Original Investigation

Psychopharmacology

, Volume 162, Issue 3, pp 292-300

Memory-related task performance by aged rhesus monkeys administered the muscarinic M1-preferring agonist, talsaclidine

  • Alvin V. TerryAffiliated withProgram in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy (Augusta Campus), Medical College of Georgia, Augusta, GA 30912, USA
  • , Jerry J. BuccafuscoAffiliated withAlzheimer's Research Center, and Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912, USA
  • , Franco BorsiniAffiliated withDepartment of CNS Research, Boehringer Ingelheim Pharma, Birkendorfer Strasse 65, 88394 Biberach an der Riss, Germany
  • , Andreas LeuschAffiliated withDepartment of Project Management Research and Development, Boehringer Ingelheim Pharma, 88397 Biberach an der Riss, Germany

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Heading

Abstract

Rationale. Muscarinic-acetylcholine receptor agonists are yet to be used clinically for the treatment of Alzheimer's disease (AD) even though laboratory evidence continues to support the potential for such an approach.

Objectives. The purpose of this study was to evaluate the M1-preferring agonist talsaclidine in aged monkeys for effects on working memory.

Methods. Three doses (0.6, 1.2, and 2.4 mg/kg, PO) of talsaclidine and two time intervals (45 min and 8 h) after drug administration were evaluated in seven aged rhesus macaques trained to perform a computer-assisted delayed matching-to-sample (DMTS) task. The relative effectiveness of talsaclidine was also compared with another M1-preferring agonist WAY-132983 that was previously studied in this laboratory.

Results. Talsaclidine improved DMTS accuracy only during sessions initiated 8 h after administration of one of the doses (i.e. 0.6 mg/kg). The drug's enhanced effectiveness at the 8-h time point relative to the 45-min time point was surprising in view of the fact that plasma concentrations were highest 45 min after administration. A higher dose of talsaclidine (4.7 mg/kg) resulted in side effects (lethargy and excessive drooling) in some animals. Individualized optimal doses of talsaclidine were associated with 7.4% and 10.6% improvement in overall (all trials averaged) DMTS accuracy during the 45 min and 8 h post-administration sessions, respectively. Under similar experimental conditions WAY-132983 increased DMTS accuracy by up to 15.6% above control levels.

Conclusion. Both talsaclidine and WAY-132983 provide at least modest improvements in DMTS accuracy in aged monkeys at some doses; however, challenges remain regarding the achievement of an adequate level of efficacy and reliability while minimizing side effects with these compounds. The positive findings do, however, support further study of the potential use of direct muscarinic agonists in the treatment age-related disorders of memory function.

Muscarinic Receptor Cholinergic Learning Memory Match to sample Monkey