Understanding the role of the NMDA receptor subunit, GluN2D, in mediating NMDA receptor antagonist-induced behavioral disruptions in male and female mice.

Noncompetitive NMDA receptor (NMDAR) antagonists like phencyclidine (PCP) and ketamine cause psychosis-like symptoms in healthy humans, exacerbate schizophrenia symptoms in people with the disorder, and disrupt a range of schizophrenia-relevant behaviors in rodents, including hyperlocomotion. This is negated in mice lacking the GluN2D subunit of the NMDAR, suggesting the GluN2D subunit mediates the hyperlocomotor effects of these drugs. However, the role of GluN2D in mediating other schizophrenia-relevant NMDAR antagonist-induced behavioral disturbances, and in both sexes, is unclear. This study aimed to investigate the role of the GluN2D subunit in mediating schizophrenia-relevant behaviors induced by a range of NMDA receptor antagonists. Using both male and female GluN2D knockout (KO) mice, we examined the effects of the NMDAR antagonist's PCP, the S-ketamine enantiomer (S-ket), and the ketamine metabolite R-norketamine (R-norket) on locomotor activity, anxiety-related behavior, and recognition and short-term spatial memory. GluN2D-KO mice showed a blunted locomotor response to R-norket, S-ket, and PCP, a phenotype present in both sexes. GluN2D-KO mice of both sexes showed an anxious phenotype and S-ket, R-norket, and PCP showed anxiolytic effects that were dependent on sex and genotype. S-ket disrupted spatial recognition memory in females and novel object recognition memory in both sexes, independent of genotype. This datum identifies a role for the GluN2D subunit in sex-specific effects of NMDAR antagonists and on the differential effects of the R- and S-ket enantiomers.

The GPR88 agonist RTI-13951-33 reduces alcohol drinking and seeking in mice.

GPR88 is an orphan G-protein-coupled receptor that is considered a potential target to treat neuropsychiatric disorders, including addiction. Most knowledge about GPR88 function stems from knockout mouse studies, and in vivo pharmacology is still scarce. Here we examine the effects of the novel brain-penetrant agonist RTI-13951-33 on several alcohol-related behaviours in the mouse. In the intermittent-access-two-bottle-choice paradigm, the compound reduced excessive voluntary alcohol drinking, while water drinking was intact. This was observed for C57BL/6 mice, as well as for control but not Gpr88 knockout mice, demonstrating efficacy and specificity of the drug in vivo. In the drinking-in-the-dark paradigm, RTI-13951-33 also reduced binge-like drinking behaviour for control but not Gpr88 knockout mice, confirming the alcohol consumption-reducing effect and in vivo specificity of the drug. When C57BL/6 mice were trained for alcohol self-administration, RTI-13951-33 decreased the number of nose-pokes over a 4-h session and reduced the number of licks and bursts of licks, suggesting reduced motivation to obtain alcohol. Finally, RTI-13951-33 did not induce any place preference or aversion but reduced the expression of conditioned place preference to alcohol, indicative of a reduction of alcohol-reward seeking. Altogether, data show that RTI-13951-33 limits alcohol intake under distinct conditions that require consummatory behaviour, operant response or association with contextual cues. RTI-13951-33 therefore is a promising lead compound to evaluate GPR88 as a therapeutic target for alcohol use disorders. More broadly, RTI-13951-33 represents a unique tool to better understand GPR88 function, disentangle receptor roles in development from those in the adult and perhaps address other neuropsychiatric disorders.

AHCODA-DB: a data repository with web-based mining tools for the analysis of automated high-content mouse phenomics data.

BACKGROUND: Systematic, standardized and in-depth phenotyping and data analyses of rodent behaviour empowers gene-function studies, drug testing and therapy design. However, no data repositories are currently available for standardized quality control, data analysis and mining at the resolution of individual mice. DESCRIPTION: Here, we present AHCODA-DB, a public data repository with standardized quality control and exclusion criteria aimed to enhance robustness of data, enabled with web-based mining tools for the analysis of individually and group-wise collected mouse phenotypic data. AHCODA-DB allows monitoring in vivo effects of compounds collected from conventional behavioural tests and from automated home-cage experiments assessing spontaneous behaviour, anxiety and cognition without human interference. AHCODA-DB includes such data from mutant mice (transgenics, knock-out, knock-in), (recombinant) inbred strains, and compound effects in wildtype mice and disease models. AHCODA-DB provides real time statistical analyses with single mouse resolution and versatile suite of data presentation tools. On March 9th, 2017 AHCODA-DB contained 650 k data points on 2419 parameters from 1563 mice. CONCLUSION: AHCODA-DB provides users with tools to systematically explore mouse behavioural data, both with positive and negative outcome, published and unpublished, across time and experiments with single mouse resolution. The standardized (automated) experimental settings and the large current dataset (1563 mice) in AHCODA-DB provide a unique framework for the interpretation of behavioural data and drug effects. The use of common ontologies allows data export to other databases such as the Mouse Phenome Database. Unbiased presentation of positive and negative data obtained under the highly standardized screening conditions increase cost efficiency of publicly funded mouse screening projects and help to reach consensus conclusions on drug responses and mouse behavioural phenotypes. The website is publicly accessible through https://public.sylics.com and can be viewed in every recent version of all commonly used browsers.

Measuring risk-taking in mice: balancing the risk between seeking reward and danger.

Assessing risk is an essential part of human behaviour and may be disrupted in a number of psychiatric conditions. Currently, in many animal experimental designs the basis of the potential 'risk' is loss or attenuation of reward, which fail to capture 'real-life' risky situations where there is a trade-off between a separate cost and reward. The development of rodent tasks where two separate and conflicting factors are traded against each other has begun to address this discrepancy. Here, we discuss the merits of these risk-taking tasks and describe the development of a novel test for mice - the 'predator-odour risk-taking' task. This paradigm encapsulates a naturalistic approach to measuring risk-taking behaviour where mice have to balance the benefit of gaining a food reward with the cost of exposure to a predator odour using a range of different odours (rat, cat and fox). We show that the 'predator-odour risk-taking' task was sensitive to the trade-off between cost and benefit by demonstrating reduced motivation to collect food reward in the presence of these different predator odours in two strains of mice and, also, if the value of the food reward was reduced. The 'predator-odour risk-taking' task therefore provides a strong platform for the investigation of the genetic substrates of risk-taking behaviour using mouse models, and adds a further dimension to other recently developed rodent tests.

Conclusive demonstration of iatrogenic Alzheimer's disease transmission in a model of stem cell transplantation.

The risk of iatrogenic disease is often underestimated as a concern in contemporary medical procedures, encompassing tissue and organ transplantation, stem cell therapies, blood transfusions, and the administration of blood-derived products. In this context, despite the prevailing belief that Alzheimer's disease (AD) manifests primarily in familial and sporadic forms, our investigation reveals an unexpected transplantable variant of AD in a preclinical context, potentially indicating iatrogenic transmission in AD patients. Through adoptive transplantation of donor bone marrow stem cells carrying a mutant human amyloid precursor protein (APP) transgene into either APP-deficient knockout or normal recipient animals, we observed rapid development of AD pathological hallmarks. These pathological features were significantly accelerated and emerged within 6-9 months post transplantation and included compromised blood-brain barrier integrity, heightened cerebral vascular neoangiogenesis, elevated brain-associated ß-amyloid levels, and cognitive impairment. Furthermore, our findings underscore the contribution of ß-amyloid burden originating outside of the central nervous system to AD pathogenesis within the brain. We conclude that stem cell transplantation from donors harboring a pathogenic mutant allele can effectively transfer central nervous system diseases to healthy recipients, mirroring the pathogenesis observed in the donor. Consequently, our observations advocate for genomic sequencing of donor specimens prior to tissue, organ, or stem cell transplantation therapies, as well as blood transfusions and blood-derived product administration, to mitigate the risk of iatrogenic diseases.

Early-life iron deficiency persistently disrupts affective behaviour in mice.

BACKGROUND/OBJECTIVE: Iron deficiency (ID) is the most common nutrient deficiency, affecting two billion people worldwide, including about 30% of pregnant women. During gestation, the brain is particularly vulnerable to environmental insults, which can irrevocably impair critical developmental processes. Consequently, detrimental consequences of early-life ID for offspring brain structure and function have been described. Although early life ID has been associated with an increased long-term risk for several neuropsychiatric disorders, the effect on depressive disorders has remained unresolved. MATERIALS AND METHODS: A mouse model of moderate foetal and neonatal ID was established by keeping pregnant dams on an iron-deficient diet throughout gestation until postnatal day 10. The ensuing significant decrease of iron content in the offspring brain, as well as the impact on maternal behaviour and offspring vocalization was determined in the first postnatal week. The consequences of early-life ID for depression- and anxiety-like behaviour in adulthood were revealed employing dedicated behavioural assays. miRNA sequencing of hippocampal tissue of offspring revealed specific miRNAs signatures accompanying the behavioural deficits of foetal and neonatal ID in the adult brain. RESULTS: Mothers receiving iron-deficient food during pregnancy and lactation exhibited significantly less licking and grooming behaviour, while active pup retrieval and pup ultrasonic vocalizations were unaltered. Adult offspring with a history of foetal and neonatal ID showed an increase in depression- and anxiety-like behaviour, paralleled by a deranged miRNA expression profile in the hippocampus, specifically levels of miR200a and miR200b. CONCLUSION: ID during the foetal and neonatal periods has life-long consequences for affective behaviour in mice and leaves a specific and persistent mark on the expression of miRNAs in the brain. Foetal and neonatal ID needs to be further considered as risk factor for the development of depression and anxiety disorders later in life.Key MessagesMarginal reduction of gestational alimentary iron intake decreases brain iron content of the juvenile offspring.Early-life ID is associated with increased depression- and anxiety-like behaviour in adulthood.Reduction of maternal alimentary iron intake during pregnancy is reflected in an alteration of miRNA signatures in the adult offspring brain.

Gene Expression Analysis of the Endocannabinoid System in Presymptomatic APP/PS1 Mice.

Alzheimer's disease (AD) is the most common type of dementia and neurodegeneration. The actual cause of AD progression is still unknown and no curative treatment is available. Recently, findings in human samples and animal models pointed to the endocannabinoid system (ECS) as a promising therapeutic approach against AD. However, the specific mechanisms by which cannabinoid drugs induce potential beneficial effects are still undefined. For this reason, it is required a full characterization of the ECS at different time points of AD progression considering important factors such as sex or the analysis of different brain regions to improve future cannabinoid-dependent therapies in AD. Thus, the main aim of the present study is to expand our knowledge of the status of the ECS in a presymptomatic period (3 months of age) using the AD mouse model APP/PS1 mice. First, we evaluated different behavioral domains including anxiety, cognitive functions, and social interactions in male and female APP/PS1 mice at 4 months of age. Although a mild working memory impairment was observed in male APP/PS1 mice, in most of the behaviors assessed we found no differences between genotypes. At 3 months of age, we performed a characterization of the ECS in different brain regions of the APP/PS1 mice considering the sex variable. We assessed the expression of the ECS components by quantitative Real-Time Polymerase Chain Reaction in the hippocampus, prefrontal cortex, hypothalamus, olfactory bulb, and cerebellum. Interestingly, gene expression levels of the type-1 and type-2 cannabinoid receptors and the anabolic and catabolic enzymes, differed depending on the brain region and the sex analyzed. For example, CB1R expression levels decreased in both hippocampus and prefrontal cortex of male APP/PS1 mice but increased in female mice. In contrast, CB2R expression was decreased in females, whereas males tended to have higher levels. Overall, our data indicated that the ECS is already altered in APP/PS1 mice at the presymptomatic stage, suggesting that it could be an early event contributing to the pathophysiology of AD or being a potential predictive biomarker.

A behaviour biometrics dataset for user identification and authentication.

As e-Commerce continues to shift our shopping preference from the physical to online marketplace, we leave behind digital traces of our personally identifiable details. For example, the merchant keeps record of your name and address; the payment processor stores your transaction details including account or card information, and every website you visit stores other information such as your device address and type. Cybercriminals constantly steal and use some of this information to commit identity fraud, ultimately leading to devastating consequences to the victims; but also, to the card issuers and payment processors with whom the financial liability most often lies. To this end, we recognise that data is generally compromised in this digital age, and personal data such as card number, password, personal identification number and account details can be easily stolen and used by someone else. However, there is a plethora of data relating to a person's behaviour biometrics that are almost impossible to steal, such as the way they type on a keyboard, move the cursor, or whether they normally do so via a mouse, touchpad or trackball. This data, commonly called keystroke, mouse and touchscreen dynamics, can be used to create a unique profile for the legitimate card owner, that can be utilised as an additional layer of user authentication during online card payments. Machine learning is a powerful technique for analysing such data to gain knowledge; and has been widely used successfully in many sectors for profiling e.g., genome classification in molecular biology and genetics where predictions are made for one or more forms of biochemical activity along the genome. Similar techniques are applicable in the financial sector to detect anomaly in user keyboard and mouse behaviour when entering card details online, such that they can be used to distinguish between a legitimate and an illegitimate card owner. In this article, a behaviour biometrics (i.e., keystroke and mouse dynamics) dataset, collected from 88 individuals, is presented. The dataset holds a total of 1760 instances categorised into two classes (i.e., legitimate and illegitimate card owners' behaviour). The data was collected to facilitate an academic start-up project (called CyberSignature1) which received funding from Innovate UK, under the Cyber Security Academic Startup Accelerator Programme. The dataset could be helpful to researchers who apply machine learning to develop applications using keystroke and mouse dynamics e.g., in cybersecurity to prevent identity theft. The dataset, entitled 'Behaviour Biometrics Dataset', is freely available on the Mendeley Data repository.

Sex Differences in Mouse Exploratory Behaviour to Fel d 1, a Cat ABP-Like Protein.

Fel d 1 is a cat protein abundantly released and found in their habitat and is closely related to mouse androgen-binding proteins (ABPs). We hypothesized that mice have developed chemical communication mechanisms to detect and avoid this protein. We tested purified natural Fel d 1, a fox faeces molecule (TMT) as a positive control, and a negative control (purified water) in three different mouse groups (n = 14 each) to evaluate exploratory behaviour and stress responses. The mice did not show clear avoidance or stress responses to Fel d 1. Our results demonstrated a sex-treatment interaction for Fel d 1, with males spending more time in the areas treated with Fel d 1 than in the untreated areas (p = 0.018). This sex-treated area interaction was also not observed for either the blank or TMT. These results suggest that Fel d 1 from domestic cats could be recognized differently by male and female mice. These sex differences could be linked to the sexual role of ABP proteins and the ABP-like characteristics of Fel d 1.

A mouse model of chemotherapy-related cognitive impairments integrating the risk factors of aging and APOE4 genotype.

Some cancer survivors experience marked cognitive impairment, referred to as cancer-related cognitive impairment (CRCI). CRCI has been linked to the genetic factor APOE4, the strongest genetic risk factor for Alzheimer's disease (AD). We used APOE knock-in mice to test whether the relationship between APOE4 and CRCI can be demonstrated in a mouse model, to identify associations of chemotherapy with behavioural and structural correlates of cognition, and to test whether chemotherapy affects markers of AD. Twelve-month old C57BL/6 J female APOE3 (n = 30) and APOE4 (n = 31) knock-in mice were randomized to treatment with either doxorubicin (10 mg/kg) or saline. Behavioural assays at 2-21 weeks-post exposure included open field maze, elevated zero maze, pre-pulse inhibition, Barnes maze, and fear conditioning. Ex-vivo magnetic resonance imaging was used to determine regional volume differences at 31-35 weeks-post exposure, and tissue sections were analyzed for markers of AD pathogenesis. Minimal toxicities were observed in the aged mice after doxorubicin exposure. In the Barnes maze assay, APOE3 mice did not exhibit impairment in spatial learning after doxorubicin treatment, but APOE4 mice demonstrated significant impairments in both the initial identification of the escape hole and the latency to full escape at 6 weeks post-exposure. Both APOE3 and APOE4 mice treated with doxorubicin showed impairment of spatial memory. Grey matter volume in the frontal cortex decreased in APOE4 mice treated with doxorubicin vs. APOE3 mice. This study demonstrates cognitive impairments in aged APOE4 knock-in mice after doxorubicin treatment and establishes this system as a novel and powerful model of CRCI.

Sorting nexin 11 knockout mice exhibit enhanced thermosensing behaviour.

Temperature sensing is an important adaptive mechanism for warm-blooded animals such as humans. ThermoTRP ion channels are activated by distinct but overlapping physiological temperatures. Our previous research demonstrated that sorting nexin 11 (SNX11) regulates lysosomal degradation of plasma membrane TRPV3, one of ThermoTRP ion channel proteins. Here, we found that SNX11, a vesicular trafficking protein, modulates mouse behaviour in response to temperature changes. Snx11-knockout mice exhibit a stronger preference for mild temperatures along with enhanced sensitivity to harmful heat. Mechanistically, keratinocytes from Snx11-knockout mice exhibit a larger temperature-gated TRPV3 membrane current and have enhanced thermoTRPV3 expression in the plasma membrane compared to wild-type keratinocytes. Additionally, Snx11-knockout mice show higher endogenous TRPV3 protein levels in skin tissues than wild-type mice do. Therefore, our results indicate that SNX11 may regulate thermal perception via alteration of functional thermoTRPV3 on the plasma membrane of thermally sensitive cells, which is the first link between vesicular trafficking and thermal transduction.

Prenatal vitamin D deficiency does not exacerbate behavioural impairments associated with prenatal ethanol exposure in juvenile male mice.

There is a high prevalence of vitamin D deficiency and exposure to low levels of ethanol in pregnant women. However, there are a paucity of studies that have addressed the impact of both vitamin D deficiency and ethanol exposure on the offspring's vulnerability to neurodevelopmental disorders later in life. The aim of this study was to examine whether the absence of vitamin D during gestation in mice would alter the effects of prenatal exposure to low dose ethanol on the behaviour and dopaminergic gene expression patterns of juvenile mice. Four-week old female C57BL/6J mice were placed on a prenatal vitamin D deficient (PVD) or standard diet for 6 weeks and mated at 10 weeks of age. Females were exposed to either 10%(v/v) ethanol or water between gestational days 0-8 and all were offered water thereafter. We found that blood ethanol concentration in the dams was not affected by maternal diet. Behavioural analyses of the offspring included ultrasonic vocalizations (USV) at postnatal day (P) 7, locomotion and social interaction at P21. The main findings were increased USV calling rate and impaired social interaction in males with prenatal ethanol exposure (PrEE). Gene expression analysis of transcripts involved in dopamine regulation revealed a main effect of ethanol exposure on dopamine- and cyclic adenosine monophosphate- regulated neuronal phosphoprotein (Darpp-32), a main effect of vitamin D diet on Dopamine 2 Receptors (D2R) and a main effect of Sex on Tyrosine Hydroxylase (TH) expression. The combination of PVD-PrEE did not exacerbate the alterations resulting from PVD or PrEE. Despite the limited evidence to support the interaction of PVD and PrEE during the postnatal period, males were more vulnerable than female offspring to the detrimental effects of PrEE. Therefore, based on these studies in mice we suggest that maintenance of optimal vitamin D levels and abstinence from ethanol during pregnancy would reduce risk of later disruption to brain function and behaviour in the offspring.

Treatment Approaches in Rodent Models for Autism Spectrum Disorder.

Recent years have seen an impressive amount of research devoted to the developing of therapies to treat autism spectrum disorder (ASD). This work has been largely based on rodent models, employing a multitude of genetic and environmental manipulations. Unfortunately, the task of identifying suitable treatments for ASD is extremely challenging, due to a variety of problems specific to the research in this field. Here, we first discuss these problems, including (I) the presence of a large variety of rodent models (often without universal consensus on their validity), (II) the difficulties in choosing the most appropriate behavioural markers to assess the efficacy of possible treatments, (III) the limited knowledge we still have of the neurobiological bases of ASD pathology and of its aetiology, and (IV) the complexity of ASD itself, including a highly heterogeneous group of disorders sometimes with markedly different symptoms (therefore unlikely to be treated with the same approaches). Second, we give a critical overview of the most relevant advances in designing treatments for ASD, focusing on the most commonly used animal model, the laboratory mouse. We include pharmacological and non-pharmacological approaches, underlining their specific advantages, but also their current limitations especially in relation to the problems discussed before. Finally, we highlight the theoretical (e.g. the combination of multiple rather than single treatments) and methodological (e.g. use of single-gene mouse models) approaches that seem more promising to us, suggesting various strategies that can be adopted to simplify the complex field of research on treatments for ASD.

Theory of Visual Attention (TVA) applied to mice in the 5-choice serial reaction time task.

RATIONALE: The 5-choice serial reaction time task (5-CSRTT) is widely used to measure rodent attentional functions. In humans, many attention studies in healthy and clinical populations have used testing based on Bundesen's Theory of Visual Attention (TVA) to estimate visual processing speeds and other parameters of attentional capacity. OBJECTIVES: We aimed to bridge these research fields by modifying the 5-CSRTT's design and by mathematically modelling data to derive attentional parameters analogous to human TVA-based measures. METHODS: C57BL/6 mice were tested in two 1-h sessions on consecutive days with a version of the 5-CSRTT where stimulus duration (SD) probe length was varied based on information from previous TVA studies. Thereafter, a scopolamine hydrobromide (HBr; 0.125 or 0.25 mg/kg) pharmacological challenge was undertaken, using a Latin square design. Mean score values were modelled using a new three-parameter version of TVA to obtain estimates of visual processing speeds, visual thresholds and motor response baselines in each mouse. RESULTS: The parameter estimates for each animal were reliable across sessions, showing that the data were stable enough to support analysis on an individual level. Scopolamine HBr dose-dependently reduced 5-CSRTT attentional performance while also increasing reward collection latency at the highest dose. Upon TVA modelling, scopolamine HBr significantly reduced visual processing speed at both doses, while having less pronounced effects on visual thresholds and motor response baselines. CONCLUSIONS: This study shows for the first time how 5-CSRTT performance in mice can be mathematically modelled to yield estimates of attentional capacity that are directly comparable to estimates from human studies.

mouseTube - a database to collaboratively unravel mouse ultrasonic communication.

Ultrasonic vocalisation is a broadly used proxy to evaluate social communication in mouse models of neuropsychiatric disorders. The efficacy and robustness of testing these models suffer from limited knowledge of the structure and functions of these vocalisations as well as of the way to analyse the data. We created mouseTube, an open database with a web interface, to facilitate sharing and comparison of ultrasonic vocalisations data and metadata attached to a recording file. Metadata describe 1) the acquisition procedure, e.g., hardware, software, sampling frequency, bit depth; 2) the biological protocol used to elicit ultrasonic vocalisations; 3) the characteristics of the individual emitting ultrasonic vocalisations ( e.g., strain, sex, age). To promote open science and enable reproducibility, data are made freely available. The website provides searching functions to facilitate the retrieval of recording files of interest. It is designed to enable comparisons of ultrasonic vocalisation emission between strains, protocols or laboratories, as well as to test different analysis algorithms and to search for protocols established to elicit mouse ultrasonic vocalisations. Over the long term, users will be able to download and compare different analysis results for each data file. Such application will boost the knowledge on mouse ultrasonic communication and stimulate sharing and comparison of automatic analysis methods to refine phenotyping techniques in mouse models of neuropsychiatric disorders.

Differential role of AMPA receptors in mouse tests of antidepressant and anxiolytic action.

Depression and anxiety often co-occur, and conventional monoamine-facilitating antidepressants show efficacy against symptoms in both disorders. Rodent studies indicate that antidepressant effects of monoamine-based antidepressants involve increased α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid glutamate receptor (AMPAR) neurotransmission, and positive allosteric modulators (PAMs) at AMPARs produced antidepressant-like effects in rodents. While this suggests that increased AMPAR-mediated neurotransmission is beneficial in depression management, preclinical studies addressing AMPARs in relation to anxiety have given ambiguous results with both anxiolytic-like and anxiogenic-like effects observed after AMPAR blockade. This study systematically compared the effects of the AMPAR potentiator LY451646 and the AMPAR antagonist GYKI-53655 on depression-related behaviour using the mouse forced swim (FST) and tail suspension tests (TST), and anxiety-related behaviour using the elevated zero maze (EZM), marble burying (MB) and novelty-induced hypophagia (NIH) tests. The serotonin-selective antidepressant citalopram was included for comparison. Due to the importance of AMPARs in learning and memory we also tested if GYKI-53655 disrupted performance in the V-maze test for attention-dependent behaviour, and the social transmission of food preference (STFP) test of long-term memory. LY451646 (3 mg/kg) showed an antidepressant-like profile in the FST and TST, and GYKI-53655 (≥ 5 mg/kg) had a depressogenic-like effect in the TST but no effect in the FST. Conversely, GYKI-53655 produced marked anxiolytic-like effects in the EZM (≥ 2.5 mg/kg), MBT (≥ 2.5 mg/kg), and NIH tests (≥ 5 mg/kg), while LY451646 (≥ 3 mg/kg) increased anxiety-like behaviour in the EZM. Citalopram showed an antidepressant-like effect in the FST (≥ 10 mg/kg), but not TST, an anxiolytic-like effect in the EZM (≥ 3 mg/kg) and MB test (≥ 2.5 mg/kg), and an anxiogenic-like effect in the NIH test (≥ 30 mg/kg). GYKI-53655 did not affect cognitive performance in the V-maze or STFP tests. Collectively, these findings suggest a differential role of AMPARs in depression and anxiety, with AMPAR activation promoting antidepressant responses and AMPAR inhibition promoting anxiolytic responses. The potential of AMPARs as a novel target in depression and anxiety pharmacotherapy is discussed.

Intraplantar injection of tetrahydrobiopterin induces nociception in mice.

Tetrahydrobiopterin (BH4) is implicated in the development and maintenance of chronic pain. After injury/inflammation, the biosynthesis of BH4 is markedly increased in sensory neurons, and the pharmacological and genetic inhibition of BH4 shows analgesic effects in pre-clinical animal pain models. Intrathecal injections of BH4 have been shown to induce and enhance pain-like behaviours in rats, suggesting that under chronic pain conditions BH4 may act by facilitating central sensitisation. So far it is unknown whether BH4 acts on peripheral sites of the somatosensory system or whether BH4 per se provokes nociceptive pain behaviours. The purpose of this study was therefore to investigate the acute nociceptive effects of intraplantar injection of BH4. BH4 was found to induce dose-dependent licking/biting of the paw lasting 5 min, which was not observed following an injection of biopterin (inactive BH4 metabolite). Paw swelling, measured as paw thickness and weight, was not observed after BH4 injection. To explore possible mechanisms of action of BH4, the effect of local pre-treatment with indomethacin, Nω-nitro-L-arginine methyl ester, Nω-nitro-L-arginine, capsazepine and ruthenium red was tested. Morphine served as a positive control. Intraplantar pre-injection of morphine dose-dependently inhibited BH4-induced nociception, while none of the other compounds showed any statistical significant antinociception. These results suggest that BH4 exhibits nociceptive properties at peripheral sites of the somatosensory system, proposing an as yet unexplored involvement of BH4 in peripheral nociceptive processes. However, this appears not to be mediated through nitric oxide and prostaglandin release or by activation of the transient receptor potential vanilloid 1.