Differing animal welfare conceptions and what they mean for the future of zoos and aquariums, insights from an animal welfare audit.

Animal welfare is a growing public concern that has the potential to undermine the social license of zoos and aquariums. The lack of consensus on how animal welfare is defined across such a diverse sector combined with and a widespread belief that commercial priorities such as entertaining visitors conflicts with animal welfare, hinders efforts to effectively address this fundamental issue for the sector. Data derived from an audit of habitats across a major North American wildlife attraction revealed that holistic animal welfare assessments undertaken by animal carers embracing three principal constructs of animal welfare, correlated strongly with visitor perceptions of animal happiness. Visitor assessments of animal happiness also correlated with animal carer assessments of social, behavioural and locomotor opportunities and inversely with the prevalence of stereotypic behaviours, supporting the proposition that folk conceptions of animal welfare are more accurate than may have previously been considered to be the case. However, the holistic animal welfare assessment inversely correlated with assessments of a habitat's capacity to safeguard welfare as determined by the facility's veterinary staff, supporting the proposition that tensions exist between physical and psychological components of captive animal welfare provisioning. This further underlines the importance of clarity on how animal welfare is conceived when developing institutional animal welfare strategies. Finally, the data also showed that both holistic animal welfare assessments and visitor perceptions of animal happiness strongly correlated with the level of enjoyment experienced by visitors, challenging the belief that animal welfare competes with the commercial priorities of zoos and aquariums. The audit supports the case that maintaining high animal welfare is a commercial imperative as well as a moral obligation for zoos and aquariums and underlines the necessity to utilize conceptions of animal welfare that acknowledge the centrality of the affective states of animals in maintaining those standards.

Surface-functionalized curcumin-loaded polymeric nanocapsules could block apomorphine-induced behavioral changes in rats.

BACKGROUND: Surface functionalization enhances the properties and characteristics of polymeric nanocapsules (NCs) mainly due to the surface charge, surfactants, and polymer coating type. Curcumin (CUR) is a bioactive compound with several proven pharmacological properties and low bioavailability. This study aimed to develop anionic (poly-ɛ-caprolactone; PCL) and cationic (Eudragit® RS100 (EUD)) NCs prepared with sorbitan monostearate (Span 60®) or sorbitan monooleate (Span 80®), coated with d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and optimized using 23 factorial analysis. Subsequently, the biological activity was evaluated. METHODS: A two-level, three-factor design (polymer, Span type, and TPGS concentration) was used. The biological effects of CUR-loaded TPGS-coated cationic and anionic NCs were assessed in apomorphine-induced stereotyped behavior in rats. RESULTS: The type of polymer (anionic or cationic) and Span® had a factorial influence on the physical and chemical characteristics of NCs according to the changes in TPGS concentrations. Both cationic and anionic CUR-NCs could block apomorphine-induced behavioral changes. CONCLUSIONS: The CUR-loaded TPGS-coated NCs proved to be a promising brain delivery system.

The Effect of Tai Chi Chuan Training on Stereotypic Behavior of Children with Autism Spectrum Disorder.

This quasi-experimental study investigated effects of Tai Chi Chuan training on stereotypic behavior of children with autism spectrum disorder. Twenty-three participants (mean age = 9.60 ± 1.40 years) were assigned to experimental (N = 12) and control (N = 11) groups. The experimental group received 12 weeks of Tai Chi training and all participants had pre, post, and one-month follow-up assessments. Stereotypic behavior measured using Gilliam Autism Rating Scale 2 Scores, was significantly altered by ~ 25% in the Tai Chi Chuan group. Behavioral change was maintained at follow up since there was no significant difference between that and the posttest. In conclusion, Tai Chi Chuan training is a useful and appropriate intervention to modulate behavior in individuals with autism spectrum disorder.

Metoprine, a histamine N-methyltransferase inhibitor, attenuates methamphetamine-induced hyperlocomotion via activation of histaminergic neurotransmission in mice.

Metoprine increases the content of histamine in brain by inhibiting histamine N-methyltransferase (HMT), a centrally acting histamine degrading enzyme. We present data demonstrating that pretreatment with metoprine attenuates the hyperlocomotive effects of METH in mice using a multi-configuration behavior apparatus designed to monitor four behavioral outcomes [horizontal locomotion, appetitive behavior (food access), and food and water intake]. Metoprine pretreatment itself induced hyperlocomotion in mice challenged with saline during the large part of light phase. The trend was also observed during the following dark phase. This is the first report that metoprine has a long-lasting locomotor stimulating property. Similarly, in a tail suspension test, a single injection of metoprine significantly reduced total time of immobility in mice, consistent with the idea that metoprine possesses motor stimulating properties. Metoprine pretreatment did not affect other aspects of behavior. Metoprine did not affect the appetitive and drinking behavior while exerted an effect on stereotypy. No stereotyped behavior was observed in mice pretreated with vehicle followed by METH, while stereotyped sniffing was observed in mice pretreated with metoprine followed by METH. The metoprine pretreatment attenuated METH-induced hyperlocomotion during the first 2 h of light phase, suggesting that metoprine-induced locomotor stimulating property might be different from that of METH. The hypothalamic content of histamine (but not its brain metabolite) was increased after metoprine or METH administration. Both METH and metoprine reduced dopamine and histamine turnover in the striatum and the nucleus accumbens and the hypothalamus, respectively, and there is a significant metoprine pretreatment x METH challenge interaction in the histamine turnover. It is likely that metoprine may attenuate METH-induced hyperlocomotion via activation of histaminergic neurotransmission. Metoprine also might induce a long-lasting locomotor stimulating effect via a putative mechanism different from that whereby METH induces the locomotor stimulating effect.

Kava decreases the stereotyped behavior induced by amphetamine in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Kava extract (Piper methysticum) is a phytotherapic mainly used for the treatment of anxiety. Although the reported effects of Kava drinking improving psychotic symptoms of patients when it was introduced to relieve anxiety in aboriginal communities, its effects on models of psychosis-like symptoms are not investigated. AIM OF THE STUDY: To investigate the effects of Kava extract on behavioral changes induced by amphetamine (AMPH) and its possible relation with alterations in monoamine oxidase (MAO) activity. MATERIALS AND METHODS: Mice received vehicle or Kava extract by gavage and, 2 h after vehicle or AMPH intraperitoneally. Twenty-five minutes after AMPH administration, behavioral (elevated plus maze, open field, stereotyped behavior, social interaction and Y maze) and biochemical tests (MAO-A and MAO-B activity in cortex, hippocampus and striatum) were sequentially evaluated. RESULTS: Kava extract exhibited anxiolytic effects in plus maze test, increased the locomotor activity of mice in open field test and decreased MAO-A (in cortex) and MAO-B (in hippocampus) activity of mice. Kava extract prevented the effects of AMPH on stereotyped behavior and, the association between Kava/AMPH increased the number of entries into arms in Y maze test as well as MAO-B activity in striatum. However, Kava extract did not prevent hyperlocomotion induced by AMPH in open field test. The social interaction was not modified by Kava extract and/or AMPH. CONCLUSION: The results showed that Kava extract decreased the stereotyped behavior induced by AMPH at the same dose that promotes anxiolytic effects, which could be useful to minimize the psychotic symptoms in patients.

Effect of fibrous diet and vitamin C inclusion on uniformity, carcass traits, skeletal strength, and behavior of broiler breeder pullets.

This experiment studied the effect of broiler breeder nutritional strategies on uniformity, carcass traits, tibia parameters, and behavior during rearing and prebreeder periods (up to 22 wk of age). One-day-old pullets (n = 384) were randomly assigned to 4 treatments arranged as a 2 × 2 factorial, with 2 fiber levels (control vs. fibrous diet, 15% diluted in AMEn and nutrient content) and 2 vitamin C feed inclusions (0 vs. 200 mg/kg). At 6, 15, and 22 wk, blood sampling was carried out (4 birds/replicate) to determine serum alkaline phosphatase (ALP) levels, and behavior was observed by visual scan sampling. At 22 wk, carcass traits, tibia parameters, and intestinal morphology were assessed (2 birds/replicate), and tail- and wing-feather integrity of all birds were scored. Fibrous diet did not modify BW uniformity, mortality, or tibia growth when compared with control diet. Pullets fed the fibrous diet had lower tibia breaking strength, elastic modulus, and ash content values (P < 0.05). They also had lower ALP serum level at 6 and 22 wk (P < 0.05), their breast muscle was less developed (18.5 vs. 19.8%, P < 0.05), and their abdominal fat deposition was higher (1.14 vs. 0.87%, P < 0.05). At 15 and 22 wk, they performed, on average, 97% less grasping feather pecking and 45% less non-food object pecking behaviors, and their wing-feather score was lower (P < 0.05) at 22 wk. Tail- and wing-feather scores of the control treatments were reduced by vitamin C inclusion (tail: 0.30 vs. 1.15, P < 0.05; wing: 0.98 vs. 1.26, P < 0.05) at 22 wk. In conclusion, fibrous diet improves carcass traits (reduces breast muscle and increases abdominal fat deposition), deteriorates bone mineral deposition and thus skeletal strength, and reduces stereotypic behaviors, improving wing-feather integrity. Vitamin C inclusion improves tail- and wing-feather integrity of lower in feed allowance.

Brief Report: Evaluating College Students' Perceptions of a Child Displaying Stereotypic Behaviors: Do Changes in Stereotypy Levels Affect Ratings?

One reason for treating stereotypic behavior is that it may negatively impact how others perceive the individual displaying the behavior, thus impeding social interactions; however, few studies have directly evaluated this possibility. As a first step toward testing this position, participants (college students) in Study 1 watched 5-min video clips of a child engaging in hand/finger motor stereotypy at varying levels (0%, 17%, 37%, and 40% of the time) while sound was muted. Following each video, participants completed a questionnaire to evaluate their perception of the child. In Study 2, additional participants completed the same questionnaire after watching the same videos with the sound unmuted to determine if the addition of vocal stereotypy altered their perceptions of the child. Results indicate that (a) observers negatively rated the child when he displayed motor stereotypy for 17% or more of a video clip and (b) the addition of vocal stereotypy yielded more negative judgements than motor stereotypy alone.

Genetic and environmental influences on corticostriatal circuits in twins with autism

Background: Corticostriatal circuits (CSC) have been implicated in the presentation of some restricted and repetitive behaviours (RRBs) in children with autism-spectrum disorder (ASD), and preliminary evidence suggests that disruptions in these pathways may be associated with differences in genetic and environmental influences on brain development. The objective of this investigation was to examine the impact of genetic and environmental factors on CSC regions in twins with and without ASD and to evaluate their relationship with the severity of RRBs. Methods: We obtained T1-weighted MRIs from same-sex monozygotic and dizygotic twin pairs, aged 6­15 years. Good-quality data were available from 48 ASD pairs (n = 96 twins; 30 pairs concordant for ASD, 15 monozygotic and 15 dizygotic; 18 pairs discordant for ASD, 4 monozygotic and 14 dizygotic) and 34 typically developing control pairs (n = 68 twins; 20 monozygotic and 14 dizygotic pairs). We generated structural measures of the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), caudate, putamen, pallidum and thalamus using FreeSurfer. Twin pair comparisons included intraclass correlation analyses and ACE modelling (a2 = additive genetics; c2 = common or shared environment; e2 = unique or nonshared environment). We also assessed correlations with RRB severity. Results: Structural variation in CSC regions was predominantly genetically mediated in typically developing twins (a2 = 0.56 to 0.87), except for ACC white matter volume (a2 = 0.42, 95% confidence interval [CI] 0.08 to 0.77). We also observed similar magnitudes of genetic influence in twins with ASD (a2 = 0.65 to 0.97), but the cortical thickness of the ACC (c2 = 0.44, 95% CI 0.22 to 0.66) and OFC (c2 = 0.60, 95% CI 0.25 to 0.95) was primarily associated with environmental factors in only twins with ASD. Twin pair differences in OFC grey matter volume were also correlated with RRB severity and were predominantly environmentally mediated. Limitations: We obtained MRIs on 2 scanners, and analytical approaches could not identify specific genetic and environmental factors. Conclusion: Genetic factors primarily contribute to structural variation in subcortical CSC regions, regardless of ASD, but environmental factors may exert a greater influence on the development of grey matter thickness in the OFC and ACC in children with ASD. The increased vulnerability of OFC grey matter to environmental influences may also mediate some heterogeneity in RRB severity in children with ASD.

Preclinical toxicity evaluation of JD5037, a peripherally restricted CB1 receptor inverse agonist, in rats and dogs for treatment of nonalcoholic steatohepatitis.

JD5037 is a novel peripherally restricted CB1 receptor (CB1R) inverse agonist being developed for the treatment of visceral obesity and its metabolic complications, including nonalcoholic fatty liver disease and dyslipidemia. JD5037 was administered by oral gavage at 10, 40, and 150 mg/kg/day dose levels for up to 34 days to Sprague Dawley rats, and at 5, 20, and 75 mg/kg/day dose levels for 28 consecutive days to Beagle dogs. In rats, higher incidences of stereotypic behaviors were observed in 10 mg/kg females and 40 mg/kg males, and slower responses for reflex and sensory tests were observed only in males at 10 and 40 mg/kg during neurobehavioral testing. Sporadic minimal incidences of decreased activity (males) and seizures (both sexes) were observed in rats during daily clinical observations, without any clear dose-relationship. Male dogs at 75 mg/kg during treatment period, but not recovery period, had an increased incidence of gut associated lymphoid tissue hyperplasia and inflammation in the intestine. In both species, highest dose resulted in lower AUCs indicative of non-linear kinetics. Free access to food increased the plasma AUC∞ by ~4.5-fold at 20 mg/kg in dogs, suggesting presence of food may help in systemic absorption of JD5037 in dogs. Based on the study results, 150 mg/kg/day in rats, and 20 and 75 mg/kg/day doses in male and female dogs, respectively, were determined to be the no-observed-adverse-effect-levels (NOAELs).

Connectivity Analyses of Bioenergetic Changes in Schizophrenia: Identification of Novel Treatments.

We utilized a cell-level approach to examine glycolytic pathways in the DLPFC of subjects with schizophrenia (n = 16) and control (n = 16) and found decreased mRNA expression of glycolytic enzymes in pyramidal neurons, but not astrocytes. To replicate these novel bioenergetic findings, we probed independent datasets for bioenergetic targets and found similar abnormalities. Next, we used a novel strategy to build a schizophrenia bioenergetic profile by a tailored application of the Library of Integrated Network-Based Cellular Signatures data portal (iLINCS) and investigated connected cellular pathways, kinases, and transcription factors using Enrichr. Finally, with the goal of identifying drugs capable of "reversing" the bioenergetic schizophrenia signature, we performed a connectivity analysis with iLINCS and identified peroxisome proliferator-activated receptor (PPAR) agonists as promising therapeutic targets. We administered a PPAR agonist to the GluN1 knockdown model of schizophrenia and found it improved long-term memory. Taken together, our findings suggest that tailored bioinformatics approaches, coupled with the LINCS library of transcriptional signatures of chemical and genetic perturbagens, may be employed to identify novel treatment strategies for schizophrenia and related diseases.

Do mentalization skills affect the perception of stigma in patients with epilepsy?

PURPOSE: We aimed to study the relationship between the mentalizing ability and stigma in patients with epilepsy. METHODS: Patients with epilepsy were administered the following battery of tests: Mini-International Neuropsychiatric Interview (MINI) form, Reading the Mind in the Eyes Test (Eyes Test), Stigma Scale of Epilepsy (SSE), Internalized Stigma of Mental Illness (ISMI) Scale, Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI). RESULTS: Assessment of an association between the Eyes Test score, ISMI Scale total score, and subscale scores revealed a negative significant correlation of Eyes Test scores with approval of stereotypes, perceived discrimination, stigma resistance, and total score. Eyes Test score and BDI scores appears to be significant predictor of internalized stigma among the clinical variables that were studied. A positive significant correlation was detected between BDI score and alienation, perceived discrimination, and total score. CONCLUSION: The presence of a correlation between the mentalization and stigma perception in our study demonstrates that these two concepts are connected and that this connection needs further study. In particular, mentalization-based therapy can have an effect on the reduction of the stigma perceptions and in this way can improve the course of the disease, potentially improving the patients' quality of life.

Treatment for Higher-Order Restricted Repetitive Behaviors (H-RRB) in Children with Autism Spectrum Disorder.

Restricted repetitive behaviors (RRB) are one of the core symptoms of autism spectrum disorder (ASD). Evidence suggests that higher-order RRB (H-RRB) are particularly challenging and can negatively impact family functioning (e.g., insistence on sameness, following idiosyncratic routines). The study examined the effects of a parent-implemented behavior intervention using a multiple baseline single case experimental design in three young children with ASD. The intervention involved self-management procedures and included principles of pivotal response treatment during which parents provided bids for children to vary from H-RRB and children obtained points for engaging in these other interests and activities. Results showed improvements in child behavior, parent and child affect and interactions, children's engagement in family activities, and overall parent ratings of RRB.

The effects of noncontingent music and response interruption and redirection on vocal stereotypy.

Vocal stereotypy is a commonly occurring challenging behavior in children with autism spectrum disorder (ASD) that is frequently maintained by automatic reinforcement and often interferes with skill acquisition. Matched stimulation (MS), and response interruption and redirection (RIRD) are two interventions that have been demonstrated to be effective in reducing the occurrence of vocal stereotypy with participants with ASD. The current study sought to determine if the combination of MS (noncontingent music) and RIRD was more effective at reducing vocal stereotypy than RIRD alone and if the parents of children with ASD found the combination of MS and RIRD more socially valid than RIRD alone. The results suggested that the combined intervention resulted in greater suppression of vocal stereotypy and increased occurrences of on-task behavior in both participants. Additionally, RIRD required fewer implementations and had a shorter duration when combined with MS. Results suggest that the combination of MS and RIRD may be an effective intervention outside of highly controlled settings.

Effects of central RVD-hemopressin(α) administration on anxiety, feeding behavior and hypothalamic neuromodulators in the rat.

BACKGROUND: The endocannabinoid (eCB) system is strongly involved in the regulation of anxiety and feeding behavior. RVD-hemopressin(α) [RVD-hp(α)], a N-terminally extended form of hemopressin, is a negative allosteric modulator of the cannabinoid (CB) 1 receptor and a positive allosteric modulator of CB2 receptor which has been recently reported to exert anxiolytic/antidepressant and anorexigenic effects after peripheral administration in rats. Pharmacological evidences reported a possible link between brain hypocretin/orexin, monoamine and eCB systems, as regards appetite and emotional behavior control. Considering this, the aim of our work was to investigated the effects of RVD-hp(α) on anxiety like behavior and food intake after central administration and related it to monoamine levels and orexin-A gene expression, in the hypothalamus. METHODS: We have studied the effects of central RVD-hp(α) (10nmol) injection on anxiety-like behavior and feeding using different behavioral tests. Hypothalamic levels of norepinephrine (NE), dopamine (DA) and serotonin (5-hydroxytryptamine, 5-HT) and gene expression of orexin-A and proopiomelanocortin (POMC) were measured by high performance liquid chromatography (HPLC) and real-time reverse transcription polymerase chain reaction (RT-PCR) analysis, respectively. RESULTS: Central RVD-hp(α) administration decreased locomotion activity and stereotypies. Moreover, RVD-hp(α) treatment inhibited anxiogenic-like behavior and food intake, NE levels and orexin-A gene expression, in the hypothalamus. CONCLUSION: Concluding, in the present study we demonstrated that central RVD-hp(α) induced anxiolytic and anorexigenic effects possibly related to reduced NE and orexin-A and POMC signaling, in the hypothalamus. These findings further support the central role of the peptide in rat brain thus representing an innovative pharmacological approach for designing new anorexigenic drugs targeting eCB system.

Investigation of the Anxiolytic and Antidepressant Effects of Crocin, a Compound from Saffron (Crocus sativus L), in the Male Sprague-Dawley Rat.

Anxiety and depression are debilitating, costly psychological disorders that account for more than $133 billion annually in direct medical expenses in the United States. Finding alternative treatments to reduce the personal and financial burden for patients with these disorders, while maintaining patient safety, is vital. The purposes of this study were to determine if crocin, a compound from saffron (Crocus sativus L), produces anxiolytic and/or antidepressant effects using rat models for anxiety and behavioral despair and to determine the effects of crocin at the benzodiazepine site on the γ-aminobutyric acid type A receptor. Fifty-five male Sprague Dawley rats were randomly assigned to 1 of 5 groups: vehicle (dimethyl sulfoxide), crocin, midazolam, flumazenil plus crocin, and midazolam plus crocin. Behavioral analyses were conducted in the elevated plus-maze and the forced swim test. Data were analyzed using multivariate analysis of variance and a least significant difference post hoc test. Data from the elevated plus-maze suggested crocin may attenuate the anxiolytic effects of midazolam, while not affecting psychomotor activity. Data from the forced swim test showed a significant increase in mean time mobile in the midazolam plus crocin group, suggesting a decrease in behavioral despair because of the interaction between crocin and midazolam.

The combination of escitalopram and aripiprazole: Investigation of psychomotor effects in rats.

Pre-clinical and clinical evidence suggests that the antidepressant efficacy of the selective serotonin reuptake inhibitor escitalopram can be enhanced by the dopamine and serotonin partial agonist aripiprazole. Given the range of possible neurochemical interactions between these drugs, the current study investigated whether aripiprazole alters the hedonic and psychomotor effects of escitalopram. Male Sprague Dawley rats ( n=116) received 10 mg/kg/day escitalopram (subcutaneous), 2 mg/kg/day aripiprazole (subcutaneous), or combined aripiprazole + escitalopram, and were tested for consumption of incentive nutritional stimuli (high-fructose corn syrup and chow), stereotypy and locomotor activity. At the conclusion of behavioral testing, mRNAs of two genes involved in reward processes were quantified: hypothalamic pro-opiomelanocortin and hippocampal brain-derived neurotrophic factor. Escitalopram produced a selective, but temporary, decrease in high fructose corn syrup consumption that was not altered by aripiprazole co-administration. Escitalopram had no significant effect on locomotion, but aripiprazole co-administration produced a persistent increase in stereotypy. Both brain-derived neurotrophic factor and pro-opiomelanocortin mRNA levels were lower in the aripiprazole + escitalopram group relative to the escitalopram group. Taken together, these results suggest that aripiprazole may enhance the antidepressant efficacy of escitalopram through improvement of psychomotor functions.

Measurement, Education and Tracking in Integrated Care (METRIC): use of a culturally adapted education tool versus standard education to increase engagement in depression treatment among Hispanic patients: study protocol for a randomized control trial.

BACKGROUND: Significant mental health disparities exist for Hispanic populations, especially with regard to depression treatment. Stigma and poor communication between patients and their providers result in low use of antidepressant medications and early treatment withdrawal. Cultural factors which influence treatment decisions among Hispanics include fears about the addictive and harmful properties of antidepressants, worries about taking too many pills, and the stigma attached to taking medications. Primary care settings often are the gateway to identifying undiagnosed or untreated mental health disorders, particularly for people with co-morbid physical health conditions. Hispanics, in particular, are more likely to receive mental healthcare in primary care settings. Recent recommendations from the U.S. Preventive Services Task Force are that primary care providers screen adult patients for depression only if systems are in place to ensure adequate treatment and follow-up. METHODS: We are conducting a randomized controlled trial among 150 depressed adult Hispanics in a primary care safety net setting, testing the effectiveness of a culturally appropriate depression education intervention to reduce stigma and increase uptake in depression treatment among Hispanics, and implement a Measurement-Based Integrated Care (MBIC) model with collaborative, multidisciplinary treatment and culturally tailored care management strategies. DISCUSSION: This study protocol represents the first randomized control trial of the culturally adapted depression education fotonovela, Secret Feelings, among Hispanics in a primary care setting. The education intervention will be implemented after diagnosis using an innovative screening technology and enrolled in measurement-based integrated care for the treatment of depression, which will help build the evidence around cultural adaptations in treatment to reduce mental health disparities. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02702596. Registered on 20 March 2016.

Antipsychotic-like activity of scopoletin and rutin against the positive symptoms of schizophrenia in mouse models.

In an earlier report, we demonstrated an antipsychotic-like activity of a methanolic extract of Morinda citrifolia Linn fruit in mouse models and postulated the contribution of its bioactive principles, scopoletin and rutin. Moreover, the antidopaminergic activities of scopoletin and rutin were reported in isolated vas deferens preparations. In the present study, scopoletin and rutin were assessed for antipsychotic-like activity using apomorphine-induced climbing behavior and methamphetamine-induced stereotypy in mice. The results of this study revealed that scopoletin and rutin (0.05, 0.1, 0.5, and 1 mg/kg, p.o.) had a "U-shaped" dose-dependent effect on climbing and stereotyped behaviors induced by apomorphine and methamphetamine, respectively, in mice. A significant reduction in climbing and stereotyped behaviors caused by scopoletin and rutin was observed only at a dose 0.1 mg/kg. This study suggests that scopoletin and rutin can alleviate positive symptoms of schizophrenia only at a specific dose. Further studies evaluating the effects of scopoletin and rutin on animal models for negative symptoms of schizophrenia are required for a novel drug discovery in the treatment of neuropsychiatric diseases.

The ethyl acetate fraction of a methanolic extract of unripe noni (Morinda citrifolia Linn.) fruit exhibits a biphasic effect on the dopaminergic system in mice.

In earlier ex vivo studies, we reported the biphasic effect of a methanolic extract of unripe Morinda citrifolia fruit (MMC) on dopamine-induced contractility in isolated rat vas deferens preparations. The present in vivo study was designed and undertaken to further explore our earlier ex vivo findings. This study examined the effect of the ethyl acetate fraction of a methanolic extract of unripe Morinda citrifolia Linn. fruit (EA-MMC; 5-100 mg/kg, p.o.) on the dopaminergic system using mouse models of apomorphine-induced climbing time and climbing behavior, methamphetamine-induced stereotypy (sniffing, biting, gnawing, and licking) and haloperidol-induced catalepsy using the bar test. Acute treatment with EA-MMC at a low dose (25 mg/kg, p.o.) significantly attenuated the apomorphine-induced climbing time and climbing behavior in mice. Similarly, EA-MMC (5 and 10 mg/kg, p.o.) significantly inhibited methamphetamine-induced stereotyped behavior in mice. These results demonstrated that the antidopaminergic effect of EA-MMC was observed at relatively lower doses (<25 mg/kg, p.o.). On the other hand, EA-MMC showed dopaminergic agonistic activity at a high dose (3,000 mg/kg, p.o.), which was evident from alleviation of haloperidol (a dopamine D2 blocker)-induced catalepsy in mice. Therefore, it is concluded that EA-MMC might possess a biphasic effect on the dopaminergic system, i.e., an antagonistic effect at lower doses (<25 mg/kg, p.o.) and an agonistic effect at higher doses (>1,000 mg/kg, p.o.). However, further receptor-ligand binding assays are necessary to confirm the biphasic effects of M. citrifolia fruit on the dopaminergic system.

Vitamin D treatment during pregnancy prevents autism-related phenotypes in a mouse model of maternal immune activation.

BACKGROUND: Prenatal exposure to infection is a recognized environmental risk factor for neuropsychiatric disorders of developmental origins such as autism or schizophrenia. Experimental work in animals indicates that this link is mediated by maternal immune activation (MIA) involving interactions between cytokine-associated inflammatory events, oxidative stress, and other pathophysiological processes such as hypoferremia and zinc deficiency. Maternal administration of the viral mimic polyriboinosinic-polyribocytidylic acid (poly(I:C)) in mice produces several behavioral phenotypes in adult offspring of relevance to autism spectrum disorder (ASD) and other neurodevelopmental disorders. METHODS: Here, we investigated whether some of these phenotypes might also present in juveniles. In addition, given the known immunomodulatory and neuroprotective effects of vitamin D, we also investigated whether the co-administration of vitamin D could block MIA-induced ASD-related behaviors. We co-administered the hormonally active form of vitamin D, 1α,25 dihydroxy vitamin D3 (1,25OHD), simultaneously with poly(I:C) and examined (i) social interaction, stereotyped behavior, emotional learning and memory, and innate anxiety-like behavior in juveniles and (ii) the levels of the pro-inflammatory cytokines IL-1ß, IL-6 and TNF-α in maternal plasma and fetal brains. RESULTS: We show that like adult offspring that were exposed to MIA, juveniles display similar deficits in social approach behavior. Juvenile MIA offspring also show abnormal stereotyped digging and impaired acquisition and expression of tone-cued fear conditioning. Importantly, our study reveals that prenatal administration of 1,25OHD abolishes all these behavioral deficits in poly(I:C)-treated juveniles. However, prenatal administration of vitamin D had no effect on pro-inflammatory cytokine levels in dams or in fetal brains suggesting the anti-inflammatory actions of vitamin D are not the critical mechanism for its preventive actions in this ASD animal model. CONCLUSIONS: This work raises the possibility that early dietary supplementation with vitamin D may open new avenues for a successful attenuation or even prevention of neurodevelopmental disorders following maternal inflammation during pregnancy.