Pharmacology Biochemi.~try & Behavior, Vol. 20, pp. 405-413, 1984. ¢ Ankho International Inc. Printed in the U.S.A. 0091-3057/84 $3.00 + .00 Investigation of the Reported Protective Effect of Cycloheximide on Memory' HASKER P. DAVIS Department of Psychology, St. John's University, Jamaica, NY 11439 MARK R. ROSENZWEIG Department of Psychology, University of California, Berkeley, CA 94720 ELIZABETH A. GROVE 2 Department of Psychology, University of California, Berkeley, CA 94720 AND EDWARD L. BENNETT Chemical Biodynamics Division, Lawrence Berkeley Laboratoo, University of California, Berkeley, CA 94720 Received 25 August 1983 DAVIS, H. P., M. R. ROSENZWEIG, E. A. GROVE AND E. L. BENNETT. Investigation of the reported protective effect ofcycloheximide on memory. PHARMACOL BIOCHEM BEHAV 20(3) 405-413, 1984.--Many findings support the hypothesis that formation of long-term memory requires synthesis of proteins in the nervous system close to the time of learning. This hypothesis has been challenged recently by reports that the protein synthesis inhibitor cycloheximide (CYC) injected 2 hr prior to passive avoidance training in mice or rats attenuated the memory impairment induced by a usually amnestic dose of CYC administered 30 min pretraining. To investigate the reports of a "protective" effect of the prior injection, we attempted to replicate them and test their generality. For replication we administered either paired injections of CYC--120 mg/kg 2 hr prior to training and 30 mg/kg 30 min prior to training--or single injections of CYC (either 120 mg/kg or 30 mg/kg) 30 min pretraining and tested for retention of the passive avoidance habit either 1 or 7 days later. No attenuation of amnesia was observed at 1 day tests. Attenuation of amnesia following the double injection of CYC was observed at 7 day tests. When another protein synthesis inhibitor, anisomycin, was used in the same experimental design, there was no "'protective" effect; two injections of anisomycin produced greater memory impairment for the pas- sive avoidance habit than did the single low dose. Also, for active avoidance training, two successive injections of CYC caused significantly greater amnesia than did a single dose; this is the opposite of a "'protective" effect. We suggest that the reported "protective" effect of CYC on memory is an as yet unexplained phenomenon that does not generalize to other antiobiotic drugs and is specific to the passive avoidance task. Active avoidance Amnesia Anisomycin Cycloheximide Memory Passive avoidance Inhibition of cerebral protein synthesis ANTIBIOTIC drugs that inhibit cerebral protein synthesis during or shortly after training impair long-term memory formation in a variety of species and for a variety of tasks [2, 3, 25], although acquisition and short-term memory are nor- mal [7,22]. These findings have been taken as support for the idea that one of the required steps in formation of long-term memory is brain protein synthesis at or near the time of training, and that antibiotic drugs induce amnesia by inhibit- ing the synthesis of proteins specifically required for long- term memory formation. Alternative hypotheses for the am- nestic action of these drugs such as electrical disturbances, altered locomotor activity, sickness, or decreased catechol- amine synthesis have been repeatedly considered and dis- sociated from effects on memory [6, 19, 26]. Recently Rainbow, Hoffman and Flexner [18] reported that a 120 mg/kg dose of the protein synthesis inhibitor cy- cloheximide (CYC) injected 2 hr prior to one-trial passive avoidance training in mice blocked the normally amnestic effect of a 30 mg/kg dose of CYC administered 0.5 hr prior to training. Single injections of CYC that produced less inhibi- ~This work was supported by ADAMHA Grant R01MH26704 to MRR and ELB, and by the Divisions of Biomedical and Environmental Research of the US Department of Energy under contract W-7405-ENG-48. A summary of this investigation was included in a paper at i.he 1980 International Congress of Psychology [19]. 2Now at the Department of Psychology, Massachusetts Institute of Technology, Cambridge, MA 02139. 405