BRIEF REPORT Effects of the Novel Acetylcholinesterase Inhibitor N-Octyl-1,2,3,4-tetrahydro-9-aminoacridine on Locomotor Activity and Avoidance Learning in Mice Francesca Capone,* Alberto Oliverio,* , † Massimo Pomponi,‡ Maurizio Marta,‡ Franco Gatta,§ and Flaminia Pavone† *Dipartimento di Genetica e Biologia Molecolare, Universita ` “La Sapienza,” Rome, Italy; ‡Facolta ` di Medicina “A. Gemelli”, Istituto di Chimica e Chimica Clinica, U.C.S.C. Rome, Italy; §Laboratorio Chimica del Farmaco, Istituto Superiore di Sanita ` , Rome, Italy; and †Istituto di Psicobiologia e Psicofarmacologia, CNR, Rome, Italy The acetylcholinesterase reversible inhibitor N-octyl-1,2,3,4-tetrahydro-9-aminoacri- dine (THA-C8) is a new synthesized derivative of tacrine (THA) characterized by an alkyl chain in the molecular structure which ameliorates the penetrability of the compound into the central nervous system. THA-C8 (0.1–5 mg/kg) significantly reduced spontaneous locomotor activity in CD1 mice at a dose of 3 mg/kg. Moreover, THA-C8 (0.2–2 mg/kg) significantly improved shuttle-box avoidance acquisition at doses (0.25, 0.3, 1 mg/kg) not affecting locomotion and that are much lower than the doses reported to be effective for THA in animal models. From the data reported it seems that the new compound could be interesting for therapeutic purposes. © 1999 Academic Press Key Words: acetylcholinesterase inhibitor; tacrine; THA-C8; active avoidance; loco- motor activity; mice. Even if in recent years substantial progress has been made in the compre- hension of Alzheimer’s disease (AD) in several fields of investigation, we are still far from a therapy for this serious disease. A great number of data showing deficits in the activity of cholinergic enzymes and degeneration in cholinergic neurons in brains of AD patients support the well-known cholin- ergic hypothesis of AD (Bartus, Dean, Beer, & Lippa, 1982) that is, to date, the most extensively investigated. Attempts have been made to compensate for deficits in cholinergic transmission by treating AD patients with cholinomi- metic agents. Among the several approaches to developing new drugs for ameliorating cognitive functions, special attention has been focused on tetra- hydroaminoacridine (tacrine, THA) (Freeman & Dawson, 1991), which was approved in 1991 by the U.S. Food and Drug Administration as a clinical strategy for AD (FDC Report, 1993). This cholinesterase inhibitor has been reported to improve memory and learning deficits in animal models (Rupniak, Field, Samson, Steventon, & Iversen, 1990; Murray, Cross, & Green, 1991; Address correspondence to Flaminia Pavone, Istituto di Psicobiologia e Psicofarmacologia, CNR, Viale Marx 43, 00137-Rome, Italy. Fax: 39-6-8278735. E-mail: pavone@kant.irmkant.rm.cnr.it. 301 Neurobiology of Learning and Memory 71, 301–307 (1999) Article ID nlme.1998.3883, available online at http://www.idealibrary.com on 1074-7427/99 $30.00 Copyright © 1999 by Academic Press All rights of reproduction in any form reserved.