Melanotan-II reverses autistic features in a maternal immune activation mouse model of autism

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impaired social interactions, difficulty with communication, and repetitive behavior patterns. In humans affected by ASD, there is a male pre-disposition towards the condition with a male to female ratio of 4:1. In part due to the complex etiology of ASD including genetic and environmental interplay, there are currently no available medical therapies to improve the social deficits of ASD. Studies in rodent models and humans have shown promising therapeutic effects of oxytocin in modulating social adaptation. One pharmacological approach to stimulating oxytocinergic activity is the melanocortin receptor 4 agonist Melanotan-II (MT-II). Notably the effects of oxytocin on environmental rodent autism models has not been investigated to date. We used a maternal immune activation (MIA) mouse model of autism to assess the therapeutic potential of MT-II on autism-like features in adult male mice. The male MIA mice exhibited autism-like features including impaired social behavioral metrics, diminished vocal communication, and increased repetitive behaviors. Continuous administration of MT-II to male MIA mice over a seven-day course resulted in rescue of social behavioral metrics. Normal background C57 male mice treated with MT-II showed no significant alteration in social behavioral metrics. Additionally, there was no change in anxiety-like or repetitive behaviors following MT-II treatment of normal C57 mice, though there was significant weight loss following subacute treatment. These data demonstrate MT-II as an effective agent for improving autism-like behavioral deficits in the adult male MIA mouse model of autism

Ontogeny of NET expression and antidepressant-like response to desipramine in wild-type and SERT mutant mice

Abstract word count: 250 Introduction word count: 74

Zebrafish Behavior in Novel Environments:Effects of Acute Exposure to Anxiolytic Compounds and Choice of Danio rerio Line

Zebrafish (Danio rerio) associative responses are useful for pharmaceutical and toxicology screening, behavioral genetics, and discovering neural mechanisms involved in behavioral modulation. In novel environments, zebrafish swim to tank bottoms and dark backgrounds, behaviors attributed to anxiety associated with threat of predation. To examine possible genetic effects of inbreeding and segregation on this behavior, we compared Zebrafish International Resource Center (ZIRC) AB and WIK lines to zebrafish and GloFish® from a pet store (PETCO) in two qualitatively different novel environments: the dive tank and aquatic light/dark plus maze. Behavior was observed in the dive tank for 5 min, immediately followed by 5 min in the light/dark plus maze. Among strains, WIK spent more time in the dive tank top than AB (76 + 30 vs. 17 + 11 sec), and AB froze in the plusmaze center for longer than PETCO or GloFish® (162 + 61 vs. 72 + 29 or 27 + 27 sec). Further,behavior of zebrafish exposed for 3 min to 25 mg/L nicotine, desipramine, chlordiazepoxide,yohimbine, 100 mg/L citalopram, 0.05% DMSO, or 0.5% ethanol was compared to controls. Approximately 0.1% of drug is available in brain after such exposures. Desipramine or citalopram exposed fish spent more time in the dive tank top, and both reuptake inhibitors bound to serotonin transporters in zebrafish brain with high affinity (K i = 7 + 5 and 9 + 5 nM). In the plus maze, chlordiazepoxide, ethanol and DMSO-exposed fish crossed more lines and spent more time in white arms. Neither 25 mg/L nicotine nor yohimbine altered zebrafish behavior in novel environments, but nicotine was anxiolytic at higher doses. Overall, the light/dark plus maze and dive tank are distinct behavioral measures that are sensitive to treatment with anxiolytic compounds, but zebrafish line selection and solvents can influence baseline behavior in these tests

Zebrafish Behavior in Novel Environments:Effects of Acute Exposure to Anxiolytic Compounds and Choice of Danio rerio Line

Zebrafish (Danio rerio) associative responses are useful for pharmaceutical and toxicology screening, behavioral genetics, and discovering neural mechanisms involved in behavioral modulation. In novel environments, zebrafish swim to tank bottoms and dark backgrounds, behaviors attributed to anxiety associated with threat of predation. To examine possible genetic effects of inbreeding and segregation on this behavior, we compared Zebrafish International Resource Center (ZIRC) AB and WIK lines to zebrafish and GloFish® from a pet store (PETCO) in two qualitatively different novel environments: the dive tank and aquatic light/dark plus maze. Behavior was observed in the dive tank for 5 min, immediately followed by 5 min in the light/dark plus maze. Among strains, WIK spent more time in the dive tank top than AB (76 + 30 vs. 17 + 11 sec), and AB froze in the plusmaze center for longer than PETCO or GloFish® (162 + 61 vs. 72 + 29 or 27 + 27 sec). Further,behavior of zebrafish exposed for 3 min to 25 mg/L nicotine, desipramine, chlordiazepoxide,yohimbine, 100 mg/L citalopram, 0.05% DMSO, or 0.5% ethanol was compared to controls. Approximately 0.1% of drug is available in brain after such exposures. Desipramine or citalopram exposed fish spent more time in the dive tank top, and both reuptake inhibitors bound to serotonin transporters in zebrafish brain with high affinity (K i = 7 + 5 and 9 + 5 nM). In the plus maze, chlordiazepoxide, ethanol and DMSO-exposed fish crossed more lines and spent more time in white arms. Neither 25 mg/L nicotine nor yohimbine altered zebrafish behavior in novel environments, but nicotine was anxiolytic at higher doses. Overall, the light/dark plus maze and dive tank are distinct behavioral measures that are sensitive to treatment with anxiolytic compounds, but zebrafish line selection and solvents can influence baseline behavior in these tests

Human Therapeutic Plasma Levels of the Selective Serotonin Reuptake Inhibitor (SSRI) Sertraline Decrease Serotonin Reuptake Transporter Binding and Shelter-Seeking Behavior in Adult Male Fathead Minnows

Selective serotonin reuptake inhibitors (SSRIs) represent a class of pharmaceuticals previously reported in aquatic ecosystems. SSRIs are designed to treat depression and other disorders in humans, but are recognized to elicit a variety of effects on aquatic organisms, ranging from neuroendocrine disruption to behavioral perturbations. However, an understanding of the relationships among mechanistic responses associated with SSRI targets and ecologically important behavioral responses of fish remains elusive. Herein, linking Adverse Outcomes Pathways (AOP) models with internal dosimetry represent potential approaches for developing an understanding of pharmaceutical risks to aquatic life. We selected sertraline as a model SSRI for a 28-d study with adult male fathead minnows. Binding activity of the serotonin reuptake transporter (SERT), previously demonstrated in mammals and fish models to respond to sertraline exposure, was selected as an endpoint associated with therapeutic activity. Shelter-seeking behavior was monitored using digital tracking software to diagnose behavioral abnormalities. Fish plasma levels of sertraline exceeding human therapeutic doses were accurately modeled from external exposure concentrations when pH influences on ionization and log D were considered. We observed statistically significant decreases in binding at the therapeutic target (SERT) and shelter-seeking behavior when fish plasma levels exceeded human therapeutic thresholds. Such observations highlights the strengths of coupling physiologically based pharmacokinetic modeling and AOP approaches and suggest that internal dosimetry should be monitored to advance an understanding of the ecological consequences of SSRI exposure to aquatic vertebrates