Dose-dependent dissociation of pro-cognitive effects of donepezil on attention and cognitive flexibility in rhesus monkeys

BACKGROUND: Donepezil exerts pro-cognitive effects by non-selectively enhancing acetylcholine (ACh) across multiple brain systems. The brain systems that mediate pro-cognitive effects of attentional control and cognitive flexibility are the prefrontal cortex and the anterior striatum which have different pharmacokinetic sensitivities to ACh modulation. We speculated that these area-specific ACh profiles lead to distinct optimal dose-ranges for donepezil to enhance the cognitive domains of attention and flexible learning. METHODS: To test for dose-specific effects of donepezil on different cognitive domains we devised a multi-task paradigm for nonhuman primates (NHPs) that assessed attention and cognitive flexibility. NHPs received either vehicle or variable doses of donepezil prior to task performance. We measured donepezil intracerebral and how strong it prevented the breakdown of ACh within prefrontal cortex and anterior striatum using solid-phase-microextraction neurochemistry. RESULTS: The highest administered donepezil dose improved attention and made subjects more robust against distractor interference, but it did not improve flexible learning. In contrast, only a lower dose range of donepezil improved flexible learning and reduced perseveration, but without distractor-dependent attentional improvement. Neurochemical measurements confirmed a dose-dependent increase of extracellular donepezil and decreases in choline within the prefrontal cortex and the striatum. CONCLUSIONS: The donepezil dose for maximally improving attention functions differed from the dose range that enhanced cognitive flexibility despite the availability of the drug in the major brain systems supporting these cognitive functions. Thus, the non-selective acetylcholine esterase inhibitor donepezil inherently trades improvement in the attention domain for improvement in the cognitive flexibility domain at a given dose range.

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Follicle-stimulating hormone stimulates inhibin in the serum of male monkeys (Macaca mulatta)

Acta Endocrinologica ◽

10.1530/acta.0.1220096 ◽

1990 ◽

Vol 122 (1) ◽

pp. 96-100 ◽

Cited By ~ 7

Author(s):

Ulrich Fingscheidt ◽

Gerhard F. Weinbauer ◽

Shafiq A. Khan ◽

Eberhard Nieschlag

Keyword(s):

Macaca Mulatta ◽

Half Life ◽

Rhesus Monkeys ◽

Follicle Stimulating Hormone ◽

Serum Levels ◽

Lag Time ◽

Dependent Manner ◽

Control Serum ◽

Dose Dependent ◽

Stimulating Hormone

Abstract. Three adult rhesus monkeys were injected intramuscularly with human FSH at doses of 2, 10 or 25 IU/kg in a cross-over design with 3-week intervals between injections. On each occasion a fourth animal received saline only as control. Serum levels of exogenous FSH were monitored by a fluoroimmunoassay specific for human FSH. Serum inhibin was measured by a heterologous radioimmunoassay. Each FSH injection was followed by a rise in serum inhibin in a dose-dependent manner. The half-life of human FSH in rhesus monkeys ranged from 25.1 to 32.9 h with no significant differences between doses. The rise of inhibin occurred with a lag time of 53.3 to 61.9 h after injection of FSH, independent of the dose administered. These findings support the concept that inhibin secretion in male primates is stimulated by FSH.

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Dose-Dependent Kinetics of Probenecid in Rhesus Monkeys – Infusion Studies

Pharmacology ◽

10.1159/000137960 ◽

1984 ◽

Vol 28 (4) ◽

pp. 181-187 ◽

Cited By ~ 5

Author(s):

Chia-Whei N. Chiang ◽

Leslie Z. Benet

Keyword(s):

Rhesus Monkeys ◽

Kinetics Of ◽

Dose Dependent Kinetics ◽

Dose Dependent

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Melamine disrupts spatial reversal learning and learning strategy via inhibiting hippocampal BDNF-mediated neural activity

PLoS ONE ◽

10.1371/journal.pone.0245326 ◽

2021 ◽

Vol 16 (1) ◽

pp. e0245326

Author(s):

Wei Sun ◽

Yuanhua Wu ◽

Dongxin Tang ◽

Xiaoliang Li ◽

Lei An

Keyword(s):

Cognitive Flexibility ◽

Reversal Learning ◽

Neural Activity ◽

Learning Strategy ◽

Learning Deficits ◽

Place Strategy ◽

Dependent Learning ◽

Dose Dependent Increase ◽

Dose Dependent

Although several studies showed adverse neurotoxic effects of melamine on hippocampus (HPC)-dependent learning and reversal learning, the evidence for this mechanism is still unknown. We recently demonstrated that intra-hippocampal melamine injection affected the induction of long-term depression, which is associated with novelty acquisition and memory consolidation. Here, we infused melamine into the HPC of rats, and employed behavioral tests, immunoblotting, immunocytochemistry and electrophysiological methods to sought evidence for its effects on cognitive flexibility. Rats with intra-hippocampal infusion of melamine displayed dose-dependent increase in trials to the criterion in reversal learning, with no locomotion or motivation defect. Compared with controls, melamine-treated rats avoided HPC-dependent place strategy. Meanwhile, the learning-induced BDNF level in the HPC neurons was significantly reduced. Importantly, bilateral intra-hippocampal BDNF infusion could effectively mitigate the suppressive effects of melamine on neural correlate with reversal performance, and rescue the strategy bias and reversal learning deficits. Our findings provide first evidence for the effect of melamine on cognitive flexibility and suggest that the reversal learning deficit is due to the inability to use place strategy. Furthermore, the suppressive effects of melamine on BDNF-mediated neural activity could be the mechanism, thus advancing the understanding of compulsive behavior in melamine-induced and other neuropsychiatric disorders.

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Capuchin and rhesus monkeys but not humans show cognitive flexibility in an optional-switch task

Scientific Reports ◽

10.1038/s41598-019-49658-0 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Julia Watzek ◽

Sarah M. Pope ◽

Sarah F. Brosnan

Keyword(s):

Working Memory ◽

Cognitive Flexibility ◽

Relative Efficiency ◽

Rhesus Monkeys ◽

Species Differences ◽

Rhesus Macaques ◽

Capuchin Monkeys ◽

Cognitive Set ◽

Strategy Versus

Abstract Learned rules help us accurately solve many problems, but by blindly following a strategy, we sometimes fail to find more efficient alternatives. Previous research found that humans are more susceptible to this “cognitive set” bias than other primates in a nonverbal computer task. We modified the task to test one hypothesis for this difference, that working memory influences the advantage of taking a shortcut. During training, 60 humans, 7 rhesus macaques, and 22 capuchin monkeys learned to select three icons in sequence. They then completed 96 baseline trials, in which only this learned rule could be used, and 96 probe trials, in which they could also immediately select the final icon. Rhesus and capuchin monkeys took this shortcut significantly more often than humans. Humans used the shortcut more in this new, easier task than in previous work, but started using it significantly later than the monkeys. Some participants of each species also used an intermediate strategy; they began the learned rule but switched to the shortcut after selecting the first item in the sequence. We suggest that these species differences arise from differences in rule encoding and in the relative efficiency of exploiting a familiar strategy versus exploring alternatives.

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Dose-Dependent Kinetics of Probenecid in Rhesus Monkeys -Intravenous Bolus Studies

Pharmacology ◽

10.1159/000137568 ◽

1981 ◽

Vol 23 (6) ◽

pp. 326-336 ◽

Cited By ~ 9

Author(s):

Chia-Whei N. Chiang ◽

Leslie Z. Benet

Keyword(s):

Rhesus Monkeys ◽

Intravenous Bolus ◽

Kinetics Of ◽

Dose Dependent Kinetics ◽

Dose Dependent

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An Increase in Kisspeptin-54 Release Occurs with the Pubertal Increase in Luteinizing Hormone-Releasing Hormone-1 Release in the Stalk-Median Eminence of Female Rhesus Monkeys in Vivo

Endocrinology ◽

10.1210/en.2008-0231 ◽

2008 ◽

Vol 149 (8) ◽

pp. 4151-4157 ◽

Cited By ~ 167

Author(s):

Kim L. Keen ◽

Frederick H. Wegner ◽

Stephen R. Bloom ◽

Mohammad A. Ghatei ◽

Ei Terasawa

Keyword(s):

Median Eminence ◽

Rhesus Monkeys ◽

Dependent Manner ◽

Microdialysis Probe ◽

Female Rhesus ◽

Nocturnal Increase ◽

Pooled Samples ◽

G Protein Coupled ◽

Dose Dependent

The G-protein coupled receptor GPR54 and its ligand, KiSS-1-derived peptide kisspeptin-54, appear to play an important role in the mechanism of puberty. This study measures the release of kisspeptin-54 in the stalk-median eminence (S-ME) during puberty and examines its potential role in the pubertal increase in LHRH-1 release in female rhesus monkeys. First, developmental changes in release of kisspeptin-54 and LHRH-1 were assessed in push-pull perfusate samples obtained from the S-ME of prepubertal, early pubertal, and midpubertal female rhesus monkeys. Whereas LHRH-1 levels in 10-min intervals had been measured previously for other experiments, kisspeptin-54 levels in 40-min pooled samples were newly measured by RIA. The results indicate that a significant increase in kisspeptin-54 release occurred in association with the pubertal increase in LHRH-1 release and that a nocturnal increase in kisspeptin-54 release was already observed in prepubertal monkeys and continued through the pubertal period. Second, we measured kisspeptin-54 release in the S-ME of midpubertal monkeys at 10-min intervals using a microdialysis method. Kisspeptin-54 release in the S-ME was clearly pulsatile with an interpulse interval of about 60 min, and approximately 75% of kisspeptin-54 pulses were correlated with LHRH-1 pulses. Finally, the effect of kisspeptin-10 on LHRH-1 release was examined with the microdialysis method. Kisspeptin-10 infusion through a microdialysis probe significantly stimulated LHRH-1 release in a dose-dependent manner. Collectively, the results are consistent with the hypothesis that kisspeptin plays a role in puberty.

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Lack of dose dependent kinetics of methyl salicylate-2-O-β-d-lactoside in rhesus monkeys after oral administration

Journal of Ethnopharmacology ◽

10.1016/j.jep.2014.12.063 ◽

2015 ◽

Vol 164 ◽

pp. 293-300

Author(s):

Yangyang He ◽

Yu Yan ◽

Tiantai Zhang ◽

Yinzhong Ma ◽

Wen Zhang ◽

...

Keyword(s):

Oral Administration ◽

Rhesus Monkeys ◽

Methyl Salicylate ◽

Kinetics Of ◽

Dose Dependent Kinetics ◽

Dose Dependent

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Interaction between Mu and Delta Opioid Receptor Agonists in an Assay of Capsaicin-Induced Thermal Allodynia in Rhesus Monkeys

Pain Research and Treatment ◽

10.1155/2012/867067 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

S. Stevens Negus ◽

Ember M. Morrissey ◽

John E. Folk ◽

Kenner C. Rice

Keyword(s):

Rhesus Monkeys ◽

Delta Opioid Receptor ◽

Preclinical Models ◽

Thermal Nociception ◽

Mu Opioid ◽

Opioid Agonists ◽

Antinociceptive Effects ◽

Mu Agonists ◽

Opioid Receptor Agonists ◽

Dose Dependent

Delta opioid agonists enhance antinociceptive effects of mu-opioid agonists in many preclinical assays of acute nociception, but delta/mu interactions in preclinical models of inflammation-associated pain have not been examined. This study examined interactions between the delta agonist SNC80 [(+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide] and the mu agonist analgesics methadone, morphine, and nalbuphine in an assay of capsaicin-induced thermal allodynia in rhesus monkeys. Thermal allodynia was produced by topical application of capsaicin to the tail. Antiallodynic effects of methadone, morphine, and nalbuphine were evaluated alone or in combination with fixed proportions of SNC80 identical to proportions previously shown to enhance acute thermal antinociceptive effects of these mu agonists in rhesus monkeys (0.9 : 1 SNC80/methadone; 0.29 : 1 SNC80/morphine; 3.6 : 1 SNC80/nalbuphine). Methadone, morphine, and nalbuphine each produced dose-dependent antiallodynia. SNC80 produced partial antiallodynia up to the highest dose tested (5.6 mg/kg). SNC80 produced a modest, enantioselective, and naltrindole-reversible enhancement of methadone-induced antiallodynia. However, SNC80 did not enhance morphine antiallodynia and only weakly enhanced nalbuphine antiallodynia. Overall, SNC80 produced modest or no enhancement of the antiallodynic effects of the three mu agonists evaluated. These results suggest that delta agonist-induced enhancement of mu agonist antiallodynia may be weaker and less reliable than previously demonstrated enhancement of mu agonist acute thermal nociception.

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