Intrathecal amyloid-beta oligomer administration increases tau phosphorylation in the medial temporal lobe in the African green monkey: A nonhuman primate model of Alzheimer's disease.

Aims: An obstacle to developing new treatment strategies for Alzheimer's disease (AD) has been the inadequate translation of findings in current AD transgenic rodent models to the prediction of clinical outcomes. By contrast, nonhuman primates (NHPs) share a close neurobiology with humans in virtually all aspects relevant to developing a translational AD model. The present investigation used African green monkeys (AGMs) to refine an inducible NHP model of AD based on the administration of amyloid-beta oligomers (AβOs), a key upstream initiator of AD pathology.

Nicotinic alpha 7 receptor agonists EVP-6124 and BMS-933043, attenuate scopolamine-induced deficits in visuo-spatial paired associates learning.

Agonists at the nicotinic acetylcholine alpha 7 receptor (nAChR α7) subtype have the potential to treat cognitive deficits in patients with Alzheimer's disease (AD) or schizophrenia. Visuo-spatial paired associates learning (vsPAL) is a task that has been shown to reliably predict conversion from mild cognitive impairment to AD in humans and can also be performed by nonhuman primates. Reversal of scopolamine-induced impairment of vsPAL performance may represent a translational approach for the development of nAChR α7 agonists.

Dosing, collection, and quality control issues in cerebrospinal fluid research using animal models.

Cerebrospinal fluid (CSF) is a complex fluid filling the ventricular system and surrounding the brain and spinal cord. Although the bulk of CSF is created by the choroid plexus, a significant fraction derives from the interstitial fluid in the brain and spinal cord parenchyma. For this reason, CSF can often be used as a source of pharmacodynamic and prognostic biomarkers to reflect biochemical changes occurring within the brain.

Preclinical Characterization of ()-3-((3,4)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169), a Novel, Intravenous, Glutamate -Methyl-d-Aspartate 2B Receptor Negative Allosteric Modulator with Potential in Major Depressive Disorder.

()-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169) and the phosphate prodrug 4-((3,4)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl dihydrogen phosphate (BMS-986163) were identified from a drug discovery effort focused on the development of novel, intravenous glutamate -methyl-d-aspartate 2B receptor (GluN2B) negative allosteric modulators (NAMs) for treatment-resistant depression (TRD). BMS-986169 showed high binding affinity for the GluN2B subunit allosteric modulatory site (K = 4.03-6.

B-973, a novel piperazine positive allosteric modulator of the α7 nicotinic acetylcholine receptor.

The alpha7 (α7) nicotinic acetylcholine receptor is a therapeutic target for cognitive disorders. Here we describe 3-(3,4-difluorophenyl)-N-(1-(6-(4-(pyridin-2-yl)piperazin-1-yl)pyrazin-2-yl)ethyl)propanamide (B-973), a novel piperazine-containing molecule that acts as a positive allosteric modulator of the α7 receptor. We characterize the action of B-973 on the α7 receptor using electrophysiology and radioligand binding.

The qEEG Signature of Selective NMDA NR2B Negative Allosteric Modulators; A Potential Translational Biomarker for Drug Development.

The antidepressant activity of the N-methyl-D-aspartate (NMDA) receptor channel blocker, ketamine, has led to the investigation of negative allosteric modulators (NAMs) selective for the NR2B receptor subtype. The clinical development of NR2B NAMs would benefit from a translational pharmacodynamic biomarker that demonstrates brain penetration and functional inhibition of NR2B receptors in preclinical species and humans. Quantitative electroencephalography (qEEG) is a translational measure that can be used to demonstrate pharmacodynamic effects across species.

Discovery of D1 Dopamine Receptor Positive Allosteric Modulators: Characterization of Pharmacology and Identification of Residues that Regulate Species Selectivity.

The present studies represent the first published report of a dopamine D1 positive allosteric modulator (PAM). D1 receptors have been proposed as a therapeutic target for the treatment of cognitive deficits associated with schizophrenia. However, the clinical utility of orthosteric agonist compounds is limited by cardiovascular side effects, poor pharmacokinetics, lack of D1 selectivity, and an inverted dose response.

Negative Allosteric Modulators Selective for The NR2B Subtype of The NMDA Receptor Impair Cognition in Multiple Domains.

Antidepressant activity of N-methyl-D-aspartate (NMDA) receptor antagonists and negative allosteric modulators (NAMs) has led to increased investigation of their behavioral pharmacology. NMDA antagonists, such as ketamine, impair cognition in multiple species and in multiple cognitive domains. However, studies with NR2B subtype-selective NAMs have reported mixed results in rodents including increased impulsivity, no effect on cognition, impairment or even improvement of some cognitive tasks.

Effects of X-ray radiation on complex visual discrimination learning and social recognition memory in rats.

The present report describes an animal model for examining the effects of radiation on a range of neurocognitive functions in rodents that are similar to a number of basic human cognitive functions. Fourteen male Long-Evans rats were trained to perform an automated intra-dimensional set shifting task that consisted of their learning a basic discrimination between two stimulus shapes followed by more complex discrimination stages (e.g.

Allosteric modulation of GABA(A) receptor subtypes:effects on visual recognition and visuospatial working memory in rhesus monkeys [corrected].

Non-selective positive allosteric modulators (PAMs) of GABAA receptors (GABAARs) are known to impair anterograde memory. The role of the various GABAAR subtypes in the memory-impairing effects of non-selective GABAAR PAMs has not been fully elucidated. The current study assessed, in rhesus monkeys, effects of modulation of α1, α2/3, and α5GABAARs on visual recognition and spatial working memory using delayed matching-to-sample (DMTS) and self-ordered spatial search (SOSS) procedures, respectively.

Long-term exposure to oral methylphenidate or dl-amphetamine mixture in peri-adolescent rhesus monkeys: effects on physiology, behavior, and dopamine system development.

The stimulants methylphenidate and amphetamine are used to treat children with attention deficit/hyperactivity disorder over important developmental periods, prompting concerns regarding possible long-term health impact. This study assessed the effects of such a regimen in male, peri-adolescent rhesus monkeys on a variety of cognitive/behavioral, physiological, and in vivo neurochemical imaging parameters. Twice daily (0900 and 1200 hours), for a total of 18 months, juvenile male monkeys (8 per group) consumed either an unadulterated orange-flavored solution, a methylphenidate solution, or a dl-amphetamine mixture.

A study of the structure-activity relationship of GABA(A)-benzodiazepine receptor bivalent ligands by conformational analysis with low temperature NMR and X-ray analysis.

The stable conformations of GABA(A)-benzodiazepine receptor bivalent ligands were determined by low temperature NMR spectroscopy and confirmed by single crystal X-ray analysis. The stable conformations in solution correlated well with those in the solid state. The linear conformation was important for these dimers to access the binding site and exhibit potent in vitro affinity and was illustrated for alpha5 subtype selective ligands.

Neurobehavioral effects of head-only gamma-radiation exposure in rats.

The present report describes initial steps in the development of an animal model for assessing the effects of low levels of radiation encountered in the space environment on human cognitive function by examining the effects of radiation on a range of neurobehavioral functions in rodents that are similar to a number of basic human cognitive functions. The present report presents baseline data on the effects of gamma radiation on neurobehavioral functions in rodents (psychomotor speed, discrimination accuracy and inhibitory control) that are similar to those in humans. Two groups of eight Long-Evans rats were trained to perform a reaction-time task that required them to depress a lever for 1-3 s and to release the lever within 1.

Consistent, high-level ethanol consumption in pig-tailed macaques via a multiple-session, limited-intake, oral self-dosing procedure.

Background: Alcohol abuse is a major public health burden that can lead to many adverse health effects such as impaired hepatic, gastrointestinal, central nervous system and immune system function. Preclinical animal models of alcohol abuse allow for experimental control over variables often difficult to control in human clinical studies (e.g.

Impaired performance on the object retrieval-detour test of executive function in the SIV/macaque model of AIDS.

NeuroAIDS, the neurological, motor, and cognitive impairments that occur in acquired immunodeficiency syndrome (AIDS) patients, is characterized by compromised function in frontal cortical and subcortical brain regions including impairments in motor control, reaction time, and executive functions. Executive function is a cognitive domain involving the regulation of behavior, including inhibitory control. The present study evaluated the effects of simian immunodeficiency virus (SIV) infection on the object retrieval detour (ORD) task to assess inhibitory control.

Effects of morphine on circadian rhythms of motor activity and body temperature in pig-tailed macaques.

Previous studies of the effects of opiates on motor activity and body temperature in nonhuman primates have been limited in scope and typically only conducted with restrained animals. The present study used radio-telemetry devices to continuously measure activity and temperature in unrestrained pig-tailed macaques for 24 h following morphine administration. Two dose-response functions (0.

Neuropsychopathology in the SIV/macaque model of AIDS.

Of the 40 million people living with HIV/AIDS worldwide in 2003, only 7% received highly active antiretroviral treatment (HAART). Without treatment, approximately half of AIDS patients will suffer from NeuroAIDS including neurological dysfunction, peripheral neuropathies, motor impairment, cognitive difficulties and frank dementia. HAART has reduced mortality from AIDS in the developed world, but CNS/neurological complications continue to be a leading cause of death or disability in AIDS patients on HAART.

Modeling a task that is sensitive to dementia of the Alzheimer's type: individual differences in acquisition of a visuo-spatial paired-associate learning task in rhesus monkeys.

Early detection of progressive diseases such as Alzheimer's Disease (AD) is crucial for both the treatment and study of the disease. Performance on a visuo-spatial paired-associates learning (vsPAL) task was recently shown to reliably predict a diagnosis of AD in aged populations. The present study reports the development of this vsPAL task for use in nonhuman primates.

Impaired performance on a rhesus monkey neuropsychological testing battery following simian immunodeficiency virus infection.

Infection with simian immunodeficiency virus (SIV) in macaques provides an excellent model of AIDS including HIV-induced central nervous system (CNS) pathology and cognitive/behavioral impairment. Recently a behavioral test battery has been developed for macaques based on the CANTAB human neuropsychological testing battery. As with human neuropsychological batteries, different tasks are thought to involve different neural substrates, and therefore performance profiles may assess function in particular brain regions.

Central nervous system correlates of behavioral deficits following simian immunodeficiency virus infection.

Despite the high incidence of cognitive and motor impairment in acquired immunodeficiency syndrome (AIDS) patients, the mechanisms of AIDS-related central nervous system (CNS) pathology are not completely understood. Infection with simian immunodeficiency virus (SIV) in macaques provides an excellent model of AIDS, including human immunodeficiency virus (HIV)-induced CNS pathology and cognitive/behavioral impairment. Co-inoculation with two SIV strains, SIV/17E-Fr and SIV/DeltaB670, accelerates SIV CNS disease, producing SIV encephalitis in over 90% of pig-tailed macaques within 3 months.

Cocaine's effects on detection, discrimination, and identification of auditory stimuli by baboons.

The perceptual effects of cocaine were examined under conditions that required baboons to detect the presence of tones as well as to identify tones of different pitches, and the results compared to the results of prior studies on cocaine's effects on the detection of tones, the discrimination of different tone pitches, and the discrimination of different human vowel sounds of similar pitch. A reaction time procedure was employed in which baboons were trained to press a lever in the presence of a visual "ready" signal, and release the lever only when one tone pitch occurred, but not release the lever when a second, different tone pitch occurred. Changes in the percentage of correct detections and median reaction times for each tone were measured following intramuscular administration of cocaine (0.

Cocaine's effects on the discrimination of simple and complex auditory stimuli by baboons.

The effects of cocaine on tone frequency discriminations by baboons were examined and compared with previous data for more complex acoustic stimuli (speech sounds) to see if cocaine's perceptual effects on these discriminations depends upon the type of stimulus employed (i.e., tones vs.

Differential muscarinic and NMDA contributions to visuo-spatial paired-associate learning in rhesus monkeys.

Rationale: Early, accurate detection of degenerative neurological disorders such as Alzheimer's disease (AD) is essential for therapies designed to slow disease progression. Performance of a touch-screen mediated visuo-spatial paired-associates learning (vsPAL) task predicts neurocognitive decline in elderly populations presenting with mild cognitive impairment and distinguishes AD patients from elderly depressed individuals. Translation of this cognitive task to a non-human model may therefore provide an improved tool for study of the etiology and treatment of dementia.