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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.AβOs or vehicle were repeatedly delivered over 4 weeks to age-matched young adult AGMs by intracerebroventricular (ICV) or intrathecal (IT) injections. Induction of AD-like pathology was assessed in subregions of the medial temporal lobe (MTL) by quantitative immunohistochemistry (IHC) using the AT8 antibody to detect hyperphosphorylated tau. Hippocampal volume was measured by magnetic resonance imaging (MRI) scans prior to, and after, intrathecal injections.IT administration of AβOs in young adult AGMs revealed an elevation of tau phosphorylation in the MTL cortical memory circuit compared with controls. The largest increases were detected in the entorhinal cortex that persisted for at least 12 weeks after dosing. MRI scans showed a reduction in hippocampal volume following AβO injections.Repeated IT delivery of AβOs in young adult AGMs led to an accelerated AD-like neuropathology in MTL, similar to human AD, supporting the value of this translational model to de-risk the clinical trial of diagnostic and therapeutic strategies.

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. To date, the effects of NR2B-selective NAMs on cognitive tests have not been reported in nonhuman primates. The current study evaluated two selective NR2B NAMs, CP101,606 and BMT-108908, along with the nonselective NMDA antagonists, ketamine and AZD6765, in the nonhuman primate Cambridge Neuropsychological Test Automated Battery (CANTAB) list-based delayed match to sample (list-DMS) task. Ketamine and the two NMDA NR2B NAMs produced selective impairments in memory in the list-DMS task. AZD6765 impaired performance in a non-specific manner. In a separate cohort, CP101,606 impaired performance of the nonhuman primate CANTAB visuo-spatial Paired Associates Learning (vsPAL) task with a selective impairment at more difficult conditions. The results of these studies clearly show that systemic administration of a selective NR2B NAM can cause transient cognitive impairment in multiple cognitive domains.

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. For instance, CSF biomarkers can be used to diagnose and track progression of disease as well as understand pharmacokinetic and pharmacodynamic relationships in clinical trials. To facilitate the use of these biomarkers in humans, studies in preclinical species are often valuable. This review summarizes methods for preclinical CSF collection for biomarkers from mice, rats, and nonhuman primates. In addition, dosing directly into CSF is increasingly being used to improve drug levels in the brain. Therefore, this review also summarizes the state of the art in CSF dosing in these preclinical species.

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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. The present study investigated the effect of treatment with the acetylcholinesterase inhibitor, donepezil, or three nAChR α7 agonists, BMS-933043, EVP-6124 and RG3487, on vsPAL performance in scopolamine-treated cynomolgus monkeys. Scopolamine administration impaired vsPAL performance accuracy in a dose- and difficulty- dependent manner. The impairment of eventual accuracy, a measure of visuo-spatial learning during the task, was significantly ameliorated by treatment with donepezil (0.3 mg/kg, i.m.), EVP-6124 (0.01 mg/kg, i.m.) or BMS-933043 (0.03, 0.1 and 0.3 mg/kg, i.m.). Both nAChR α7 agonists showed inverted-U shaped dose-effect relationships with EVP-6124 effective at a single dose only whereas BMS-933043 was effective across at least a 10 fold dose/exposure range. RG3487 was not efficacious in this paradigm at the dose range examined (0.03-1 mg/kg, i.m.). These results are the first demonstration that the nAChR α7 agonists, EVP-6124 and BMS-933043, can ameliorate scopolamine-induced cognitive deficits in nonhuman primates performing the vsPAL task.

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. The DMTS procedure (n=8) involved selecting a previously presented 'sample' image from a set of multiple images presented after a delay. The SOSS procedure (n=6) involved touching a number of boxes without repeats. The non-selective GABAAR PAM triazolam and the α1GABAA preferential PAMS zolpidem and zaleplon reduced accuracy in both procedures, whereas the α5GABAA preferential PAMs SH-053-2'F-R-CH3 and SH-053-2'F-S-CH3, and the α2/3GABAA preferential PAM TPA023B were without effects on accuracy or trial completion. The low-efficacy α5GABAAR negative allosteric modulator (NAM) PWZ-029 slightly increased only DMTS accuracy, whereas the high-efficacy α5GABAAR NAMs RY-23 and RY-24 did not affect accuracy under either procedure. Finally, the slopes of the accuracy dose-effect curves for triazolam, zolpidem, and zaleplon increased with box number in the SOSS procedure, but were equivalent across DMTS delays. The present results suggest that (1) α1GABAARs, compared with α2/3 and α5GABAARs, are primarily involved in the impairment, by non-selective GABAAR PAMs, of visual recognition and visuospatial working memory in nonhuman primates; and (2) relative cognitive impairment produced by positive modulation of GABAARs increases with number of locations to be remembered, but not with the delay for remembering.

Studies of the effects of drugs of abuse on HIV immune status, disease progression, and neuroAIDS have produced conflicting data and have not definitively shown whether this combination promotes cognitive impairment or disease progression. Using a consistent SIV–macaque model, we investigated the effects of cocaine on behavior, virologic parameters, and CNS inflammation. Macaques received either vehicle or chronic administration of behaviorally active doses of cocaine (1.7 or 3.2 mg/kg/day). Chronic cocaine administration reduced CD8+ T cell counts during acute and late stage infection but had no effect on CD4+ T cell counts. Low-dose cocaine-treated animals had lower CSF vRNA levels late in infection, but cocaine did not alter plasma viral load or vRNA or protein in brain. There were no differences in CSF CCL-2 or interleukin (IL)-6 levels or severity of encephalitis in cocaine-treated as compared to vehicle-treated macaques. There were no differences in brain inflammation or neurodegeneration markers, as determined by interferon (IFN)-β, MxA, CCL2, IL-6, TNFα, IFNγ, and indolamine 2,3-deoxygenase mRNA levels. APP levels also were not altered. The executive function of inhibitory control was not impaired in cocaine-treated or control animals following SIV infection. However, animals receiving 3.2 mg/kg/day cocaine performed more slowly in a bimanual motor test. Thus, chronic administration of cocaine produced only minor changes in behavior, encephalitis severity, CNS inflammation/neurodegeneration, and virus replication in SIV-infected pigtailed macaques, suggesting that cocaine would have only modest effects on the progression of neuroAIDS in HIV-infected individuals.

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. NMDA receptor channel blockers, such as ketamine and phencyclidine, increase the EEG gamma power band, which has been used as a pharmacodynamic biomarker in the development of NMDA receptor antagonists. However, detailed qEEG studies with ketamine or NR2B NAMs are lacking in nonhuman primates. The aim of the present study was to determine the effects on the qEEG power spectra of the NR2B NAMs traxoprodil (CP-101,606) and BMT-108908 in nonhuman primates, and to compare them to the NMDA receptor channel blockers, ketamine and lanicemine. Cynomolgus monkeys were surgically implanted with EEG radio-telemetry transmitters, and qEEG was measured after vehicle or drug administration. The relative power for a number of frequency bands was determined. Ketamine and lanicemine increased relative gamma power, whereas the NR2B NAMs traxoprodil and BMT-108908 had no effect. Robust decreases in beta power were elicited by ketamine, traxoprodil and BMT-108908; and these agents also produced decreases in alpha power and increases in delta power at the doses tested. These results suggest that measurement of power spectra in the beta and delta bands may represent a translational pharmacodynamic biomarker to demonstrate functional effects of NR2B NAMs. The results of these studies may help guide the selection of qEEG measures that can be incorporated into early clinical evaluation of NR2B NAMs in healthy humans.

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. A number of these challenges may be overcome by utilization of a selective D1 PAM. The current studies describe two chemically distinct D1 PAMs: Compound A [1-((rel-1S,3R,6R)-6-(benzo[d][1,3]dioxol-5-yl)bicyclo[4.1.0]heptan-3-yl)-4-(2-bromo-5-chlorobenzyl)piperazine] and Compound B [rel-(9R,10R,12S)-N-(2,6-dichloro-3-methylphenyl)-12-methyl-9,10-dihydro-9,10-ethanoanthracene-12-carboxamide]. Compound A shows pure PAM activity, with an EC50 of 230 nM and agonist activity at the D2 receptor in D2-expressing human embryonic kidney cells. Compound B shows superior potency (EC50 of 43 nM) and selectivity for D1 versus D2 dopamine receptors. Unlike Compound A, Compound B is selective for human and nonhuman primate D1 receptors, but lacks activity at the rodent (rat and mouse) D1 receptors. Using molecular biology techniques, a single amino acid was identified at position 130, which mediates the species selectivity of Compound B. These data represent the first described D1-selective PAMs and define critical amino acids that regulate species selectivity.

The immune effects of chronic opiate exposure and/or opiate withdrawal are not well understood. The results of human studies with opiate abusers are variable and may not be able to control for important factors such as subjects' drug histories, health and nutritional status. Nonhuman primate models are necessary to control these important factors. A model of opiate dependence in macaques was developed to study the effects of opiate dependence and withdrawal on measures of immune function. Four pigtailed macaques drank a mixture of morphine (20 mg/kg/session) and orange-flavored drink every 6 h for several months. During stable morphine dependence, absolute numbers of neutrophils, monocytes and lymphocytes did not change relative to pre-morphine levels. However, there was a significant decrease in the absolute number and percentage of natural killer (NK) cells in morphine dependence. Either precipitated withdrawal or abstinence for 24 h resulted in behavioral withdrawal signs in all animals. Absolute lymphocyte counts decreased and absolute netrophil counts increased significantly in withdrawal, relative to levels during morphine dependence. Lymphocyte subset (CD4+, CD8+, CD20+) cells were also decreased in absolute numbers with little change in their percentage distributions. There was, however, a significant increase in the percentage of NK cells in withdrawal relative to levels during morphine dependence. This study demonstrates the usefulness of voluntary oral self-dosing procedures for maintaining morphine dependence in nonhuman primates and demonstrates that the morphine withdrawal syndrome includes large alterations in blood parameters of immune system function, including nearly 50% reduction in numbers of CD4+, CD8+ and CD20+ cells.

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. In the present study, this SIV model was employed to identify cellular and viral correlates of behavioral impairment following SIV infection. Measures of psychomotor speed (simple reaction time), fine motor control (bimanual motor task), and general motor activity (home cage movement) were all adversely affected by SIV disease. Prior to euthanasia, performance was significantly impaired in both a simple reaction time task in 6 of 12 monkeys and a bimanual motor task in 5 of 6 monkeys. All monkeys evaluated (11 of 11) showed significant reductions in spontaneous motor activity. Significant correlations were found between impaired performance on the bimanual motor test and axonal damage (accumulation of beta-amyloid precursor protein in the corpus callosum) as well as increased microglial activation and macrophage infiltration (levels of CD68 and Ham56 immunostaining). These results suggest that axonal damage is related to the behavioral impairment induced by infection with SIV. The axonal damage may result from neuroimmune responses, including microglial and macrophage activation. Therefore, axonal damage may be a morphologic manifestation of neuronal dysfunction that underlies development of behavioral impairment in HIV/SIV CNS infection.

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 (0.01–1.0 mg/kg). Cocaine impaired tone identification and shortened reaction times to the tones in all baboons. Cocaine's effects on accuracy, however, were primarily due to elevations in false alarm rates, as opposed to detection of the stimuli themselves. The results demonstrate that cocaine impairs the discriminability of tone pitches in baboons, and that such impairments can depend upon the type of stimuli employed (tones vs. speech sounds) and the type of procedure employed (discrimination vs. identification).

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. speech sounds). Baboons pressed a lever to produce one repeating “standard” tone and released the lever only when one of four other “comparison” tones occasionally occurred in place of the standard tone. Cocaine's effects were assessed once or twice weekly by giving an intramuscular injection of cocaine hydrochloride (0.01–0.56 mg/kg) immediately prior to performing the task and by examining correct detections and reaction times for each tone following drug administration. Cocaine impaired tone discriminability, with greater impairments occurring for those tones that were more similar in frequency to the standard tone. Cocaine's perceptual effects occurred within 20–70 min following drug administration. Cocaine also impaired or facilitated the speed of responding to auditory stimuli, depending upon the drug dose and subject. The results demonstrate that cocaine can impair auditory discriminations involving simple tones, as well as speech sounds, and further supports the suggestion that cocaine's effects are focused on CNS mechanisms related to the use of pitch cues.

Self-injurious behavior (SIB) is a common comorbidity of psychiatric disorders but there is a dearth of information about neurological mechanisms underlying the behavior, and few animal models exist. SIB in humans is characterized by any intentional self-directed behavior that leads to wounds, whereas in macaques it is not always accompanied by wounds. We describe a cohort of rhesus macaques displaying SIB as adults, in which changes within the central nervous system were associated with the SIB. In these macaques, increases in central nervous system striatal dopamine (DA) receptor binding (BPND) measured by positron emission tomography (PET) [11C]raclopride imaging correlated with severity of wounding (rs=0.662, P=0.014). Furthermore, utilizing standardized cognitive function tests, we showed that impulsivity (stop signal reaction time, SSRT) and deficits in attentional set shifting (intra-/extradimensional shift) were correlated with increased severity of SIB (rs=0.563, P=0.045 and rs=0.692, P=0.009, respectively). We also tested the efficacy of guanfacine, an α2A adrenergic agonist that acts to improve postsynaptic transmission of neuronal impulses, in reducing SIB. A subset of these animals were enrolled in a randomized experimenter-blinded study that demonstrated guanfacine decreased the severity of wounding in treated animals compared with vehicle-only-treated controls (P=0.043), with residual beneficial effects seen for several weeks after cessation of therapy. Animals with the highest severity of SIB that received guanfacine also showed the most significant improvement (rs=−0.761, P=0.009). The elevated PET BPND was likely due to low intrasynaptic DA, which in turn may have been improved by guanfacine. With underlying physiology potentially representative of the human condition and the ability to affect outcome measures of disease using pharmacotherapy, this model represents a unique opportunity to further our understanding of the biology and treatment of SIB in both animals and humans.

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., a discrimination reversal, a compound discrimination, a compound reversal, a new shape discrimination, and an intra-dimensional stimulus discrimination reversal). One group of rats was exposed to head-only X-ray radiation (2.3 Gy at a dose rate of 1.9 Gy/min), while a second group received a sham-radiation exposure using the same anesthesia protocol. The irradiated group responded less, had elevated numbers of omitted trials, increased errors, and greater response latencies compared to the sham-irradiated control group. Additionally, social odor recognition memory was tested after radiation exposure by assessing the degree to which rats explored wooden beads impregnated with either their own odors or with the odors of novel, unfamiliar rats; however, no significant effects of radiation on social odor recognition memory were observed. These data suggest that rodent tasks assessing higher-level human cognitive domains are useful in examining the effects of radiation on the CNS, and may be applicable in approximating CNS risks from radiation exposure in clinical populations receiving whole brain irradiation.

Six rhesus monkeys were trained to stable performance on neuropsychological tests of memory, reinforcer efficacy, reaction time and bimanual motor coordination. Three monkeys were then exposed to a high-dose, short course regimen of (+/-)3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") (4 days, 10 mg/kg i.m., b.i.d.). Following treatment, concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) were reduced by approximately 50% in the treated animals, and this effect persisted for approximately three months post-MDMA. Behavioral performance was disrupted during acute MDMA treatment but returned to baseline within one week following treatment. MDMA also produced persistent alterations in late peak latencies of brainstem auditory evoked potentials (BSAEP), lasting three months post-MDMA. Both CSF 5-HIAA concentrations and evoked potential latencies were normalized four months after treatment. These findings indicate that serotonergic alterations associated with MDMA use may result in persisting changes in brain function.

A computerized behavioral battery based upon human neuropsychological tests (CANTAB, CeNeS, Cambridge, UK) has been developed to assess cognitive behaviors of rhesus monkeys. Monkeys reliably performed multiple tasks, providing long-term assessment of changes in a number of behaviors for a given animal. The overall goal of the test battery is to characterize changes in cognitive behaviors following central nervous system (CNS) manipulations. The battery addresses memory (delayed non-matching to sample, DNMS; spatial working memory, using a self-ordered spatial search task, SOSS), attention (intra-/extra-dimensional shift, ID/ED), motivation (progressive-ratio, PR), reaction time (RT) and motor coordination (bimanual task). As with human neuropsychological batteries, different tasks are thought to involve different neural substrates, and therefore performance profiles should assess function in particular brain regions. Monkeys were tested in transport cages, and responding on a touch sensitive computer monitor was maintained by food reinforcement. Parametric manipulations of several tasks demonstrated the sensitivity of performance to increases in task difficulty. Furthermore, the factors influencing difficulty for rhesus monkeys were the same as those shown to affect human performance. Data from this study represent performance of a population of healthy normal monkeys that will be used for comparison in subsequent studies of performance following CNS manipulations such as infection with simian immunodeficiency virus (NeuroAIDS) or drug administration.

For several decades methylphenidate (MPH, Ritalin) has been the primary treatment for children with attention-deficit disorder (ADD), a disorder affecting 3–5% of U.S. children. The therapeutic effects of MPH are mediated through its action at the dopamine transporter (DAT, Cheon et al., 2003; Krause et al., 2000; Vles et al., 2003). Currently, positron emission tomography (PET) is being used to study the DAT effects of MPH and other psychomotor stimulants that can be related to their behavioral or therapeutic effects (Volkow et al., 1999; Volkow et al., 1998; Wilcox et al., 2002). For instance, Volkow et al. (1998) reported that therapeutic doses of oral MPH produced at least 50% DAT occupancy in adults without ADD. Macaques are used in common preclinical models of the effects of psychomotor stimulants on the central nervous system (CNS); however, few studies have investigated the bioavailability and CNS penetration of oral MPH in macaques. One study in adult rhesus monkeys found that blood plasma concentration reached 16 ng/ml after oral administration of 3.0 mg/kg MPH (Doerge et al., 2000). In adult humans with ADD therapeutic doses of oral MPH range from 0.15 to 0.3 mg/kg and produce blood plasma levels of 3.5–7.8 ng/ml (Volkow et al., 1998; Wargin et al., 1983). In children with ADD, MPH is prescribed in the range of 10–60 mg/day (0.4–2.4 mg/kg/day, (Patrick and Markowitz, 1997), and a dose of 20mg in children (0.8 mg/kg) results in a blood plasma concentration of 20 ng/ml two hours after dosing (Swanson and Volkow, 2003). These studies suggest that oral MPH is less bioavailable in macaques than in humans. Preadolescent macaques are being increasingly used in preclinical studies of drugs of abuse, including stimulants used to treat ADD; therefore, the present study evaluated the relationship between DAT occupancy in the striatum, and blood plasma concentration for several doses of oral MPH in preadolescent macaques. Two preadolescent male rhesus monkeys (2–2.5 yrs old) served as the subjects for the present study. Anesthesia was maintained with saffan in all studies with one subject (04-207; derived from (Guilarte et al., 2006). However, in the middle of the study saffan became unavailable and some scans for one monkey (04-185) were performed using propofol (adapted from: (Hartvig et al., 1997). Monkey 04-185 received an additional baseline PET scan when the anesthesia was changed to propofol. There were no apparent differences in binding potential due to the change in anesthesia. Monkeys received the MPH orally after induction of anesthesia with MPH dissolved in 5 ml/kg water 2 hrs prior to the scans. Dynamic PET scans were performed on a high resolution research tomography (HRRT) PET scanner (Horti et al., 2006). A bolus of [11C]MPH [injected dose 6.2 mCi (0.1 sem); specific activity 6115 mCi/hmol (481 sem)] was injected i.v. and dynamic images of 30 frames were reconstructed for 90 min data acquisition in each study. Tracer binding potential (BP) was estimated by fitting a simplified reference tissue model to the measured striatum time activity curve (Lammertsma and Hume, 1996; Zhou et al., 2007), where cerebellum was used a reference tissue devoid of specific binding. The occupancy of MPH was calculated as percent changes of BP from baseline as 100(BP(baseline)-BP(MPH))/BP(baseline). Blood was drawn every 30 minutes during the 90 minute scan to determine MPH plasma levels. Figure 1 shows percent DAT occupancy for various doses of MPH (0.8–32 mg/kg) in each monkey. The dose of MPH was increased until DAT occupancy was at least 50%, which required the administration of 17 mg/kg (04-185) or 32 mg/kg (04-207). The EC50 for DAT occupancy was 21.5 mg/kg with a 95% confidence of 13.00 to 35.64. Average peak plasma levels ranged from 3.0 ng/ml (SEM 0.15) for 5.6 mg/kg to 61 ng/ml (SEM 19) for 32 mg/kg (Table 1). Each monkey also received 5.6 mg/kg MPH 1 hour prior to a scan, and those data suggest that DAT occupancy was similar at 1 and 2 hrs (Figure 1, inset). There was a positive relationship between plasma concentration and DAT occupancy for MPH, consistent with a previous report (Volkow et al., 1998). Figure 1 Reductions in DAT binding following oral MPH administration. Main panel: Y axis represents percent of baseline [11C]-MPH binding. X axis represents oral dose of MPH (mg/kg) administered 2 hour prior to PET scan. Inset: X axis represents oral dose of 5.6 ... Table 1 Peak plasma concentration for oral MPH (0.80–32 mg/kg) in two male juvenile rhesus monkeys. Oral MPH was much less potent to occupy the DAT in juvenile macaques than human adults. The EC50 for DAT occupancy was 21.5 mg/kg in macaques (present study), compared to 0.25 mg/kg in humans (Volkow et al., 1998). Blood plasma concentrations support the finding that oral MPH is less bioavailable in preadolescent macaques. A dose of 0.8 mg/kg in children results in a blood plasma concentration of 20 ng/ml two hours after dosing (Swanson and Volkow, 2003). Blood plasma concentrations in the juvenile monkeys did not reach 20 ng/ml until 17 or 32 mg/kg MPH were administered. Interestingly, MPH was also less bioavailable in juvenile than adult macaques with juveniles requiring doses approximately 5 to 10-fold higher than required for therapeutic blood levels in adult rhesus macaques (Doerge et al., 2000; Volkow et al., 1998; Wargin et al., 1983). In the present study, blood concentrations are not likely to be affected by oral administration after anesthesia as an additional 8 juvenile macaques have demonstrated similar blood levels after drinking MPH in a Tang solution (data not shown). In summary, oral MPH is less bioavailable in juvenile macaques than humans; however, once sufficient MPH enters the blood, occupancy of striatal DATs occurs at similar blood levels between juvenile macaques, and humans. Therefore, once the dose is titrated to the appropriate blood levels, the juvenile macaque is a good model for investigating the CNS effects of oral MPH administration.

Several phenyl-benzazepine compounds, putatively selective dopamine D1 receptor agonists, have been used to study the effects of dopamine D1 receptor stimulation in rodents and nonhuman primates. However, the dopamine receptor selectivities of these compounds have not been established in nonhuman primates. Accordingly, the relative selectivities of six phenyl-benzazepines for dopamine D1-like and D2-like receptors were assessed in rhesus monkey and, for comparison, rat striata. The compounds tested had higher affinity for D1 than D2 receptors in both species; however, their selectivity varied by up to three orders of magnitude. GTP (100 microM) reduced agonist binding at the high-affinity state of the dopamine D1 receptor, but the magnitude of the effect of GTP did not reliably predict a compound's efficacy. Furthermore, a history of cocaine self-administration did not appear to influence dopamine receptor binding characteristics in the rhesus monkeys in this study. The present results will aid the comparison of dopamine receptor binding characteristics and behavioral effects of D1 dopamine receptor agonists.

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. Doses were titrated to reach blood/plasma levels comparable to therapeutic levels in children. [¹¹C]MPH and [¹¹C]raclopride dynamic PET scans were performed to image dopamine transporter and D₂-like receptors, respectively. Binding potential (BP(ND)), an index of tracer-specific binding, and amphetamine-induced changes in BP(ND) of [¹¹C]raclopride were estimated by kinetic modeling. There were no consistent differences among groups on the vast majority of measures, including cognitive (psychomotor speed, timing, inhibitory control, cognitive flexibility), general activity, physiological (body weight, head circumference, crown-to-rump length), and neurochemical (ie, developmental changes in dopamine transporter, dopamine D₂ receptor density, and amphetamine-stimulated dopamine release were as expected). Cytogenetic studies indicated that neither drug was a clastogen in rhesus monkeys. Thus, methylphenidate and amphetamine at therapeutic blood/plasma levels during peri-adolescence in non-human primates have little effect on physiological or behavioral/cognitive development.

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., ethanol exposure before or during the study, history of other drug use, access to medical care, nutritional status, etc). Nonhuman primate models in particular provide increased genetic, anatomic and physiologic similarity to humans, relative to rodent models. A small percentage of macaques will spontaneously consume large quantities of ethanol; however, most nonhuman primate models of “voluntary” ethanol intake produce relatively low daily ethanol intake in the majority of monkeys. Methods: To facilitate study of chronic exposure to high levels of ethanol intake, a macaque model has been developed that induces consistent, daily high-level ethanol consumption. This multiple-session procedure employed 4 drinking sessions per day, with sessions occurring once every 6 hours. Results: The group average alcohol consumption was 4.6 g/kg/d (SEM 0.4), roughly twice the group average consumption of previous reports. Ethanol drinking sessions produced group mean blood ethanol levels of 95 mg/dl after 60 minutes, and fine motor control was impaired up to 90 minutes after a drinking session. Conclusion: This model of multiple-session, limited access, oral ethanol self-dosing produced consistent, high-level ethanol consumption with each session qualifying as a “binge” drinking session using the definition of “binge” provided by the NIAAA (>80 mg/dl/session). This model of ethanol drinking in macaques will be of great utility in the study of immunological, physiological and behavioral effects of ethanol in nonhuman primates.

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. The ORD task measures the ability to inhibit the prepotent response of reaching directly toward a food reinforcer placed in a transparent box. The box has one open side, and the animal must inhibit the initial reaching response and look to see which side is open. Subjects were 12 experimentally naive pigtailed macaques; six monkeys were infected with SIV. Baseline performance was compared to performance under "terminal" conditions (the week prior to the scheduled euthanasia) to determine if progression of SIV disease led to decreased ORD performance. SIV-infected monkeys acquired ORD performance at the same levels as uninfected control monkeys, and had similar latencies and error rates. However, in the terminal week there was a significant difference between the groups in the number of barrier reach errors (touching the side of the transparent box). Three individual SIV-infected monkeys were impaired on ORD performance both in terms of errors and speed of performance. Given the sensitivity of ORD performance to dopaminergic dysfunction, these results further implicate dopaminergic dysfunction as a mechanism of cognitive and motor impairments in NeuroAIDS.

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 (0.56 to 5.6 mg/kg, i.m.) were determined, one with morphine administered at 9 a.m. and one with morphine administrated at 3 p.m. Under both the 9 a.m. or 3 p.m. administration schedules, body temperature and activity were increased acutely. Activity was also reduced the following morning after morphine administered at either time. In other regards, morphine's effects on both temperature and activity differed between 9 a.m. and 3 p.m. injection, including periods of decreased activity immediately after the acute increases after 9 a.m. but not 3 p.m. administration. Surprisingly, motor activity also increased 9-12 h post-injection following morphine administered at 9 a.m., but not at 3 p.m. These results clearly show an interaction between timing of morphine administration and effects on temperature and activity. These results also underscore the fact that single injections of drugs may have multiple and delayed effects on circadian rhythms in macaques.

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. Translation of vsPAL to a nonhuman model may provide improved preclinical tools for study of the etiology and treatment of dementia. Twelve young adult male rhesus monkeys were trained to perform the vsPAL task concurrently with tests comprising a nonhuman primate neuropsychological test battery. Monkeys successfully learned to perform vsPAL and did so in a task-difficulty ranked fashion. Despite significant individual differences in capability in the acquisition of the recognition memory aspects of the task, all monkeys evidenced the ability to learn within-trial, i.e. to improve with repeated stimulus-location pairings. These results support the use of vsPAL performance under various challenge conditions to investigate the possible substrates of early cognitive decline in AD. Comparison of performance on vsPAL with performance on other memory tasks in the battery will be of more general use in differentiating mechanisms involved in various aspects of mnemonic function.

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. Ten rhesus monkeys were infected with SIV after being trained on two or more of the battery tasks addressing memory (delayed nonmatching to sample, DNMS), spatial working memory (using a self-ordered spatial search task, SOSS), motivation (progressive-ratio, PR), reaction time (RT), and/or fine motor skills (bimanual motor skill, BMS). Performance was compared to that of 9 uninfected monkeys. Overall, some aspect of performance was impaired in all 10 monkeys following infection. Consistent with results in human AIDS patients, individual performance was impaired most often on battery tasks thought to be sensitive to frontostriatal dopaminergic functioning such as SOSS, RT, and BMS. These results further demonstrate the similarity of behavioral impairment produced by SIV and HIV on homologous behavioral tests, and establish the utility of the testing battery for further investigations into the CNS mechanisms of the reported behavioral changes.

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. Objective: The goal of the current study was to contrast cholinergic and glutamatergic contributions to performance of this AD-sensitive task by challenging rhesus monkeys performing vsPAL with muscarinic antagonist and non-competitive NMDA antagonist drugs. Methods: Seven monkeys were trained to perform vsPAL and then serially challenged with acute doses of scopolamine (3, 10, 17 µg/kg, IM) and ketamine (0.3, 1.0, 1.78 mg/kg, IM). Results: Scopolamine produced a dose×difficulty related impairment of both recognition memory and incremental acquisition aspects of task performance. In contrast, ketamine administration resulted in a dose-dependent impairment of recognition memory but not incremental acquisition. Conclusions: Monkeys' performance of a task sensitive to AD in humans was impaired by two classic pharmacological models of cognitive impairment, therefore supporting the use of this nonhuman model to explore mechanisms of AD-associated cognitive decline. The differential pattern of impairment observed is consistent with a hypothesis that muscarinic mechanisms are required for linking external events with an existing internal representation, whereas NMDA mechanisms are required for the formation/strengthening of such an internal representation.

Simian immunodeficiency virus (SIV) infection of rhesus monkeys provides an excellent model of the central nervous system (CNS) consequences of HIV infection. To discern the relationship between viral load and abnormalities induced in the CNS by the virus, we infected animals with SIV and later instituted antiviral treatment to lower peripheral viral load. Measurement of sensory-evoked potentials, assessing CNS neuronal circuitry, revealed delayed latencies after infection that could be reversed by lowering viral load. Cessation of treatment led to the reappearance of these abnormalities. In contrast, the decline in general motor activity induced by SIV infection was unaffected by antiviral treatment. An acute increase in the level of the chemokine monocyte chemoattractant protein-1 (MCP-1) was found in the cerebrospinal fluid (CSF) relative to plasma in the infected animals at the peak of acute viremia, likely contributing to an early influx of immune cells into the CNS. Examination of the brains of the infected animals after return of the electrophysiological abnormalities revealed diverse viral and inflammatory findings. Although some of the physiological abnormalities resulting from SIV infection can be at least temporarily reversed by lowering viral load, the viral-host interactions initiated by infection may result in long-lasting changes in CNS-mediated functions.

Central nervous system (CNS) damage and dysfunction are devastating consequences of HIV infection. Although the CNS is one of the initial targets for HIV infection, little is known about early viral-induced abnormalities that can affect CNS function. Here we report the detection of early physiological abnormalities in simian immunodeficiency virus-infected monkeys. The acute infection caused a disruption of the circadian rhythm manifested by rises in body temperature, observed in all five individuals between 1 and 2 weeks postinoculation (p.i.), accompanied by a reduction in daily motor activity to 50% of control levels. Animals remained hyperthermic at 1 and 2 months p.i. and returned to preinoculation temperatures at 3 months after viral inoculation. Although motor activity recovered to baseline values at 1 month p.i., activity levels then decreased to approximately 50% of preinoculation values over the next 2 months. Analysis of sensory-evoked responses 1 month p.i. revealed distinct infection-induced changes in auditory-evoked potential peak latencies that persisted at 3 months after viral inoculation. These early physiological abnormalities may precede the development of observable cognitive or motor deficiencies and can provide an assay to evaluate agents to prevent or alleviate neuronal dysfunction.

A model is proposed in which a neurovirulent, microglial-passaged, simian immunodeficiency virus (SIV) is used to produce central nervous system (CNS) pathology and behavioral deficits in rhesus monkeys reminiscent of those seen in humans infected with human immunodeficiency virus (HIV). The time course of disease progression was characterized by using functional measures of cognition and motor skill, as well as neurophysiologic monitoring. Concomitant assessment of immunological and virological parameters illustrated correspondence between impaired behavioral performance and viral pathogenesis. Convergent results were obtained from neuropathological findings indicative of significant CNS disease. In ongoing studies, this SIV model is being used to explore the behavioral sequelae of immunodeficiency virus infection, the viral and host factors leading to neurologic dysfunction, and to begin testing potential therapeutic agents.

Many CNS pathologies, including Parkinson's, Alzheimer's and Huntington's diseases, as well as AIDS dementia complex, involve some degree of movement dysfunction. Reaction time (RT) performance has been shown to be a sensitive measure of motor function for these disorders. Useful models of RT performance exist in a variety of species, but few are performed in the same manner as with humans. To facilitate species comparisons, the present RT task was developed from a human RT task. Dopaminergic drugs were then used to characterize the sensitivity of the model to CNS changes and to investigate their effects on RT performance in intact rhesus monkeys. With cumulative dosing, the selective dopamine receptor antagonists (D1) SCH 39166 and (D2) raclopride produced dose-dependent slowing of RT performance. Results following bolus administration of these drugs were consistent with the cumulative dosing procedure, although of smaller magnitude and higher variability. Amphetamine had no significant effect on group RT performance with either dosing scheme, but RT performance in individual monkeys was either speeded or slowed by d-amphetamine. The present results suggest that blockade of either D1-like or D2-like dopamine receptors can slow RT performance in rhesus monkeys and that this paradigm may be useful to study movement dysfunction in non-human primates.

In behavioral economics, the unit price (UP) model of drug consumption defines UP as the ratio of the response requirement to the dose of drug. This model makes two predictions: increasing UP will decrease consumption, and consumption at a given UP will be constant regardless of the response requirement and dose that make up the UP. The present experiment was designed to test the UP model in rhesus monkeys allowed to choose between an IV injection of cocaine and food in a discrete-trials choice procedure. Both response requirement/injection and dose of cocaine were varied in such a way as to yield UPs from 40 to 10,000 responses per mg/kg. The response requirement for food was always 30 and there was a 30-min time-out between trials to allow the direct effects of cocaine on responding to dissipate. Consistent with the UP model, cocaine consumption decreased as UP increased. However, at a given UP, cocaine consumption was usually higher at the higher dose. Thus, under the conditions of the present experiment an important component of the UP model of drug consumption was not supported. It may be that UP is not a reliable predictor of consumption under conditions in which the direct effects of a drug on responding are minimized.

Rhesus monkeys with IV catheters were allowed to self-administer cocaine for 1 h/day. When responding was stable, saline or the D1 dopamine agonist SKF 81297 (SKF; 0.001–0.3 mg/kg/inj) was substituted for cocaine. At least two doses of SKF maintained responding above saline levels in all monkeys. The D1 antagonist SCH 39166 (0.001–0.03 mg/kg, IM) was then administered 30 min before sessions of self-administration of the lowest dose of SKF that maintained behavior (0.01 mg/kg/inj). SKF-maintained responding decreased in a dose-related manner, suggesting antagonism of the reinforcing effect. These results suggest that stimulation of D1 receptors can initiate a reinforcing effect and further implicate D1 receptors in the reinforcing effects of drugs that increase dopamine neurotransmission.

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. Despite years of use in developed countries, it is still not clear what the long-term impact of HAART will be on NeuroAIDS. The mechanisms of AIDS-related CNS pathology, in the presence or absence of HAART, are not completely understood. Infection with simian immunodeficiency virus (SIV) in macaques provides an excellent research model of AIDS, including AIDS-related CNS pathology and cognitive/behavioral impairments. A major goal of research with the SIV/macaque model has been to characterize behavioral and cognitive impairments in NeuroAIDS and elucidate the CNS pathology behind these impairments. Review of the studies assessing cognitive impairment in SIV infected macaques demonstrates the high concordance between neuropsychological impairment in human and simian AIDS. Consistent with results in human AIDS patients, SIV-infected monkeys tend to be impaired most often on tasks dependent upon intact frontal cortical and/or subcortical functioning. Building on the strengths of the SIV/macaque model of AIDS, directions for future research are discussed including further mechanistic studies of the neuropathology leading to cognitive impairment as well as assessment of the impact of antiretroviral therapy or drugs of abuse on NeuroAIDS.