1. ¹Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA
2. ²Central Research Division, Pfizer, Inc., Groton, CT, USA

Correspondence: Dr AH Lichtman, Department of Pharmacology and Toxicology, Virginia Commonwealth University, Medical College of Virginia Campus, PO Box 980613, Richmond, VA 23298-0613, USA. Tel: +1 804 828 8480, Fax: +1 804 828 2117, E-mail: alichtma@vcu.edu

Received 31 July 2006; Revised 20 September 2006; Accepted 3 November 2006; Published online 10 January 2007.

Abstract

The observations that the cannabinoid₁(CB₁) receptor antagonist/inverse agonist, rimonabant, and the selective noncompetitive inhibitor of acetylcholinesterase (AChE), donepezil, improve performance in a variety of animal memory models, suggest that these neurochemical systems play integral roles in cognition. The present study tested whether each of these agents administered alone or in combination will prolong the duration of spatial memory. Rats were trained in a two-phase radial-arm maze procedure, consisting of acquisition and retrieval tests, which were separated by an 18 h delay. Each drug was administered 30 min before the acquisition phase, immediately after the acquisition phase, or 30 min before the retrieval test to assess acquisition/consolidation, consolidation, and retrieval mnemonic processes, respectively. Rimonabant or donepezil administered before the acquisition phase, but not immediately after acquisition or before retrieval, led to a significant decrease in the number of errors committed during the retrieval test. Combined administration of subthreshold doses of rimonabant and donepezil that had no discernable effects on performance when given alone, enhanced memory. These results taken together demonstrate that the delay radial-arm maze task is sufficiently sensitive to detect memory enhancing effects of these drugs. Moreover, these findings suggest that combined administration of subthreshold doses of rimonabant and donepezil can improve memory and may represent a novel approach to treat cognitive deficits associated with neurodegenerative disorders.