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Research studies have indicated that the comorbidity burden of mood disorders and obesity is reasonably high. Insulin signaling has been shown to modulate multiple physiological functions in the brain, indicating its association with neuropsychiatric diseases, including mood disorders. Leptin is a hormone responsible for regulating body weight and insulin homeostasis. Previous studies on db/db mice (a mouse model that carries a spontaneous genetic mutation in leptin receptor Leprdb ) have shown that they exhibit inflammation as well as neurobehavioral traits associated with mood. Therefore, targeting inflammatory pathways such as TNF-α may be an effective strategy in the treatment of obesity-linked mood disorders. The objective of this study was to investigate the effect of long-term administration of etanercept (a TNF-α blocker) on anxiety and depressive-like behaviors in db/db mice. This was performed using light/dark box, forced swim, and open field tests with lean littermate wild type (WT) mice serving as a control group. Using flow cytometry in peripheral blood, we further examined the molecular effects of etanercept on NF-κB p65, TNF-α, IL-17A, and TLR-4 expressing CD4+, CD8+, and CD14+ cells in the peripheral blood. Our data show that peripheral administration of etanercept decreased these cells in db/db mice. Furthermore, our results indicated that peripheral administration of etanercept reduced anxiety and depressive-like behaviors. Therefore, targeting TNF-α signaling might be an effective strategy for modulating obesity-associated depression and anxiety.

The objective of the present study is to investigate the role of α4, α5, α6 or β2 nAChR subunits in the antidepressant-like effect of bupropion. Adult male mice were treated with subcutaneous acute doses of bupropion (3 and 10 mg/kg) 30 min before the forced swim test (FST) in α4, α5, α6, or β2 nAChR subunit knockout (KO) and wild-type (WT) mice. In addition, the effects of β2* antagonist dihydro-β-erythroidine (DHβE, 3 mg/kg) on antidepressant-like effects of bupropion in C57BL/6 J mice were assessed. Our results showed that baseline immobility and climbing time did not differ between KO and corresponding WT mice except for β2 KO. Bupropion significantly decreased immobility time and increased climbing time in the α4, α6 and β2 nAChR KO mice in comparison to WT littermates, indicating that lack of these nAChR subunits enhanced antidepressant effects of bupropion. On the contrary, the α5 nAChR subunit deletion did not alter the FST behavior in the bupropion-treated mice. Not only in the transgenic mice, bupropion also showed antidepressant-like effects in the WT mice. In addition, DHβE pretreatment before bupropion administration resulted in decreased immobility time and increased climbing time. Taken together, the present study provides evidence on the involvement of α4*, α6*, and β2* (* indicates possible presence of other subunits) nAChRs in the antidepressant-like effects of bupropion in the FST.

5-Fluorouracil (5-FU) is one of the most commonly prescribed anti-cancer agent. However, its use is associated with several debilitating adverse effects such as intestinal mucositis (IM) and myelosuppression. Oxidative stress and inflammation are major contributors in the development of mucositis. Diadzein is known for its potent anti-inflammatory and anti-oxidative activities from decades. The present study focused on investigating the effects of diadzein on intestinal mucositis induced by 5-FU by mainly focusing on oxidative stress and inflammatory markers in mice. Mucositis was induced in mice by administration of 5-FU (50 mg/kg, i.p.), once daily for three days and diadzein (1, 5, 10 mg/kg) was administered once daily for seven days. Diadzein pretreatment was found to reduce the severity of mucosal injury in a dose-dependent manner. Diadzein significantly reversed weight loss, relieved diarrhea, and improved histopathological deformities associated with inflammation. Moreover, diadzein remarkably improved the intestinal wall histopathology by reducing inflammatory mediators infiltration and prevented suppression of antioxidants (glutathione, glutathione sulfo-transferase, and catalase) by 5-FU administration. Furthermore, nitrite production in intestinal tissue was reduced by diadzein consistent with the observed modulation of inflammatory markers. Additionally, diadzein also improved the amended microflora profile, by reducing the number of pathogenic bacteria and increasing the abundance of probiotics. Taken together, the behavioral, biochemical and histological outcomes of the present study demonstrates that diadzein has significant anti-mucositis properties in 5-FU induced mucositis model, and the attenuative potential of diadzein might be due to inhibition of oxidative stress and inflammatory mediators.

There is an increased prevalence of comorbid major depressive disorders with a number of inflammatory conditions which is thought to result from activation of the immune system. Acute lung injury (ALI) in humans has been also shown to be associated with depression previously. However, no study has explored the mechanism behind ALI-induced depression. NADPH oxidase (NOX-2) derived reactive oxygen species (ROS) are associated with neuropsychiatric disorders including depression. ROS generation via NOX-2 is also shown to be involved in the pathogenesis of ALI. Therefore, we hypothesized that ROS generation may be a common link between ALI and depression. The present study utilized LPS model of ALI in mice to explore the effect of lung inflammation on depression-like behavior and further delineate the role of NOX-2 signaling in it. ALI led to enhanced NOX-2 activation in neutrophils/brain and neuronal oxidative stress which was concurrent with depression-like symptoms as assessed by sucrose preference and tail suspension test. Role of neutrophilic NOX-2 in ALI-induced depression was confirmed by depletion of neutrophils as well NOX-2 inhibitor, apocynin. Both of these approaches led to reduction in depressive symptoms induced by ALI. The present study suggests that ALI-induced upregulation of neutrophilic NOX-2/ROS may contribute to depression-like symptoms in mice.

Paclitaxel, one of the most commonly used cancer chemotherapeutic drugs, effectively extends the progression-free survival of breast, lung, and ovarian cancer patients. However, paclitaxel and other chemotherapy drugs elicit peripheral nerve fiber dysfunction or degeneration that leads to peripheral neuropathy in a large proportion of cancer patients. Patients receiving chemotherapy also often experience changes in mood, including anxiety and depression. These somatic and affective disorders represent major dose-limiting side effects of chemotherapy. Consequently, the present study was designed to develop a preclinical model of paclitaxel-induced negative affective symptoms in order to identify treatment strategies and their underlying mechanisms of action. Intraperitoneal injections of paclitaxel (8 mg/kg) resulted in the development and maintenance of mechanical and cold allodynia. Carboplatin, another cancer chemotherapeutic drug that is often used in combination with paclitaxel, sensitized mice to the nociceptive effects of paclitaxel. Paclitaxel also induced anxiety-like behavior, as assessed in the novelty suppressed feeding and light/dark box tests. In addition, paclitaxel-treated mice displayed depression-like behavior during the forced swim test and an anhedonia-like state in the sucrose preference test. In summary, paclitaxel produced altered behaviors in assays modeling affective states in C57BL/6J male mice, while increases in nociceptive responses were longer in duration. The characterization of this preclinical model of chemotherapy-induced allodynia and affective symptoms, possibly related to neuropathic pain, provides the basis for determining the mechanism(s) underlying severe side effects elicited by paclitaxel, as well as for predicting the efficacy of potential therapeutic interventions. United States Department of Health & Human Services National Institutes of Health (NIH) - USA - R01-CA206028 VCU Massey Cancer Center NIH-NCI Cancer Center Support Grant - P30 CA016059 United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Cancer Institute (NCI) - R01CA206028 - P30CA016059

Pain encompasses both a sensory as well as an affective dimension and these are differentially processed in the brain and periphery. It is therefore important to develop animal models to reflect the non-reflexive assays in pain. In this study, we compared effects of the mu opioid receptor agonist morphine, the nonsteroidal anti-inflammatory drug ketoprofen and the kappa receptor opioid agonist U50,488H and antagonist JDTic on acetic acid-induced stretching and acetic acid-induced aversion in the condition place aversion (CPA) test in male ICR mice. Intraperitoneal administration of acetic acid (0.32-1%) was equipotent in stimulating stretching and CPA. Ketoprofen, morphine and U50,488H all inhibited the acid induced stretching. Ketoprofen and morphine also blocked the acid-induced CPA but U50,488H failed to do so. The reversal ability of ketoprofen and morphine on acid-induced CPA is unique to pain-stimulated place aversion since these drugs failed to reduce non-noxious LiCl-induced CPA. Overall, this study characterized and validated a preclinical mouse model of pain-related aversive behavior that can be used to assess genetic and biological mechanisms of pain as well as improving the predictive validity of preclinical studies on candidate analgesics. United States Department of Health & Human Services National Institutes of Health (NIH) - USA - R01DA-019377 - R01NS070715 - R01DA030404 NIH National Institute of Neurological Disorders & Stroke (NINDS) - R01NS070715 NIH National Institute on Drug Abuse (NIDA) - R01DA030404 European Commission

Several studies demonstrated that impairment in glutamatergic neurotransmission is linked to drug dependence and drug-seeking behavior. Increased extracellular glutamate concentration in mesocorticolimbic regions has been observed in animals developing nicotine dependence. Changes in glutamate release might be associated with stimulatory effect of nicotinic acetylcholine receptors (nAChRs) via nicotine exposure. We and others have shown increased extracellular glutamate concentration, which was associated with down regulation of the major glutamate transporter, glutamate transporter 1 (GLT-1), in brain reward regions of animals exposed to drug abuse, including nicotine and ethanol. Importantly, studies from our laboratory and others showed that upregulation of GLT-1 expression in the mesocorticolimbic brain regions may have potential therapeutic effects in drug dependence. In this review article, we discussed the effect of antagonizing presynaptic nAChRs in glutamate release, the upregulatory effect in GLT-1 expression and the role of glutamate receptors antagonists in the treatment of nicotine dependence.

Nicotinic acetylcholine receptors can regulate inflammation primarily through the vagus nerve via the cholinergic anti-inflammatory pathway. α9α10 nicotinic receptors (nAChRs) are a new promising target for chronic pain and inflammation. Recently, α9α10 selective α-conotoxin antagonists were shown to have antinociception effect in neuropathic and tonic inflammatory pain animal models. However, limited data available on the role of α9α10 nAChRs in experimental colitis. In this study, we report for the first time, the role of α9α10 nAChRs in the dextran sodium sulfate (DSS) experimental animal colitis model. We determined the effect of the α9α10 nAChRs antagonist, α-conotoxin RgIA (α-RgIA) in DSS-induced colitis model in adult male and female C57BL/6 J mice. DSS solution was freely given in the drinking water for seven consecutive days, and tap water was given on the 8th day. We then sacrificed mice on day 8 to examine the entire colon. Disease severity, colon tissue histology, and tumor necrosis factor-α (TNF-α) were evaluated. The lower doses (0.02 and 0.1 nmol/mouse, s.c.) of α-RgIA treatment in DSS-treated mice were inactive, whereas the higher dose (0.2 nmol/mouse, s.c.) reversed the disease activity index (DAI) score, loss of body weight, total histological damage score, as well as the colonic level of TNF-α compared to the DSS-control group. Moreover, the highest dose of α-RgIA (0.2 nmol/mouse, s.c.) significantly rescued the colon length shortening in DSS-treated mice compared to the DSS-control mice. The availability of α9*-selective conotoxins has opened new avenues in pharmacology research and potential targets in inflammatory disorders.

The aim of the present study was to determine the impact of α 5 nicotinic acetylcholine receptor (nAChR) subunit deletion in the mouse on the development and intensity of nociceptive behavior in various chronic pain models. The role of α 5 -containing nAChRs was explored in mouse models of chronic pain, including peripheral neuropathy (chronic constriction nerve injury, CCI), tonic inflammatory pain (the formalin test) and short and long-term inflammatory pain (complete Freund's adjuvant, CFA and carrageenan tests) in α 5 knock-out (KO) and wild-type (WT) mice. The results showed that paw-licking time was decreased in the formalin test, and the hyperalgesic and allodynic responses to carrageenan and CFA injections were also reduced. In addition, paw edema in formalin-, carrageenan- or CFA-treated mice were attenuated in α 5 -KO mice significantly. Furthermore, tumor necrosis factor-alpha (TNF-α) levels of carrageenan-treated paws were lower in α 5 -KO mice. The antinociceptive effects of nicotine and sazetidine-A but not varenicline were α 5 -dependent in the formalin test. Both hyperalgesia and allodynia observed in the CCI test were reduced in α 5 -KO mice. Nicotine reversal of mechanical allodynia in the CCI test was mediated through α 5 -nAChRs at spinal and peripheral sites. In summary, our results highlight the involvement of the α 5 nAChR subunit in the development of hyperalgesia, allodynia and inflammation associated with chronic neuropathic and inflammatory pain models. They also suggest the importance of α 5 -nAChRs as a target for the treatment of chronic pain.