Explore the vast range of titles available.

Although nicotine exposure upregulates the alpha 4 beta 2* subtype of nicotinic acetylcholine receptors (nAChRs), the upregulation of nAChRs in non-human primates voluntarily self-administering nicotine has never been demonstrated. The objective of the study is to determine if short access to nicotine in a non-human primate model of nicotine self-administration is sufficient to induce nAChRs upregulation. We combined a nicotine self-administration paradigm with in vivo measure of alpha 4 beta 2* nAChRs using 2-[ super(18)F]fluoro-A-85380 (2-FA) and positron emission tomography (PET) in six squirrel monkeys. PET measurement was performed before and after intravenous nicotine self-administration (unit dose 10 mu g/kg per injection). Monkeys were trained to self-administer nicotine under a fixed-ratio (FR) schedule of reinforcement. Intermittent access (1 h daily per weekday) to nicotine was allowed for 4 weeks and levels of alpha 4 beta 2* nAChRs were measured 4 days later. This intermittent access was sufficient to induce upregulation of alpha 4 beta 2* receptors in the whole brain (31 % upregulation) and in specific brain areas (+36 % in amygdala and +62 % in putamen). These results indicate that intermittent nicotine exposure is sufficient to produce change in nAChRs expression.

Features of the tumor microenvironment influence the efficacy of cancer nanotherapeutics. The ability to directly radiolabel nanotherapeutics offers a valuable translational tool to obtain biodistribution and tumor deposition data, testing the hypothesis that the extent of delivery predicts therapeutic outcome. In support of a first in-human clinical trial with super(64)Cu-labeled HER2-targeted liposomal doxorubicin ( super(64)Cu-MM-302), a preclinical dosimetric analysis was performed. Whole-body biodistribution and pharmacokinetic data were obtained in mice that received super(64)Cu-MM-302 and used to estimate absorbed radiation doses in normal human organs. PET/CT imaging revealed non-uniform distribution of super(64)Cu signal in mouse kidneys. Kidney micro-dosimetry analysis was performed in mice and squirrel monkeys, using a physiologically based pharmacokinetic model to estimate the full dynamics of the super(64)Cu signal in monkeys. Organ-level dosimetric analysis of mice receiving super(64)Cu-MM-302 indicated that the heart was the organ receiving the highest radiation absorbed dose, due to extended liposomal circulation. However, PET/CT imaging indicated that super(64)Cu-MM-302 administration resulted in heterogeneous exposure in the kidney, with a focus of super(64)Cu activity in the renal pelvis. This result was reproduced in primates. Kidney micro-dosimetry analysis illustrated that the renal pelvis was the maximum exposed tissue in mice and squirrel monkeys, due to the highly concentrated signal within the small renal pelvis surface area. This study was used to select a starting clinical radiation dose of super(64)Cu-MM-302 for PET/CT in patients with advanced HER2-positive breast cancer. Organ-level dosimetry and kidney micro-dosimetry results predicted that a radiation dose of 400 MBq of super(64)Cu-MM-302 should be acceptable in patients.

Rationale: Benzodiazepines (BZs) are effective anxiolytics and hypnotics, but their use is limited by unwanted side effects, such as motor impairment. Objectives: To assess the contribution of a1 subunit-containing g-aminobutyric acidA (GABAA) receptor subtypes to the motor-impairing effects of BZs, the present study evaluated two observable measures of motor coordination (balance on a pole, resistance to hind-limb flexion) engendered by nonselective and selective BZ-site agonists in squirrel monkeys. Materials and methods: Multiple doses of nonselective BZs (triazolam, alprazolam, diazepam, and chlordiazepoxide) and a1 subunit-preferring agonists (zolpidem and zaleplon) were administered to adult male squirrel monkeys (N=4-6), and experimenters rated the monkey's ability to balance on a horizontal pole ('ataxic-like effects'), as well as the degree of resistance to hind-limb flexion ('myorelaxant-like effects'). Results: Administration of all BZ-type drugs resulted in ataxic-like and myorelaxant-like effects. Pretreatment with the a1 subunit-preferring antagonist b-carboline-3-carboxylate-t-butyl ester (bCCT) attenuated the ataxic-like effects engendered by both types of drugs. However, bCCT was largely ineffective at blocking the ability of both BZs and non-BZs to induce myorelaxant-like effects. Conclusions: These experiments demonstrate dose-dependent motor impairment in squirrel monkeys using quantitative behavioral observation techniques. Altogether, these findings suggest a lack of a prominent role for a1 subunit-containing receptors in the alteration of hind-limb flexion, a putative measure of myorelaxation, induced by BZ-type drugs in monkeys.

The platyrrhine family Cebidae (capuchin and squirrel monkeys) exhibit among the largest primate encephalization quotients. Each cebid lineage is also characterized by notable lineage-specific traits, with capuchins showing striking similarities to Hominidae such as high sensorimotor intelligence with tool use, advanced cognitive abilities, and behavioral flexibility. Here, we take a comparative genomics approach, performing genome-wide tests for positive selection across five cebid branches, to gain insight into major periods of cebid adaptive evolution. We uncover candidate targets of selection across cebid evolutionary history that may underlie the emergence of lineage-specific traits. Our analyses highlight shifting and sustained selective pressures on genes related to brain development, longevity, reproduction, and morphology, including evidence for cumulative and diversifying neurobiological adaptations across cebid evolution. In addition to generating a high-quality reference genome assembly for robust capuchins, our results lend to a better understanding of the adaptive diversification of this distinctive primate clade.

alpha-Synuclein expression is increased in dopaminergic neurons challenged by toxic insults. Here, we assessed whether this upregulation is accompanied by pathologic accumulation of alpha-synuclein and protein modifications (i.e. nitration, phosphorylation, and aggregation) that are typically observed in Parkinson disease and in other synucleinopathies. A single injection of the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to squirrel monkeys caused a buildup of alpha-synuclein but not of beta-synuclein or synaptophysin within nigral dopaminergic cell bodies. Immunohistochemistry and immunoelectron microscopy also revealed large numbers of dystrophic axons labeled with alpha-synuclein. Antibodies that recognize nitrated and phosphorylated (at serine 129) alpha-synuclein stained neuronal cell bodies and dystrophic axons in the midbrain of MPTP-treated animals. After toxicant exposure, alpha-synuclein deposition occurred at the level of neuronal axons in which amorphous protein aggregates were observed by immunoelectron microscopy. In a subset of these axons, immunoreactivity for alpha-synuclein was still evident after tissue digestion with proteinase K, further indicating the accumulation of insoluble protein. These data indicate that toxic injury can induce alpha-synuclein modifications that have been implicated in the pathogenesis of human synucleinopathies. The findings are also consistent with a pattern of evolution of alpha-synuclein pathology that may begin with the accumulation and aggregation of the protein within damaged axons.

Due to many physiological and genetic characteristic similarities to humans, squirrel monkeys provide an ideal animal model specifically for studying malaria, and transmissible spongiform encephalopathies (Creutzfeldt-Jacob disease). While squirrel monkeys three years and older are generally considered adult subjects suitable for use in medical research studies, little is known about the functional properties of lymphocytes in relation to the age of these animals, which could significantly impact the quality and quantity of innate and adaptive immune responses. In this study, we investigated differences in the phenotype and function of lymphocytes subsets of young (3-4 years), adult (8-10 years) and aged (16-19 years) squirrel monkeys. In general, animals in all three age groups exhibited comparable numbers of different lymphocyte subsets except for CD20+ B cells that were significantly lower in aged relative to young animals and T cells subsets expressing both CD4 and CD8 (double positive) were significantly higher in aged relative to young animals. With increasing age, phenotypic differences in central and effector memory T cells subsets were observed, that were more pronounced for the CD8+ T cells. Despite equal proportions of CD3+ T cells among the three age groups, responses of peripheral blood mononuclear cells to T cell mitogens PHA and Con A showed lower IFN- gamma producing cells in the aged group than that in the young group. Furthermore, aged animals showed significantly higher plasma levels of inflammatory cytokines IL-6, IFN- gamma , TNF- alpha , IL-10 and IL-12. These findings suggest that while the squirrel monkeys in general share phenotypic and functional similarities of lymphocyte subsets with humans in relation to age, specific differences exist in immune function of lymphocytes between young and old animals that could potentially impact experimental outcomes for which the measurement of immunologic endpoints are critical.

Rationale: Benzodiazepine agonists characteristically increase food intake in humans and non-human subjects, and the underlying mechanisms of this effect are not understood completely. Objective: Compounds with selectivity for GABA sub(A) receptor subtypes were used to evaluate the role of GABA sub(A) receptors containing alpha 1 and alpha 5 subunits ( alpha 1GABA sub(A) and alpha 5GABA sub(A) receptors, respectively) in benzodiazepine-induced increases in sucrose pellet consumption. Materials and methods: Adult male squirrel monkeys (N=4-6), maintained under free-feeding conditions, were administered with intramuscular injections of the nonselective benzodiazepines diazepam and alprazolam, the alpha 1GABA sub(A)-preferring compounds zolpidem and zaleplon, or the alpha 5GABA sub(A)-preferring agonist QH-ii-066 before daily 10-min periods when sucrose pellets were available. In a separate experiment, observable behavioral effects (e.g., ataxia and procumbent posture) were quantified after administration of alprazolam, zaleplon, and QH-ii-066. To further assess the roles of GABA sub(A) receptor subtypes, zolpidem-induced increases in pellet consumption were re-evaluated after pretreatment with nonselective antagonist flumazenil, the alpha 1GABA sub(A)-preferring antagonist beta -carboline-3-carboxylate-t-butyl ester (BCCT), or QH-ii-066. Results: Alprazolam, diazepam, zolpidem, and zaleplon but not QH-ii-066 significantly increased sucrose pellet consumption. In addition, all agonists decreased locomotion and environment-directed behavior as well as engendered ataxia and procumbent posture. For all compounds except QH-ii-066, these behaviors occurred at doses similar to those that increased pellet consumption. Flumazenil and BCCT, but not QH-ii-066, antagonized zolpidem-induced increases in pellet consumption in a surmountable fashion. Conclusion: These results suggest that the alpha 1GABA sub(A) receptor subtype plays a key role in benzodiazepine-induced increases in consumption of palatable food, whereas the alpha 5GABA sub(A) receptor subtype may not be involved in this effect.

Prior research on non-human primates has produced contradictory results regarding behavioral flexibility and habit formation. Most observational studies of wild primates show flexibility in foraging behavior, whereas experimental data suggest captive primates tend to form habits, thus displaying conservative tendencies. Jacobson and Hopper (2019) proposed and supported the hypothesis that captive apes’ conservatism resulted from causally-unclear experimental apparatuses rather than a lack of flexibility as previous studies concluded. We replicated the experiment conducted by Jacobson and Hopper (2019) on apes with 18 brown capuchin monkeys ( Cebus [ Sapajus ] apella ) and five squirrel monkeys ( Saimiri sciureus ). Our goal was to investigate if they showed a similar degree of flexibility to chimpanzees ( Pan troglodytes ) and western lowland gorillas ( Gorilla gorilla gorilla ) when presented with a causally-clear task. Thus, the primary aim of this study was to determine whether this task was causally clear to monkeys, and if so, to compare their performance to that of apes. Monkeys were presented with a baited, clear tube where the removal of rods would allow the reward to drop, thus enabling the subject to retrieve said reward. Phase 1 of the study allowed us to determine whether the monkeys had a causal understanding of the task and provided an opportunity for habits to develop. Phase 2 presented the monkeys with a new reward configuration, requiring the removal of fewer rods to retrieve the reward to test if their causal understanding of the task would result in a flexible, more efficient response. The capuchins demonstrated cognitive flexibility and possible causal understanding in a manner similar to that of the apes. However, only one of five squirrel monkeys was efficient, suggesting the majority may not have understood a causal relationship between removing the rods and receiving the reward. Our study supports Jacobson and Hopper’s (2019) conclusion that causally-clear tasks reduce habit formation and conservatism in capuchins, but more evidence is needed with respect to squirrel monkeys.

New World monkeys are especially vulnerable to develop severe clinical manifestations and succumb to acute toxoplasmosis. This study aimed to describe the histopathological findings and genotypic characterization of the Toxoplasma gondii strain involved in a lethal case occurring in a zoo-housed black-capped squirrel monkey (Saimiri boliviensis) in Portugal. Cyst-like structures suggestive of Sarcocystidae parasites and acute injuries in liver and brain were observed by light microscopy examination. By immunohistochemistry, calprotectin, T. gondii antigen and Iba1 antigen had a positive signaling in lung, liver and brain tissues. Toxoplasma gondii B1, ITS1 and 529 repetitive element fragments amplifications together with the genotyping of 13 microsatellite markers confirmed a systemic T. gondii infection linked to a non-clonal type II strain. This description is consistent to the majority T. gondii strains circulating in Europe.

Rationale. Experimental evidence from animal studies suggests reciprocal functional interactions between endogenous brain cannabinoid and opioid systems. There is recent evidence for a role of the opioid system in the modulation of the reinforcing effects of synthetic cannabinoid CB1 receptor agonists in rodents. Since Delta super(9)-tetrahydrocannabinol (THC), the natural psychoactive ingredient in marijuana, is actively and persistently self-administered by squirrel monkeys, this provides an opportunity to directly study involvement of opioid systems in the reinforcing effects of THC in non-human primates.Objectives. To study the effects of naltrexone, an opioid antagonist, on THC self-administration behavior in squirrel monkeys.Methods. Monkeys pressed a lever for intravenous injections of THC under a ten-response, fixed-ratio (FR) schedule with a 60-s time-out after each injection. Effects of pre-session treatment with naltrexone (0.03-0.3 mg/kg intramuscularly, 15 min before session) for 5 consecutive days on self-administration of different doses of THC (2-8 mu g/kg per injection) were studied.Results. Self-administration responding for THC was significantly reduced by pretreatment with 0.1 mg/kg naltrexone for five consecutive daily sessions. Naltrexone pretreatment had no significant effect on cocaine self-administration responding under identical conditions.Conclusions. Self-administration behavior under a fixed-ratio schedule of intravenous THC injection was markedly reduced by daily pre-session treatment with naltrexone, but remained above saline self-administration levels. These findings demonstrate for the first time the modulation of the reinforcing effects of THC by an opioid antagonist in a non-human primate model of marijuana abuse.