Protracted cognitive effects produced by clonidine in Macaca nemestrina performing a delayed matching task

Buccafusco, Jerry J.; Webster, Scott J.; Terry, Alvin V.; Kille, Nancy J.; Blessing, Donna

doi:10.1007/s00213-008-1318-1

Cited by 10 publications

(8 citation statements)

References 25 publications

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“…These findings are consistent with other reports of beneficial effects of α2 adrenergic agonists on attention regulation and working memory in a variety of animal models [2, 3, 4, 10, 21, 25]. Noradrenergic systems, particularly in the prefrontal cortex (PFC), have been suggested to be involved in the control of working memory and attention [1], although PFC dopaminergic lesions have also been shown to disrupt similar cognitive processes [9].…”

Section: Discussionsupporting

confidence: 90%

Clonidine improves attentional and memory components of delayed response performance in a model of early Parkinsonism

Schneider

Tinker

Decamp

2010

Behavioural Brain Research

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Cognitive deficits, including attention and working memory deficits, are often described in Parkinson's disease (PD) patients even during the early stages of the disease. However, cognitive deficits associated with PD have proven difficult to treat and often do not respond well to the dopaminergic therapies used to treat the motor symptoms of the disease. Chronic administration of low doses of the neurotoxin 1-methy, 4-phenyl, 1,2,3,6-tetrahydropyridine (MPTP) can induce cognitive dysfunction in non-human primates, including impaired performance on a variable delayed response (VDR) task with attentional and memory components. Since alpha-2 adrenergic receptor agonists have been suggested to improve attention and working memory in a variety of conditions, the present study assessed the extent to which the alpha-2 noradrenergic agonist clonidine might influence VDR performance in early Parkinsonian non-human primates. Clonidine (0.02 -0.10 mg/ kg) improved performance on both attentional and memory components of the task, performed in a modified Wisconsin General Test Apparatus, in a dose-dependent manner and the cognition enhancing effects of clonidine were blocked by co-administration of the alpha-2 noradrenergic antagonist idazoxan (0.10 mg/kg). These data suggest that clonidine or drugs of this class, perhaps with greater receptor subtype selectivity and low sedation liability, might be effective therapeutics for cognitive dysfunction associated with PD.

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Section: Discussionsupporting

confidence: 90%

Clonidine improves attentional and memory components of delayed response performance in a model of early Parkinsonism

Schneider

Tinker

Decamp

2010

Behavioural Brain Research

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“…In fact, improvement in DMTS task accuracies by adult macaques recorded during sessions (run 24 and 48 h after clonidine administration) was substantially more impressive than the measurements recorded during the first (60 min) test session. 29 Moreover, significant increases in task accuracy were apparent for up to 6 days after a single administration. Returning to the example of combining clonidine with physostigmine, the data presented in FIG.…”

Section: A Two-compound Regimen and The Role Of Pharmacodynamic Actionsmentioning

confidence: 96%

“…Clearly this protracted mnemonic action could be attributed to the pharmacodynamic actions that are characteristic of the response to clonidine. 29 Therefore, in this example, the following factors appear to contribute to the superior effectiveness of the combination regimen: 1) the targeting of separate neural substrates that each play a role in cognitive function; 2) a widening of the therapeutic window associated with physostigmine treatment, most likely contributing a reduction in physostigmine-associated side effects; and 3) the addition of clonidine extended the regimen's overall duration of action, possibly through a unique pharmacodynamic action. In this particular study we used a fixed dose of clonidine previously determined to be optimal when used alone.…”

Section: Figmentioning

confidence: 99%

Multifunctional Receptor-Directed Drugs for Disorders of the Central Nervous System

Buccafusco

2009

Neurotherapeutics

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“…Thus, the mechanism of this pharmacokinetic–pharmacodynamic discordance is unknown, but we have observed the phenomenon with drugs from other classes (e.g. the nicotinic acetylcholine receptor agonist nicotine), which have relatively short half lives (Jackson and Buccafusco, 1991; Buccafusco et al ., 2009)…”

Section: Discussionmentioning

confidence: 94%

The acute effects of dimebolin, a potential Alzheimer's disease treatment, on working memory in rhesus monkeys

Webster

Wilson

Lee

et al. 2011

British J Pharmacology

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BACKGROUNDDimebolin (latrepirdine), a compound with multiple potential drug targets, is being evaluated in clinical trials for the treatment of Alzheimer's disease (AD) and preliminary results suggest it can slow the disease process. There is also evidence that dimebolin directly improves aspects of cognition. Here we examined the acute effect of dimebolin on components of working memory in non-human primates, young adult (11-17 years old) and aged (20-31 years old) rhesus macaques. EXPERIMENTAL APPROACHThe effects of dimebolin (3.9-118 mg kg -1 ) on working memory, as measured by performance on delayed matching-to-sample (DMTS), were examined in the normal young adult monkeys and aged adult monkeys. All the monkeys studied were proficient in the performance of a computer-assisted DMTS task. In a subsequent experiment in the same subjects, dimebolin was administered 15 min before a cognitively-impairing dose (20 mg kg -1 ) of scopolamine. KEY RESULTSIn both the young adult and aged monkeys, dimebolin significantly increased the DMTS task accuracies. In young adults, the task improvement was associated with long (retention/retrieval) delay trials, and a protracted enhancement was observed for sessions run 24 h post administration of a single dose. Dimebolin did not significantly attenuate the scopolamine-induced impairment. In the aged monkeys, dimebolin significantly improved the reduced task accuracies associated with long delay intervals. CONCLUSIONS AND IMPLICATIONSHere we demonstrated that dimebolin is able to improve components of working memory in monkeys and to induce a protracted response for at least 24 h after administration of a single dose.

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Protracted cognitive effects produced by clonidine in Macaca nemestrina performing a delayed matching task

Abstract: Early (attentional) and late (retention) components of memory appeared to be differentially sensitive to the dose of clonidine. Central alpha(2)-adrenergic receptors should be considered legitimate drug targets for future compound development for cognition enhancement.

Cited by 10 publications

References 25 publications

Clonidine improves attentional and memory components of delayed response performance in a model of early Parkinsonism

Clonidine improves attentional and memory components of delayed response performance in a model of early Parkinsonism

Multifunctional Receptor-Directed Drugs for Disorders of the Central Nervous System

The acute effects of dimebolin, a potential Alzheimer's disease treatment, on working memory in rhesus monkeys

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