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Memory-related task performance by aged rhesus monkeys administered the muscarinic M(1)-preferring agonist,
Alvin V Terry1, Jerry J Buccafusco, Franco Borsini
1Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Medical College of Georgia, Augusta, GA 30910, USA. aterry@mail.mcg.edu
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 M(1)-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 M(1)-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.
Insights
Muscarinic-acetylcholine receptor agonists like talsaclidine showed modest improvements in working memory in aged monkeys. Further research is needed to optimize efficacy and minimize side effects for Alzheimer's disease treatment.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Muscarinic-acetylcholine receptor agonists show potential for Alzheimer's disease (AD) treatment, but clinical use is limited.
- Laboratory evidence supports the therapeutic potential of targeting these receptors for cognitive enhancement.
Purpose of the Study:
- To evaluate the M(1)-preferring agonist talsaclidine in aged rhesus macaques.
- To assess the effects of talsaclidine on working memory performance.
Main Methods:
- Aged rhesus macaques were trained on a delayed matching-to-sample (DMTS) task.
- Talsaclidine was administered at three doses (0.6, 1.2, 2.4 mg/kg) at two time points (45 min and 8 h).
- Talsaclidine's efficacy was compared to another M(1)-preferring agonist, WAY-132983.
Main Results:
- Talsaclidine improved DMTS accuracy 8 hours post-administration (0.6 mg/kg), with a 10.6% increase.
- The drug's effectiveness at 8 hours was unexpected given peak plasma concentrations at 45 minutes.
- Higher doses of talsaclidine caused side effects like lethargy and drooling; WAY-132983 improved accuracy by up to 15.6%.
Conclusions:
- Both talsaclidine and WAY-132983 demonstrated modest improvements in working memory in aged monkeys.
- Challenges remain in achieving optimal efficacy and minimizing side effects for clinical application.
- Findings support further investigation of direct muscarinic agonists for age-related memory disorders.