.K. and M.M.B. are fellows from the University of Buenos Aires. Correspondence and reprint requests should be addressed to Carlos Marı ´a Baratti. Fax: 54-1- 962-5341. E-mail: cbaratti@ffyb.uba.ar. 305 NEUROBIOLOGY OF LEARNING AND MEMORY 70, 305–313 (1998) ARTICLE NO. NL983855 1074-7427/98 $25.00 Copyright © 1998 by Academic Press All rights of reproduction in any form reserved.