Polyamines (PAs), including spermidine, spermine and their precursor, putrescine, are ubiquitous molecules that are vital for a variety of physiological processes. Recently, PAs gained research attention because of their roles in promoting longevity and preventing age-related diseases. Circulating and tissue levels of PAs appear to decline with age, while higher intake of PAs in humans is correlated with better health during aging. Many foods, including plants and offal (organ meats), are good sources of dietary PAs, but are consumed much less in regions with prevailing Western diets. Elevating the circulating levels of PAs through dietary supplementation with PA-rich plant extracts or foods, on the other hand, has proven to be challenging, most likely due to their low bioavailability. In this study, we evaluated the effectiveness of nutritional supplements derived from bovine glandular tissues and/or plant material in elevating blood and tissue levels of spermidine, spermine and putrescine in adult rats. We detected appreciable amounts of PAs in the following materials: 1) spermidine-rich supplement (SRS), containing wheat germ, 2) a cytosolic fraction extract of bovine thymus gland (Thymus Cytosolic Fraction - TCF) and 3) a nuclear fraction extract of bovine thymus gland (Thymus Nuclear Fraction - TNF). We showed that all three PA-containing supplements also contain liposomes, with TNF displaying the largest amounts of liposomal PAs, as well as RNAs, among the tested supplements. We demonstrated that oral administration of SRS, TCF and TNF induce rapid changes in blood PA concentrations. Finally, we showed that TNF supplement is superior to SRS and TCF in elevating the levels of spermidine in the blood, liver and heart following a 28-day supplementation period. Considering the importance of PAs in prevention of age-related disease, supplementation with TNF could be a plausible approach towards the maintenance of proper cellular PA homeostasis during aging.

Ketamine is noted for its rapid onset antidepressant response and effectiveness in patients with treatment resistant depression. While most research has focused on glutamatergic mechanisms, recent studies show that antidepressant-like effects in rodents are dependent upon the serotonergic (5-HT) system and suggest a potential contribution of the 5-HT1B receptor. In this study we utilized CP-94253 to examine whether 5-HT1B receptor agonism produces rapid and sustained antidepressant-like effects, focusing on rodent models and treatment approaches commonly used to demonstrate the differentiated response to ketamine. We first confirmed that CP94253 is a potent 5-HT1B agonist in vitro and that CP-94253 occupies brain 5-HT1B receptors at the doses tested. CP-94253 reduced immobility in the mouse forced swim test (FST) and exhibited a prominent antidepressant signature in the mouse-behavior phenotyping platform SmartCube (R). When examined 24 h after acute treatment, CP-94253 reduced FST immobility in both na & iuml;ve rats and in rats receiving chronic interferon alpha treatment. Ex vivo hippocampal long-term potentiation was also enhanced in na & iuml;ve rats receiving acute CP-94253 treatment, 24 h prior to the recordings. In mice exposed to chronic social defeat stress, antidepressant-like effects in the tail suspension and sucrose preference tests were seen 1 h and 24 h after acute treatment, respectively. Finally, whole brain c-fos imaging in mice showed that CP-94253 modulates neuronal activity in discrete brain regions including the lateral habenula circuit implicated in depression and the ketamine treatment response. Collectively these results support the further investigation of 5-HT1B agonism as a novel treatment approach for major depressive disorder.

Objective: N-methyl-D-aspartate receptor (NMDAR) antagonist antidepressants have known potential for abuse liability. The aim of this study was to evaluate the abuse liability of D-cycloserine (DCS), using a selfadministration paradigm in which DCS was tested for its efficacy in substituting for ketamine in ketaminedependent rats. Methods: A standard intravenous self-administration study was conducted in male adult Sprague-Dawley rats to study abuse liability. Potential for self-administration was assessed in ketamine-habituated subjects. Subjects were trained to press a lever to obtain food, prior to connection of the lever to the intravenous drug administration apparatus. DCS was provided for self-infusion by test subjects at doses of 1.5, 5.0, and 15 mg/kg per lever press. Results: S-ketamine was seen to substitute for ketamine and to result in self-administration at the same frequency. DCS was not seen to result in self-administration at any of the test doses. The self-infusion behavior of DCS was similar to control (saline). Conclusion: D-cycloserine, a partial agonist of the NMDAR glycine site, which has been shown to have antidepressant and anti-suicidal properties in clinical studies, has no apparent potential for abuse liability in a standard rodent self-administration model.

Amylin, a 37 amino acid peptide pancreatic hormone co-secreted with insulin, normalizes the altered eating patterns induced by chronic stress in the rat. Because these stress-induced changes are driven, in part, by brain corticotropin-releasing factor and corticosterone, and because alterations in the activity of these molecules and the stress system are commonly associated with neuropsychiatric diseases like anxiety, depression, and schizo-phrenia, we hypothesized that amylin might mitigate behavioral states associated with stress. Therefore, we tested the effects of rat amylin in rodent-based behavioral assays sensitive to neuropsychiatric drugs, including anxiolytic, antidepressant, antipsychotic, and cognitive enhancing drugs: stress-induced hyperthermia (SIH); marble burying; elevated plus maze (EPM)), forced swim test (FST), pre-pulse inhibition, and phencyclidine-induced locomotion. To assess the neural underpinnings of amylin's anxiolytic-like effects, we examined the effect of amylin on SIH after lesioning the area postrema (AP), which mediates amylin's metabolic effects. Amylin injection (IP, 0.1, 1.0, & 10 mg/kg) significantly (P < 0.05) decreased SIH (97% below vehicle) and AP lesions inhibited this effect. Amylin also reduced marble burying (72% below vehicle), but had no effect in the EPM. Together, these effects suggest anxiolytic-like activity or potential. Amylin injection also enhanced cognitive performance in the novel object recognition test. When administered continuously by implanted os-motic pumps, amylin (300 mg/kg/d) blocked SIH when tested at 1 and 4 weeks. Compared to vehicle, amylin infusion (1 and 3 mg/kg/d) reduced the time immobile in the FST (P < 0.05; 30% below vehicle), suggesting antidepressant-like potential. Although further testing is needed, our findings support a potential for peripherally administered amylin to access and benefit pathways that regulate memory, emotion, and mood.

Objectives Inadequate dietary magnesium (Mg) intake is a growing public health concern. Mg is critical for diverse metabolic processes including energy production, macromolecule biosynthesis, and electrolyte homeostasis. Inadequate free Mg2+ ion concentration ([Mg2+]) in the brain is associated with several neurological and behavioral disorders. Elevating [Mg2+]in the brain using oral Mg supplementation has proven to be challenging due to the tight regulation of Mg2+ transport to the brain. This study explored the effect of short-term moderate reduction in dietary Mg intake (87% of normal Mg diet for 30 days) on [Mg2+] in the cerebrospinal fluid (CSF) ([Mg2+](CSF)) and red blood cells (RBCs) ([Mg2+](RBC)) in adult male rats. In addition, we investigated the effectiveness of magnesium-rich blend of Swiss chard and buckwheat extracts (SC/BW extract) in increasing brain [Mg2+] compared to various Mg salts commonly used as dietary supplements. Methods Animals were assigned to either normal or low Mg diet for 30 - 45 days. Following this, animals maintained on low Mg diet were supplemented with various Mg compounds. [Mg2+](CSF) and [Mg2+](RBC) were measured at baseline and following Mg administration. Anxiety-like behavior and cognitive function were also evaluated. Results The present study showed that a short-term and moderate reduction in Mg dietary intake results in a significant decline in [Mg2+](CSF) and [Mg2+](RBC) and the emergence of anxiety-like behavior in comparison to animals maintained on normal Mg diet. Supplementation with SC/BW extract significantly elevated [Mg2+](CSF) and improved animal performance in the novel object recognition test in comparison with animals maintained on reduced Mg intake and supplemented with various Mg compounds. Discussion These observations indicate that brain [Mg2+] is more sensitive to a short-term and moderate reduction in Mg dietary intake than previously thought and emphasizes the importance of dietary Mg in replenishing brain Mg2+ reserves.

BACKGROUND:The study of depression in humans depends on animal models that attempt to mimic specific features of the human syndrome. Most studies focus on one or a few behavioral domains, with time and practical considerations prohibiting a comprehensive evaluation. Although machine learning has enabled unbiased analysis of behavior in animals, this has not yet been applied to animal models of psychiatric disease.METHODS:We performed chronic social defeat stress (CSDS) in mice and evaluated behavior with PsychoGenics' SmartCube, a high-throughput unbiased automated phenotyping platform that collects >2000 behavioral features based on machine learning. We evaluated group differences at several times post-CSDS and after administration of the antidepressant medication imipramine.RESULTS:SmartCube analysis after CSDS successfully separated control and defeated-susceptible mice, and defeated-resilient mice more resembled control mice. We observed a potentiation of CSDS effects over time. Treatment of susceptible mice with imipramine induced a 40.2% recovery of the defeated-susceptible phenotype as assessed by SmartCube.CONCLUSIONS:High-throughput analysis can simultaneously evaluate multiple behavioral alterations in an animal model for the study of depression, which provides a more unbiased and holistic approach to evaluating group differences after CSDS and perhaps can be applied to other mouse models of psychiatric disease.