Development of a primate model to evaluate the effects of ketamine and surgical stress on the neonatal brain.

With advances in pediatric and obstetric surgery, pediatric patients are subject to complex procedures under general anesthesia. The effects of anesthetic exposure on the developing brain may be confounded by several factors including pre-existing disorders and surgery-induced stress. Ketamine, a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, is routinely used as a pediatric general anesthetic. However, controversy remains about whether ketamine exposure may be neuroprotective or induce neuronal degeneration in the developing brain. Here, we report the effects of ketamine exposure on the neonatal nonhuman primate brain under surgical stress. Eight neonatal rhesus monkeys (postnatal days 5-7) were randomly assigned to each of two groups: Group A (n = 4) received 2 mg/kg ketamine via intravenous bolus prior to surgery and a 0.5 mg/kg/h ketamine infusion during surgery in the presence of a standardized pediatric anesthetic regimen; Group B (n = 4) received volumes of normal saline equivalent to those of ketamine given to Group A animals prior to and during surgery, also in the presence of a standardized pediatric anesthetic regimen. Under anesthesia, the surgery consisted of a thoracotomy followed by closing the pleural space and tissue in layers using standard surgical techniques. Vital signs were monitored to be within normal ranges throughout anesthesia. Elevated levels of cytokines interleukin (IL)-8, IL-15, monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein (MIP)-1ß at 6 and 24 h after surgery were detected in ketamine-exposed animals. Fluoro-Jade C staining revealed significantly higher neuronal degeneration in the frontal cortex of ketamine-exposed animals, compared with control animals. Intravenous ketamine administration prior to and throughout surgery in a clinically relevant neonatal primate model appears to elevate cytokine levels and increase neuronal degeneration. Consistent with previous data on the effects of ketamine on the developing brain, the results from the current randomized controlled study in neonatal monkeys undergoing simulated surgery show that ketamine does not provide neuroprotective or anti-inflammatory effects.

Establishment of neural stem cells from fetal monkey brain for neurotoxicity testing.

Neurotoxicity assessments are generally performed using laboratory animals. However, as in vitro neurotoxicity models are continuously refined to reach adequate predicative concordance with in vivo responses, they are increasingly used for some endpoints of neurotoxicity. In this study, gestational day 80 fetal rhesus monkey brain tissue was obtained for neural stem cells (NSCs) isolation. Cells from the entire hippocampus were harvested, mechanically dissociated, and cultured for proliferation and differentiation. Immunocytochemical staining and biological assays demonstrated that the harvested hippocampal cells exhibited typical NSC phenotypes in vitro: (1) cells proliferated vigorously and expressed NSC markers nestin and sex-determining region Y-box 2 (SOX2) and (2) cells differentiated into neurons, astrocytes, and oligodendrocytes, as confirmed by positive staining with class III ß-tubulin, glial fibrillary acidic protein, and galactocerebroside, respectively. The NSC produced detectable responses following neurotoxicant exposures (e.g. trimethyltin and 3-nitropropionic acid). Our results indicated that non-human primate NSCs may be a practical tool to study the biology of neural cells and to evaluate the neurotoxicity of chemicals in vitro, thereby providing data that are translatable to humans and may also reduce the number of animals needed for developmental neurotoxicological studies.

Discontinuation of methylphenidate after long-term exposure in nonhuman primates.

Attention-deficit hyperactivity disorder (ADHD) is a common human neurobehavioral disorder that usually begins in early childhood. Methylphenidate (MPH) has been used extensively as a first-line medicine for the treatment of ADHD. Since ADHD is often diagnosed in early childhood and can persist for the entire lifespan, individuals may take MPH for many years. Given that in the course of one's lifetime a person may stop taking MPH for periods of time, or may implement lifestyle changes that may reduce the need for MPH entirely, it is important to understand how cessation of MPH affects the adult brain following long-term use of MPH. The blockage of the dopamine transporter (DAT) and the norepinephrine transporter (NET) by MPH may help with ADHD symptoms by boosting monoamine levels in the synapse. In the present study, microPET/CT was used to investigate possible neurochemical alterations in the cerebral dopamine system after cessation of long-term MPH administration in nonhuman primates. MicroPET/CT images were collected from adult male rhesus monkeys 6 months after they stopped receiving vehicle or MPH following 12 years of chronic treatment. The neurochemical status of brain dopaminergic systems was evaluated using the vesicular monoamine transporter 2 (VMAT2) ligand [18F]-AV-133 and a tracer for imaging dopamine subtype 2 (D2) and serotonin subfamily 2 (5HT2) receptors, [18F]-FESP. Each tracer was injected intravenously and ten minutes later microPET/CT images were obtained over 120 min. The binding potential (BP) of each tracer in the striatum was obtained using the Logan reference tissue model with the cerebellar cortex time activity curve (TAC) as an input function. Brain metabolism was also evaluated using microPET/CT images of [18F]-FDG. [18F]-FDG was injected intravenously, and ten minutes later, microPET/CT images were obtained over 120 min. Radiolabeled tracer accumulation in regions of interest (ROIs) in the prefrontal cortex, temporal cortex, striatum, and cerebellum were converted into standard uptake values (SUVs). Compared to the vehicle control group, the BPs of [18F] AV-133 and [18F]-FESP in the striatum were not significantly altered in MPH treated groups. Additionally, no significant differences were detected in the SUVs of [18F]-FDG in the MPH treated group compared with control. This study demonstrates that 6 months after cessation of long-term, chronic MPH treatment, there are no significant neurochemical or neural metabolic changes in the central nervous system (CNS) of non-human primates (NHPs) and suggests that microPET imaging is helpful in assessing the status of biomarkers of neurochemical processes linked to chronic CNS drug exposure. (Supported by NCTR).

The effects of long-term methylphenidate administration and withdrawal on progressive ratio responding and T2 MRI in the male rhesus monkey.

Methylphenidate is a frequently prescribed drug treatment for Attention-Deficit/Hyperactivity Disorder. However, methylphenidate has a mode of action similar to amphetamine and cocaine, both powerful drugs of abuse. There is lingering concern over the long-term safety of methylphenidate, especially in a pediatric population, where the drug may be used for years. We performed a long-term evaluation of the effects of chronic methylphenidate use on a behavioral measure of motivation in male rhesus monkeys. Animals were orally administered a sweetened methylphenidate solution (2.5 or 12.5 mg/kg, twice a day, Mon-Fri) or vehicle during adolescence and into adulthood. These animals were assessed on a test of motivation (progressive ratio responding), during methylphenidate treatment, and after cessation of use. Moreover, animals were evaluated with quantitative T2 MRI about one year after cessation of use. During the administration phase of the study animals treated with a clinically relevant dose of methylphenidate generally had a higher rate of responding than the control group, while the high dose group generally had a lower rate of responding. These differences were not statistically significant. In the month after cessation of methylphenidate, responding in both experimental groups dropped compared to their previous level of performance (p = 0.19 2.5 mg/kg, p = 0.06 12.5 mg/kg), and responding in the control animals was unchanged (p = 0.81). While cessation of methylphenidate was associated with an acute reduction in responding, group differences were not observed in the following months. These data suggest that methylphenidate did not have a significant impact on responding, but withdrawal from methylphenidate did cause a temporary change in motivation. No changes in T2 MRI values were detected when measured about one year after cessation of treatment. These data suggest that long-term methylphenidate use does not have a negative effect on a measure of motivation or brain function / microstructure as measured by quantitative T2 MRI. However, cessation of use might be associated with temporary cognitive changes, specifically alteration in motivation. Importantly, this study modeled use in healthy individuals, and results may differ if the same work was repeated in a model of ADHD.

Genotoxicity evaluation using primary hepatocytes isolated from rhesus macaque (Macaca mulatta).

Non-human primates (NHPs) have played a vital role in fundamental, pre-clinical, and translational studies because of their high physiological and genetic similarity to humans. Here, we report a method to isolate primary hepatocytes from the livers of rhesus macaques (Macaca mulatta) after in situ whole liver perfusion. Isolated primary macaque hepatocytes (PMHs) were treated with various compounds known to have different pathways of genotoxicity/carcinogenicity and the resulting DNA damage was evaluated using the high-throughput CometChip assay. The comet data were quantified using benchmark dose (BMD) modeling and the BMD50 values for treatments of PMHs were compared with those generated from primary human hepatocytes (PHHs) in our previous study (Seo et al. Arch Toxicol 2020, 2207-2224). The results showed that despite varying CYP450 enzyme activities, PMHs had the same sensitivity and specificity as PHHs in detecting four indirect-acting (i.e., requiring metabolic activation) and seven direct-acting genotoxicants/carcinogens, as well as five non-carcinogens that are negative or equivocal for genotoxicity in vivo. The BMD50 estimates and their confidence intervals revealed species differences for DNA damage potency, especially for direct-acting compounds. The present study provides a practical method for maximizing the use of animal tissues by isolating primary hepatocytes from NHPs. Our data support the use of PMHs as a reliable surrogate of PHHs for evaluating the genotoxic hazards of chemical substances for humans.

Can SARS-CoV-2 infect the central nervous system via the olfactory bulb or the blood-brain barrier?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China in December 2019. On February 11, the World Health Organization (WHO) announced the name for the new illness caused by SARS-CoV-2: COVID-19. By March 11, the outbreak of COVID-19 was declared a pandemic by the WHO. This virus has extensively altered daily life for many across the globe, while claiming hundreds of thousands of lives. While fundamentally a respiratory illness, many infected individuals experience symptoms that involve the central nervous system (CNS). It is likely that many of these symptoms are the result of the virus residing outside of the CNS. However, the current evidence does indicate that the SARS-CoV-2 virus can use olfactory neurons (or other nerve tracts) to travel from the periphery into the CNS, and that the virus may also enter the brain through the blood-brain barrier (BBB). We discuss how the virus may use established infection mechanisms (ACE2, NRP1, TMPRSS2, furin and Cathepsin L), as well mechanisms still under consideration (BASIGIN) to infect and spread throughout the CNS. Confirming the impact of the virus on the CNS will be crucial in dealing with the long-term consequences of the epidemic.

This is your teen brain on drugs: In search of biological factors unique to dependence toxicity in adolescence.

Response variability across the lifespan is an important consideration in toxicology and risk assessment, and the toxic effects of drugs and chemicals during adolescence need more research. This paper summarizes a workshop presented in March 2019, at the Society of Toxicology Annual Meeting in Baltimore, Maryland, that brought together experts in research on drug dependence and toxicity related to nicotine, cannabis, cocaine, and other illicit drugs during adolescence. The goal of the workshop was to address the following issues: (1) Do the effects of adolescent exposure differ from the same exposure in adults? (2) Are there unique biological markers of adolescent brain development? If so, what are they and how reliable are they? (3) Since multiple factors influence substance use disorder, can we disentangle risk factors for abuse and/or toxicity? What are the underlying biological susceptibilities that lead to dependence and neurotoxicity? What are the social, psychosocial and environmental factors that contribute to abuse susceptibilities? This paper reviews drug policy and national trends in adolescent substance use; the public health consequences of e-cigarettes; rat models of adolescent-onset nicotine self-administration and persisting effects of gestational nicotine; sex-dependent effects of delta-9-tetrahydrocannabinol on adolescent brain-behavior relationships; and translational approaches for identifying adolescent risk factors for transition to drug dependence. There is strong evidence that drug exposure prior to adulthood has longer lasting effects on behavior and the underlying neural circuitry. These effects, which are sex-dependent and influenced by stress, may be candidates as predictors of adolescent vulnerability. A major challenge to determining if adolescents have a unique susceptibility to dependence is whether and to what extent the human data allow distinction between the increased risk due to biological immaturity, an underlying biological susceptibility to dependence, or psychosocial and environmental factors for substance dependence. Factors important to consider for development of animal models include the timing and pattern of exposure as it relates to adolescence; age of assessment, and direct comparison with similar effects following exposures to adults to demonstrate that these effects are unique to adolescence. Here we provide a roadmap for further research into what makes adolescent brain development unique.

Acetyl-l-carnitine does not prevent neurodegeneration in a rodent model of prolonged neonatal anesthesia.

Many studies have shown that prolonged or repeated use of general anesthesia early in life can cause an increase in neurodegeneration and lasting changes in behavior. While short periods of general anesthesia appear to be safe, there is a concern about the neurotoxic potential of prolonged or repeated general anesthesia in young children. Unfortunately, the use of general anesthesia in children cannot be avoided. It would be a great benefit to develop a strategy to reduce or reverse anesthesia mitigated neurotoxicity. The mechanisms behind anesthesia related neurotoxicity are unknown, but evidence suggests that mitochondrial dysfunction and abnormal energy utilization are involved. Recent research suggests that a class of compounds known as carnitines may be effective at preventing anesthesia related neurotoxicity by influencing fatty acid metabolism in the mitochondria. However, it is unknown if carnitines can provide protection against changes in behavior associated with early life exposure to anesthesia. Accordingly, we evaluated the neuroprotective potential of acetyl-l-carnitine in 7-day old rats. Rat pups were exposed to 6 h of general anesthesia with sevoflurane or a control condition, with and without acetyl-l-carnitine. The oxygenation level of animals was continuously monitored during sevoflurane exposure, and any animal showing signs of hypoxia was removed from the study. Animals exposed to sevoflurane showed clear signs of neurodegeneration 2 h after sevoflurane exposure. The hippocampus, cortex, thalamus, and caudate putamen all had elevated levels of Fluoro-Jade C staining. Despite the elevated levels of Fluoro-Jade C, few behavioral changes were observed in an independent cohort of animals treated with sevoflurane. Furthermore, acetyl-l-carnitine had little impact on levels of Fluoro-Jade C staining in animals treated with sevoflurane. These data suggest that acetyl-l-carnitine may offer little protection again anesthesia related neurotoxicity in fully oxygenated animals.

Regions of the basal ganglia and primary olfactory system are most sensitive to neurodegeneration after extended sevoflurane anesthesia in the perinatal rat.

Extended general anesthesia early in life is neurotoxic in multiple species. However, little is known about the temporal progression of neurodegeneration after general anesthesia. It is also unknown if a reduction in natural cell death, or an increase in cell creation, occurs as a form of compensation after perinatal anesthesia exposure. The goal of this study was to evaluate markers of neurodegeneration and cellular division at 2, 24, or 72 h after sevoflurane (Sevo) exposure (6 h) in fully oxygenated postnatal day (PND) 7 rats. Neurodegeneration was observed in areas throughout the forebrain, while the largest changes (fold increase above vehicle) were observed in areas associated with either the primary olfactory learning pathways or the basal ganglia. These regions included the indusium griseum (IG, 25-fold), the posterior dorso medial hippocampal CA1 (17-fold), bed nucleus of the stria terminalis (Bed Nuclei STM, 5-fold), the shell of the nucleus accumbens (Acb, 5-fold), caudate/putamen (CPu, 5-fold), globus pallidus (GP, 9-fold) and associated thalamic (11-fold) and cortical regions (5-fold). Sevo neurodegeneration was minimal or undetectable in the ventral tegmentum, substantia nigra, and most of the hypothalamus and frontal cortex. In most brain regions where neurodegeneration was increased 2 h post Sevo exposure, the levels returned to <4-fold above control levels by 24 h. However, in the IG, CA1, GP, anterior thalamus, medial preoptic nucleus of the hypothalamus (MPO), anterior hypothalamic area (AHP), and the amygdaloid nuclei, neurodegeneration at 24 h was double or more than that at 2 h post exposure. Anesthesia exposure causes either a prolonged period of neurodegeneration in certain brain regions, or a distinct secondary degenerative event occurs after the initial insult. Moreover, regions most sensitive to Sevo neurodegeneration did not necessarily coincide with areas of new cell birth, and new cell birth was not consistently affected by Sevo. The profile of anesthesia related neurotoxicity changes with time, and multiple mechanisms of toxicity may exist in a time-dependent fashion.

Sevoflurane exposure has minimal effect on cognitive function and does not alter microglial activation in adult monkeys.

Postoperative Cognitive Dysfunction (POCD) is a complication that has been observed in a subset of adult and elderly individuals after general anesthesia and surgery. Although the pathogenesis of POCD is largely unknown, a growing body of preclinical research suggests that POCD may be caused by general anesthesia. A significant amount of research has examined the effects of general anesthesia on neurocognitive function in rodents, yet no studies have assessed the adverse effects of general anesthesia on brain function in adult nonhuman primates. Thus, this study sought to determine the effects of an extended exposure to sevoflurane anesthesia on cognitive function and neural inflammation in adult rhesus macaques. Five adult rhesus macaques (16-17 years of age) were exposed to sevoflurane anesthesia for 8 h and, and micro-positron emission tomography (PET)/computed tomography (CT) imaging and a battery of operant tasks were used to assess the effects of anesthesia exposure on 18F-labeled fluoroethoxybenzyl-N-(4-phenoxypyridin-3-yl) acetamide ([18F]-FEPPA) uptake, a biomarker of microglia activation, and aspects of complex cognitive function. Exposure to sevoflurane anesthesia for 8 h did not increase [18F]-FEPPA uptake in the adult monkey brain. Sevoflurane anesthesia significantly decreased accuracy (mean difference = 22.79) on a learning acquisition task 6 days after exposure [t(3) = 6.92, p = 0.006], but this effect did not persist when measured 1 week and 2 weeks after additional exposures. Further, sevoflurane anesthesia had no impact on performance in 4 additional cognitive tasks. These data suggest that exposure to anesthesia alone may not be sufficient to cause persistent POCD in adult populations.

Early life exposure to extended general anesthesia with isoflurane and nitrous oxide reduces responsivity on a cognitive test battery in the nonhuman primate.

Despite the widespread use of general anesthesia, a growing body of research suggests that anesthesia exposure early in life may be associated with acute neurotoxicity and lasting behavioral changes. To better evaluate the risk posed by early life anesthesia on cognitive development, infant rhesus monkeys were exposed to an anesthesia regimen previously shown to be neurotoxic and their cognitive development was subsequently measured using a translational operant test battery. On postnatal day 5 or 6, animals were exposed to 8 h of isoflurane (n = 6, 1% isoflurane in a vehicle gas of 70% nitrous oxide and 30% oxygen) or a control condition (n = 8). Starting at 7 months of age, the monkeys were continuously trained and assessed on the NCTR Operant Test Battery (OTB). The OTB consists of cognitive tests which also exist in near identical forms for use in rats and humans, and includes tests of learning, memory, color discrimination, and motivation. Monkeys previously exposed to anesthesia showed a clear decrease in responding in a measure of motivation, as well as a lower response rate in a learning task. These data further support the hypothesis that prolonged anesthesia early in life may increase the risk of developing cognitive impairments later in life.

Evaluating aged mice in three touchscreen tests that differ in visual demands: Impaired cognitive function and impaired visual abilities.

Normal aging is often accompanied by reductions in cognitive abilities as well as impairments in visual acuity in men and mice. In preclinical models of human cognition this concomitance can make it difficult to assess the relative contributions of declined vision and cognitive ability on behavioral measures of cognition. To assess the influence of age on cognition and the impact of visual decline on the performance of touchscreen-based behavioral paradigms in mice, aged (11, 12, 16, 17, 19 and 21 months old) male C57BL/6J mice were compared to young (3 or 4 months old) male C57BL/6J mice using three tests of cognition as well as an assessment of visual acuity. Performance of a Visual Discrimination, Spatial Reversal, and an Automated Search Task were all affected by age. However, there was no relationship between reduced visual acuity and the observed performance impairments. Moreover, the visual acuity of animals with profound cognitive impairments overlapped with those showing normal cognitive ability. Despite the potential confound of impaired visual ability, it appears that the touchscreen approach might be particularly effective in studying age-related cognitive decline. This approach will increase the utility of aged mice as a model of decreased cognitive flexibility and may be particularly important for the study of age-related disorders such as Alzheimer's disease.

Symptomatic thinking: the current state of Phase III and IV clinical trials for cognition in schizophrenia.

Research indicates that relieving the cognitive and negative symptoms of schizophrenia is crucial for improving patient quality of life. However effective pharmacotherapies for cognitive and negative symptoms do not currently exist. A review of ongoing Phase III clinical trials indicates that, despite numerous compounds being investigated for cognition in schizophrenia, few are actually novel and most are not backed by empirically driven preclinical research efforts. Based on these trials, and a general disinvestment in development of novel therapies for schizophrenia, the likelihood of a major advancement in treating cognitive differences in schizophrenia does not look promising. Possible ways in which the remaining resources for development of novel treatment for schizophrenia can best be leveraged are discussed.

Do wholes become more than the sum of their parts in the rodent (Rattus Norvegicus) visual system? A test case with the configural superiority effect.

The rodent has been used to model various aspects of the human visual system, but it is unclear to what extent human visual perception can be modelled in the rodent. Research suggests rodents can perform invariant object recognition tasks in a manner comparable to humans. There is further evidence that rodents also make use of certain grouping cues, but when performing a shape discrimination they have a tendency to rely much more on local image cues than human participants. In the current work, we exploit the fact that humans sometimes discriminate better between whole shapes, rather than the parts from which they are constructed, to ask whether rodents show a classic Configural Superiority Effect. Using touchscreen-equipped operant boxes, rats were trained to discriminate 'part' or 'whole' images based off of those used by J. R. Pomerantz et al. () J Exp Psychol Hum Percept Perform, 3, 422-435. Here, we show that rats show no advantage for wholes and that they perform better when presented with simpler image parts, a pattern of effect opposite to what was seen in humans when highly comparable stimuli were used. These results add to our understanding of the similarities and differences between the human and rodent visual system, and suggest that the rodent visual system may not compute part whole relationships in a way comparable to humans. These results are significant from both a comparative anatomy perspective, and of particular relevance for those wishing to use rodents to model visuo-perceptual deficits associated with human psychiatric disorders.

Dissociable effects of NR2A and NR2B NMDA receptor antagonism on cognitive flexibility but not pattern separation.

RATIONALE: N-methyl-D-aspartate (NMDA) receptors play crucial roles in learning and memory, but the role of each NMDA receptor subtype in a specific cognitive process is unclear. Non-selective blockers of NMDA receptor are used to model the cognitive impairment in schizophrenia and Alzheimer's disease. Counter-intuitively selective NR2A and 2B NMDA receptor antagonists are thought to have pro-cognitive properties. These seemingly contrasting findings might in part be the result of different compounds and behavioral measures used across studies. OBJECTIVE: We compared the effect of NVP-AAM077 (NR2A antagonist), CP 101-606 (NR2B antagonist), and MK-801 (non-selective antagonist) in a series of touch screen tasks that can be used to measure spatial cognition and cognitive flexibility. METHODS: NVP-AAM077, CP 101-606, and MK-801 were administered prior to testing, in adult male Lister-hooded rats trained in tasks of location discrimination, paired associate learning (PAL), and trial unique non-match to location (TUNL). RESULTS: Results showed that MK-801 impaired performance on all the tasks. In contrast, CP 101-606 only impaired reversal learning in location discrimination and had minimal effect on working memory in TUNL and caused a modest improvement in accuracy in PAL and acquisition of a spatial discrimination. NVP-AAM077 had little effect on performance across tasks, although these data allude to a potential enhancement of acquisition of a spatial location and impairments in spatial reversal learning in a separation-dependent manner. CONCLUSIONS: These data demonstrated that non-selective NMDA antagonism will disrupt numerous aspects of cognitive function. However, selective antagonism is capable of impairing or enhancing cognitive function in a task-dependent fashion.

The subchronic phencyclidine rat model: relevance for the assessment of novel therapeutics for cognitive impairment associated with schizophrenia.

RATIONALE: Current treatments for schizophrenia have modest, if any, efficacy on cognitive dysfunction, creating a need for novel therapies. Their development requires predictive animal models. The N-methyl-D-aspartate (NMDA) hypothesis of schizophrenia indicates the use of NMDA antagonists, like subchronic phencyclidine (scPCP) to model cognitive dysfunction in adult animals. OBJECTIVES: The objective of this study was to assess the scPCP model by (1) reviewing published findings of scPCP-induced neurochemical changes and effects on cognitive tasks in adult rats and (2) comparing findings from a multi-site study to determine scPCP effects on standard and touchscreen cognitive tasks. METHODS: Across four research sites, the effects of scPCP (typically 5 mg/kg twice daily for 7 days, followed by at least 7-day washout) in adult male Lister Hooded rats were studied on novel object recognition (NOR) with 1-h delay, acquisition and reversal learning in Morris water maze and touchscreen-based visual discrimination. RESULTS: Literature findings showed that scPCP impaired attentional set-shifting (ASST) and NOR in several labs and induced a variety of neurochemical changes across different labs. In the multi-site study, scPCP impaired NOR, but not acquisition or reversal learning in touchscreen or water maze. Yet, this treatment regimen induced locomotor hypersensitivity to acute PCP until 13-week post-cessation. CONCLUSIONS: The multi-site study confirmed that scPCP impaired NOR and ASST only and demonstrated the reproducibility and usefulness of the touchscreen approach. Our recommendation, prior to testing novel therapeutics in the scPCP model, is to be aware that further work is required to understand the neurochemical changes and specificity of the cognitive deficits.

Biased mGlu5-Positive Allosteric Modulators Provide In Vivo Efficacy without Potentiating mGlu5 Modulation of NMDAR Currents.

Schizophrenia is associated with disruptions in N-methyl-D-aspartate glutamate receptor subtype (NMDAR)-mediated excitatory synaptic signaling. The metabotropic glutamate receptor subtype 5 (mGlu5) is a closely associated signaling partner with NMDARs and regulates NMDAR function in forebrain regions implicated in the pathology of schizophrenia. Efficacy of mGlu5 positive allosteric modulators (PAMs) in animal models of psychosis and cognition was previously attributed to potentiation of NMDAR function. To directly test this hypothesis, we identified VU0409551 as a novel mGlu5 PAM that exhibits distinct stimulus bias and selectively potentiates mGlu5 coupling to Gαq-mediated signaling but not mGlu5 modulation of NMDAR currents or NMDAR-dependent synaptic plasticity in the rat hippocampus. Interestingly, VU0409551 produced robust antipsychotic-like and cognition-enhancing activity in animal models. These data provide surprising new mechanistic insights into the actions of mGlu5 PAMs and suggest that modulation of NMDAR currents is not critical for in vivo efficacy. VIDEO ABSTRACT.

Opposing effects of glutamatergic and GABAergic pharmacological manipulations on a visual perception task with relevance to schizophrenia.

RATIONALE: Numerous psychiatric disorders and neurodegenerative diseases have been associated with differences in visual perception, and it has been proposed that the treatment of these differences may represent a novel means to treat disorders like schizophrenia. Unfortunately, few methods exist to study visual perception in pre-clinical species. OBJECTIVE: The purpose of the present study was to adapt a task of visual integration by proximity with relevance to schizophrenia to a rodent touchscreen environment to determine the effects of glutamatergic and GABAergic compounds. In this way, we could evaluate the effects of common models of cognitive impairment, as well as the effects of net excitation versus inhibition, on a task of visual integration. METHOD: Rats were trained to perform a visual discrimination where the stimuli were composed of rows of dots differing only in there horizontal and vertical proximity. Once stable performance had been achieved, animals were tested under the influence of glutamatergic or GABAergic drugs (ketamine, MK-801, PCP, memantine, chlordiazepoxide, or diazepam) while attempting to perform a visual discrimination with altered stimuli. RESULTS: Ketamine appeared to impair perceptual grouping in this paradigm, while the GABA agonist chlordiazepoxide enhanced grouping even in the presence of non-selective effects. CONCLUSIONS: In general, these findings support the theory that NMDA antagonists may disrupt visual grouping by proximity and highlight a potential beneficial effect of enhanced GABA activity in perception. However, additional research will be required to confirm the stimulus selectivity of this effect, and the clinical significance of this approach.

Executive function.

Components of human executive function, like rule generation and selection in response to stimuli (attention set-shifting) or overcoming a habit (reversal learning), can be reliably modelled in rodents. The rodent paradigms are based upon tasks that assess cognitive flexibility in clinical populations and have been effective in distinguishing the neurobiological substrates and the underlying neurotransmitter systems relevant to executive function. A review of the literature on the attentional set-shifting task highlights a prominent role for the medial region of the prefrontal cortex in the ability to adapt to a new rule (extradimensional shift) while the orbitofrontal cortex has been associated with the reversal learning component of the task. In other paradigms specifically developed to examine reversal learning in rodents, the orbitofrontal cortex also plays a prominent role. Modulation of dopamine, serotonin, and glutamatergic receptors can disrupt executive function, a feature commonly exploited to develop concepts underlying psychiatric disorders. While these paradigms do have excellent translational construct validity, they have been less effective as predictive preclinical models for cognitive enhancers, especially for cognition in health subjects. Accordingly, a more diverse battery of tasks may be necessary to model normal human executive function in the rodent for drug development.

MK-801 and amphetamine result in dissociable profiles of cognitive impairment in a rodent paired associates learning task with relevance for schizophrenia.

RATIONALE: Paired associates learning (PAL) has been suggested to be predictive of functional outcomes in first episode psychosis and of conversion from mild cognitive impairment to Alzheimer's disease. An automated touch screen-based rodent PAL (rPAL) task has been developed and is sensitive to manipulations of the dopaminergic and glutamatergic system. Accordingly, rPAL when used with pharmacological models of schizophrenia, like NMDA receptor blockade with MK-801 or dopaminergic stimulation with amphetamine, may have utility as a translational model of cognitive impairment in schizophrenia. OBJECTIVE: The purpose of this study was to determine if amphetamine- and MK-801-induced impairment represent distinct models of cognitive impairment by testing their sensitivity to common antipsychotics and determine the relative contributions of D1 versus D2 receptors on performance of PAL. METHOD: Rats were trained in rPAL and were then treated with MK-801, amphetamine, risperidone, haloperidol, quinpirole, SK-82958, or SCH-23390 alone and in combination. RESULTS: While both amphetamine and MK-801 caused clear impairments in accuracy, MK-801 induced a profound "perseverative" type behavior that was more pronounced when compared to amphetamine. Moreover, amphetamine-induced impairments, but not the effects of MK-801, could be reversed by antipsychotics as well as the D1 receptor antagonist SCH-23390, suggesting a role for both the D1 and D2 receptor in the amphetamine impairment model. CONCLUSIONS: These data suggest that amphetamine and MK-801 represent dissociable models of impairment in PAL, dependent on different underlying neurobiology. The ability to distinguish dopaminergic versus glutamatergic effects on performance in rPAL makes it a unique and useful tool in the modeling of cognitive impairments in schizophrenia.