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

Alvin V Terry, Jerry J. Buccafusco, Franco Borsini, Andreas Leusch

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)292-300
Number of pages9
JournalPsychopharmacology
Volume162
Issue number3
DOIs
StatePublished - Jul 23 2002

Fingerprint

Task Performance and Analysis
Macaca mulatta
Cholinergic Agents
Haplorhini
Sialorrhea
Cholinergic Agonists
Muscarinic Agonists
Lethargy
Memory Disorders
Muscarinic Receptors
Short-Term Memory
Pharmaceutical Preparations
Alzheimer Disease
WAY 132983

Keywords

  • Cholinergic
  • Learning
  • Match to sample
  • Memory
  • Monkey
  • Muscarinic
  • Receptor

ASJC Scopus subject areas

  • Pharmacology

Cite this

Memory-related task performance by aged rhesus monkeys administered the muscarinic M1-preferring agonist, talsaclidine. / Terry, Alvin V; Buccafusco, Jerry J.; Borsini, Franco; Leusch, Andreas.

In: Psychopharmacology, Vol. 162, No. 3, 23.07.2002, p. 292-300.

Research output: Contribution to journalArticle

Terry, Alvin V ; Buccafusco, Jerry J. ; Borsini, Franco ; Leusch, Andreas. / Memory-related task performance by aged rhesus monkeys administered the muscarinic M1-preferring agonist, talsaclidine. In: Psychopharmacology. 2002 ; Vol. 162, No. 3. pp. 292-300.
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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.",
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