Conscious Monkeys Research Articles

Comparison of heart rate and blood pressure values in conscious monkeys using two recording methods: Telemetry and blood pressure cuff

Comparison of heart rate and blood pressure values in conscious monkeys using two recording methods: Telemetry and blood pressure cuff

Application of feedback‐controlled bolus plus infusion (FC‐B/I) method for quantitative PET imaging of dopamine transporters with [18F]β‐CFT‐FE in conscious monkey brain

The competitive inhibition of dopamine transporters (DAT) with cocaine, a specific DAT inhibitor, was evaluated with a feedback-controlled bolus plus infusion (FC-B/I) method using animal positron emission tomography (PET) in the living brain of conscious monkey. 2β-Carbomethoxy-3β-(4-fluorophenyl)-8-(2-[(18)F]fluoroethyl) nortropane ([(18)F]β-CFT-FE; Harada et al. [2004] Synapse 54:37-45) was used for this study because it provided specific, fast, and reversible kinetic properties to DAT in the striatum. In FC-B/I method, the real-time image reconstruction was started just after intravenous bolus injection of [(18)F]β-CFT-FE to generate a time-activity curve in the striatum, and the infusion rate was adjusted to achieve an equilibrium state of the striatal radioactivity concentrations by means of a feedback-control algorithm. The first equilibrium state in the brain was reached within 20 min after the infusion start. Intravenous administration of cocaine at the doses of 0.02, 0.1, and 0.5 mg/kg shifted the equilibrium radioactivity level to the second equilibrium state in a dose-dependent manner, while no significant alterations was observed in the cerebellum. The present results demonstrated that the combined use of FC-B/I method and PET probe with fast kinetics like [(18)F]β-CFT-FE could be useful to assess the occupancy of drugs in the living brain with PET.

Feedback-Controlled Bolus plus Infusion (FC-B/I) Method for Quantitative Drug Assessment in Living Brain with PET

We have developed a feedback-controlled bolus plus infusion (FC-B/I) method for monitoring the interaction between positron emission tomography (PET) ligands and their specific target molecules with PET. The usefulness of the FC-B/I method was evaluated by the direct interaction between [11C]raclopride, a dopamine D2 receptor (D2R) ligand, and cold raclopride (10 and 100 μg/kg) in the brains of conscious monkeys. The present results demonstrated that the FC-B/I method could achieve the equilibrium state of [11C]raclopride in the striatum of monkey brain, and also that the cold raclopride-induced reduction of [11C]raclopride binding to D2R was observed in a dose-dependent manner. Good correlations of distribution volume ratio of the striatum to cerebellum between the conventional bolus plus infusion (B/I) method and the FC-B/I method as well as between the conventional bolus injection method and the FC-B/I method were observed. These results indicated that the system could be a useful tool for the evaluation of interaction between drug candidates and their target molecules like enzymes, receptors, and transporters by using of their specific PET ligands.

Simultaneous evaluation of cardiovascular, respiratory and CNS functions in the conscious Cynomolgus monkey

Simultaneous evaluation of cardiovascular, respiratory and CNS functions in the conscious Cynomolgus monkey

Arousal and spectral analysis: EEG in conscious cynomolgus monkeys

Arousal and spectral analysis: EEG in conscious cynomolgus monkeys

P1‐233: Effect of a novel BACE inhibitor in the cisterna magna ported conscious rhesus monkey model

P1‐233: Effect of a novel BACE inhibitor in the cisterna magna ported conscious rhesus monkey model

Use of a functional observational battery in the assessment of safety pharmacology endpoints in general toxicology studies in conscious cynomolgus monkey

Use of a functional observational battery in the assessment of safety pharmacology endpoints in general toxicology studies in conscious cynomolgus monkey

Effect of oxybutynin and imidafenacin on central muscarinic receptor occupancy and cognitive function: A monkey PET study with [11C](+)3-MPB

Although antimuscarinic agents are widely used to treat overactive bladder (OAB), they have been shown to induce side effects including dry mouth and cognitive impairment. The present study was aimed to investigate the effects of antimuscarinic agents, oxybutynin and imidafenacin, on temporal changes in cognitive function and central mAChR occupancy in conscious monkeys (Macaca mulatta). Three conscious monkeys underwent positron emission tomography (PET) scans with a mAChR radioligand N-[(11)C]methyl-3-piperidyl benzilate ([(11)C](+)3-MPB). The scan sequence was pre, and 1, 4, and 24h post oral administration of oxybutynin (0.1-1.0mg/kg) or imidafenacin (0.01-0.1mg/kg). Maximum cognitive impairment was observed 1h post-oxybutynin at oral doses of 0.3 and 1.0mg/kg, in a dose-dependent manner, and oxybutynin produced significant positive correlations between mAChR occupancy and cognitive impairment in the cortices, thalamus, brainstem, and striatum. The most significant correlation was observed in the brainstem, and then cortices. In contrast, imidafenacin did not induce discernible cognitive impairment, despite having obtained some lesser occupancy in cortices and brainstem. We propose that the thresholds of mAChR occupancy to produce cognitive impairment by antimuscarinic agents are ca. 30-40% in cortices and ca. 20-30% in brainstem, and a desirable drug for OAB treatment should not occupy central mAChR above these thresholds.

Muscarinic Receptor Occupancy and Cognitive Impairment: A PET Study with [11C](+)3-MPB and Scopolamine in Conscious Monkeys

The muscarinic cholinergic receptor (mAChR) antagonist scopolamine was used to induce transient cognitive impairment in monkeys trained in a delayed matching to sample task. The temporal relationship between the occupancy level of central mAChRs and cognitive impairment was determined. Three conscious monkeys (Macaca mulatta) were subjected to positron emission tomography (PET) scans with the mAChR radioligand N-[(11)C]methyl-3-piperidyl benzilate ([(11)C](+)3-MPB). The scan sequence was pre-, 2, 6, 24, and 48 h post-intramuscular administration of scopolamine in doses of 0.01 and 0.03 mg/kg. Occupancy levels of mAChR were maximal 2 h post-scopolamine in cortical regions innervated primarily by the basal forebrain, thalamus, and brainstem, showing that mAChR occupancy levels were 43-59 and 65-89% in doses of 0.01 and 0.03 mg/kg, respectively. In addition, dose-dependent impairment of working memory performance was measured 2 h after scopolamine. A positive correlation between the mAChR occupancy and cognitive impairment 2 and 6 h post-scopolamine was the greatest in the brainstem (P<0.00001). Although cognitive impairment was not observed 24 h post-scopolamine, sustained mAChR occupancy (11-24%) was found with both doses in the basal forebrain and thalamus, but not in the brainstem. These results indicate that a significant degree of mAChRs occupancy is needed to produce cognitive impairment by scopolamine. Furthermore, the importance of the brainstem cholinergic system in working memory in monkey is described.

Validation of reference tissue model of PET ligand [11C](+)3‐MPB for the muscarinic cholinergic receptor in the living brain of conscious monkey

N-[¹¹C]methyl-3-piperidyl benzilate ([¹¹C]+3-MPB) was developed as a positron emission tomography (PET) ligand for muscarinic cholinergic receptor (mAChR). The aim of the present study was to validate a Logan reference tissue method as an analytical method for in vivo binding of [¹¹C]+3-MPB to mAChR. Seven monkeys (Macaca mulatta) underwent [¹¹C]+3-MPB PET scans with an arterial blood sampling. Logan plot with arterial input function (Logan arterial input method) was performed to determine the binding potential (BP(ND)). The BP(ND) was also determined by Logan plot with the cerebellum as the reference region (Logan reference tissue method). BP(ND) values determined by Logan arterial input method and Logan reference tissue method showed a significant linear relationship. The present study suggests that the cerebellum is a suitable reference region for quantification of mAChR in the living brain with [¹¹C]+3-MPB and PET.

In vivo evaluation of carbon-11-labelled non-sarcosine-based glycine transporter 1 inhibitors in mice and conscious monkeys

Glycine transporter 1 (GlyT-1) is an attractive target in positron emission tomography (PET) studies. Here, we report the in vivo evaluation of three carbon-11-labelled non-sarcosine-type GlyT-1 inhibitors--[(11)C]SA1, [(11)C]SA2 and [(11)C]SA3--as novel PET tracers for GlyT-1. The regional brain distributions of the three compounds in mice were studied at baseline and under receptor-blockade conditions with co-injection of carrier loading or pretreatment with an excess of selective GlyT-1 inhibitors (ALX-5407 and SSR504734). Metabolic stability was investigated by radio high-performance liquid chromatography. Dynamic PET scans in conscious monkeys were performed with/without selective GlyT-1 inhibitors. The IC(50) values of SA1, SA2 and SA3 were 9.0, 6400 and 39.7 nM, respectively. The regional brain uptakes of [(11)C]SA1 and [(11)C]SA3 in mice were heterogeneous and consistent with the known distribution of GlyT-1. [(11)C]SA2 showed low and homogeneous uptake in the brain. Most radioactivity in the brain was detected in unchanged form, although peripherally these compounds were degraded. Carrier loading decreased the uptake of [(11)C]SA1 in GlyT-1-rich regions. However, similar reductions were not observed with [(11)C]SA3. Pretreatment with ALX-5407 decreased the uptake of [(11)C]SA1 in GlyT-1-rich regions. In the monkey at baseline, regional brain uptake of [(11)C]SA1 was heterogeneous and consistent with the known GlyT-1 distribution. Pretreatment with selective GlyT-1 inhibitors significantly decreased the distribution volume ratio of [(11)C] SA1 in GlyT-1-rich regions. [(11)C]SA1 has the most suitable profile among the three carbon-11-labelled GlyT-1 inhibitors. Lead optimization of [(11)C]SA1 structure will be required to achieve in vivo selective GlyT-1 imaging.

Potential for serotonergic agents to treat elevated intraocular pressure and glaucoma: focus on 5-HT2 receptor agonists

Although several classes of drugs, including FP-receptor prostaglandin agonist analogs, are available to treat elevated intraocular pressure (IOP) associated with glaucoma, novel pharmaceuticals to treat this potentially blinding disease are still being sought. With recent demonstration of potent IOP-lowering activity of serotonin-2 receptor agonists in conscious ocular hypertensive Cynomolgus monkey eyes, the prospects of this unexampled class of compounds yielding new drugs for the treatment of elevated IOP look bright. This article reviews the ocular serotonergic literature pertaining to elevated IOP in patients with ocular hypertension and glaucoma, the data on ocular hypotensive serotonin-2 agonists, and discusses their potential mechanism(s) of action at the cellular and whole-animal level.

The Gross Temporal Correlation of Nearby Neuron Activity in the Macaque Postcentral Somatosensory Cortex Representing Orofacial Structures: With Special Reference to Numerical Methods for Analysis

Evaluation of the temporal correlation between two spike trains is an important issue when studying the dynamics of local neural networks. In the postcentral somatosensory cortex (SI), the temporal profile of neural activity during sustained stimulation is quite variable on the order of 100 msec, reflecting various thalamocortical inputs as well as various stages of the integrating process that might take place within local neural networks. Therefore, a numerical method is needed to evaluate the difference in the gross temporal profile over several hundreds of msec or more. To address this requirement, we tested a method using the dot product between a pair of spike trains. We applied the method to our own data, i. e., 88 pairs of SI neurons recorded simultaneously in one conscious monkey. Each discrete spike train was first smoothed by convolving with a Gaussian function, then the normalized dot product (similarity index) was taken between a pair of spike trains. We next conducted a simulation study using random spike trains (surrogate data set), in which the number of trials and the number of spikes of both units in each trial were set strictly to those of the original data set. The simulation was repeated 100 times for each pair, and the mean and standard deviation of the similarity index were taken. Finally, the difference in the similarity indexes was determined between the original and surrogate data set (z-score). The method successfully quantifies the gross temporal difference of activity in each pair of SI neurons.

Measurement of glomerular filtration rate in anesthetized and conscious rhesus monkeys (Macaca mulatta)

To validate a method to assess glomerular filtration rate (GFR) in conscious monkeys via transcutaneous radiation detection after IV injection of technetium Tc 99m pentatate (99mTc-DTPA). 4 healthy rhesus monkeys. On day 1, each monkey was anesthetized, lothalamate sodium I 125 (125l-iothalamate) was administered via continuous rate infusion (0.0037 MBq/min); blood and urine samples were obtained for determination of 125l-iothalamate plasma clearance variables and estimation of GFR. One dose of 99mTc-DTPA (74 MBq/kg, IV) was also administered during the 125l-iothalamate plasma clearance test, and transcutaneous measurements of technetium 99m-emitted radiation were obtained by use of an ambulatory renal monitor (ARM) applied to a brachium of each monkey. Determination of GFR by use of the ARM was repeated on days 8 and 45 in the same monkeys without anesthesia. Sensitivity, accuracy, and precision of the 2 methods were similar. By use of the ARM, GFR determined by use of the renal rate constant (κGFR) was calculated; the value obtained on day 1 under anesthesia was similar to values determined via 125l-iothalamate plasma clearance testing on the same day, but was 16% to 23% less than that measured on days 8 and 45 in conscious monkeys. The ARM method for assessment of GFR was less invasive, faster, and more convenient than the standard clearance method, but yielded comparable results. The need to train animals and size restrictions of the device may limit the use of this technique in other nonhuman animals.

Differential effects of stress on [11C]raclopride and [11C]MNPA binding to striatal D2/D3 dopamine receptors: A PET study in conscious monkeys

It has been reported that stress and facilitation of dopamine neuronal system are closely related. In the present study, the effects of stress on the binding of antagonist-based [¹¹C]raclopride and agonist-based (R)-2-CH3O-N-n- propylnorapomorphine ([¹¹C]MNPA) to D₂/D₃ receptors were evaluated in the striatum of conscious monkey brain. The stress state assessed from plasma cortisol level was negatively correlated with [¹¹C]raclopride binding as expected. It was noteworthy that [¹¹C]MNPA binding exhibited a positive correlation with stress state; thus, the animals with higher cortisol levels showed higher binding to D₂/D₃ receptors.

In Vivo Evaluation of α7 Nicotinic Acetylcholine Receptor Agonists [11C]A-582941 and [11C]A-844606 in Mice and Conscious Monkeys

BackgroundThe α7 nicotinic acetylcholine receptors (nAChRs) play an important role in the pathophysiology of neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. The goal of this study was to evaluate the two carbon-11-labeled α7 nAChR agonists [11C]A-582941 and [11C]A-844606 for their potential as novel positron emission tomography (PET) tracers.Methodology/Principal FindingsThe two tracers were synthesized by methylation of the corresponding desmethyl precursors using [11C]methyl triflate. Effects of receptor blockade in mice were determined by coinjection of either tracer along with a carrier or an excess amount of a selective α7 nAChR agonist (SSR180711). Metabolic stability was investigated using radio-HPLC. Dynamic PET scans were performed in conscious monkeys with/without SSR180711-treatment. [11C]A-582941 and [11C]A-844606 showed high uptake in the mouse brain. Most radioactive compounds in the brain were detected as an unchanged form. However, regional selectivity and selective receptor blockade were not clearly observed for either compound in the mouse brain. On the other hand, the total distribution volume of [11C]A-582941 and [11C]A-844606 was high in the hippocampus and thalamus but low in the cerebellum in the conscious monkey brain, and reduced by pretreatment with SSR180711.Conclusions/SignificanceA nonhuman primate study suggests that [11C]A-582941 and [11C]A-844606 would be potential PET ligands for imaging α7 nAChRs in the human brain.

Fast, effortless, and accurate measurement of glomerular filtration rate in conscious monkeys

Fast, effortless, and accurate measurement of glomerular filtration rate in conscious monkeys

Video-electroencephalography in conscious monkeys using telemetry and computer analysis: Refinement of a safety pharmacology model

Video-electroencephalography in conscious monkeys using telemetry and computer analysis: Refinement of a safety pharmacology model

Urodynamics telemetry: A tool for investigating the urinary bladder function in conscious cynomolgus monkey

Urodynamics telemetry: A tool for investigating the urinary bladder function in conscious cynomolgus monkey

An improved method for ECG recording in conscious dogs and monkeys: Pericardial lead placement

Introduction Assessing the effects of new chemical entities on cardiovascular function is an essential component of nonclinical safety evaluation. Regulatory guidelines advocate the use of telemetry to evaluate drug effects on the cardiovascular system of animal including electrocardiogram (ECG) waveforms. Currently, standard method is to place ECG electrodes subcutaneously and the ECG signals have a suboptimal signal mainly due to movement artifacts. In order to improve and optimize the ECG signal and minimize movement artifacts, a model for continuous monitoring of the ECG in conscious, unrestrained animals by placing ECG electrodes on the pericardium was evaluated.