The potential effect of α7 nicotinic receptors modulation on palatable food-induced dependence-like behaviors.

Background: The recent global increase in obesity rates, coupled with excessive palatable food (PF) consumption, has become a serious societal concern. Literature indicates that rewarding PF, especially upon cessation, can lead to overeating, binge eating, and compulsive eating, potentially resulting in obesity. Challenges in dietary paradigms, alongside limitations in approved treatments for eating disorders and anti-obesity medications, underscore the need to explore novel targets. In this context, α7nAChR (alpha-7 nicotinic acetylcholine receptor) may serve as a promising therapeutic target in combating food dependence and obesity. The present study aims to assess the role of α7nAChR in palatable food-induced dependence-like behaviors. Method: The study involved male C57BL/6J mice exposed to three different feeding paradigms over 6 weeks to induce obesity and food addiction. On day 43, palatable food was replaced with standard chow, and the mice received treatments (vehicle, PNU-282987 [α7nAChR agonist], or methyllycaconitine citrate [MLA; α7nAChR antagonist]). Addiction-like behaviors, including craving for palatable food, motivation-effort interaction tests, and compulsive eating-like behavior, were measured during abstinence with and without treatment. Results: The present study shows that chronic intermittent and continuous exposure to palatable food induces craving, motivation, and effort interaction behaviors as well as compulsive eating-like behaviors in palatable food-abstinent mice. Administration of the α7nAChR agonist, PNU-282987, significantly attenuated the craving behavior only in mice continuously fed palatable food (reduced calorie intake from 63.19 % to 48.21 %; p = 0.0053). Also, PNU-282987 suppressed the effort behaviors in either intermittently or continuously fed mice (significant reduction in the Δ number of active events per minute; p-values = 0.038 and 0.0098, respectively). However, it attenuated the compulsive-like eating behavior exclusively in the continuously fed group (p = 0.0433). Active and total interaction efforts were reversed by the MLA. These findings indicate the involvement of α7nAChR in dependence-like behaviors toward palatable food in mice. Conclusion: Our findings demonstrate that dependence-like behaviors toward palatable food can emerge after prolonged exposure. Mice fed on palatable food continuously exhibited more dependence-like behaviors toward palatable food, and activation of α7nAChR signaling attenuated the vulnerability to develop such behaviors.

Activation of α7 nicotinic receptors attenuated hyperalgesia and anxiety induced by palatable obesogenic diet withdrawal.

Consumption of palatable food (PF) can alleviate anxiety, and pain in humans. Contrary, spontaneous withdrawal of long-term PF intake produces anxiogenic-like behavior and abnormal pain sensation, causing challenges to weight-loss diet and anti-obesity agents. Thus, we examined α7-nicotinic acetylcholine receptors (α7nAChR) involvement since it plays essential role in nociception and psychological behaviors. METHODS: Adult male C57BL/6 mice were placed on a Standard Chow (SC) alone or with PF on intermittent or continuous regimen for 6 weeks. Then, mice were replaced with normal SC (spontaneous withdrawal). Body weight, food intake, and calories intake with and without the obesogenic diet were measured throughout the study. During PF withdrawal, anxiety-like behaviors and pain sensitivity were measured with PNU-282987 (α7nAChR agonist) administration. RESULTS: Six weeks of SC + PF-intermittent and continuous paradigms produced a significant weight gain. PF withdrawal displayed hyperalgesia and anxiety-like behaviors. During withdrawal, PNU-282987 significantly attenuated hyperalgesia and anxiety-like behaviors. CONCLUSION: The present study shows that a PF can increase food intake and body weight. Also, enhanced pain sensitivity and anxiety-like behavior were observed during PF withdrawal. α7nAChR activation attenuated anxiolytic-like behavior and hyperalgesia in PF abstinent mice. These data suggest potential therapeutic effects of targeting α7 nAChRs for obesity-withdrawal symptoms in obese subjects.

Semaglutide ameliorated autism-like behaviors and DNA repair efficiency in male BTBR mice by recovering DNA repair gene expression.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that is marked by impaired social interactions, and increased repetitive behaviors. There is evidence of genetic changes in ASD, and several of these altered genes are linked to the process of DNA repair. Therefore, individuals with ASD must have improved DNA repair efficiency to mitigate risks associated with ASD. Despite numerous milestones in ASD research, the disease remains incurable, with a high occurrence rate and substantial financial burdens. This motivates scientists to search for new drugs to manage the disease. Disruption of glucagon-like peptide-1 (GLP-1) signaling, a regulator in neuronal development and maintains homeostasis, has been associated with the pathogenesis and progression of several neurological disorders, such as ASD. Our study aimed to assess the impact of semaglutide, a new GLP-1 analog antidiabetic medication, on behavioral phenotypes and DNA repair efficiency in the BTBR autistic mouse model. Furthermore, we elucidated the underlying mechanism(s) responsible for the ameliorative effects of semaglutide against behavioral problems and DNA repair deficiency in BTBR mice. The current results demonstrate that repeated treatment with semaglutide efficiently decreased autism-like behaviors in BTBR mice without affecting motor performance. Semaglutide also mitigated spontaneous DNA damage and enhanced DNA repair efficiency in the BTBR mice as determined by comet assay. Moreover, administering semaglutide recovered oxidant-antioxidant balance in BTBR mice. Semaglutide restored the disrupted DNA damage/repair pathways in the BTBR mice by reducing Gadd45a expression and increasing Ogg1 and Xrcc1 expression at both the mRNA and protein levels. This suggests that semaglutide holds great potential as a novel therapeutic candidate for treating ASD traits.

Effects of novel beta-lactam, MC-100093, and ceftriaxone on astrocytic glutamate transporters and neuroinflammatory factors in nucleus accumbens of C57BL/6 mice exposed to escalated doses of morphine.

Chronic exposure to opioids can lead to downregulation of astrocytic glutamate transporter 1 (GLT-1), which regulates the majority of glutamate uptake. Studies from our lab revealed that beta-lactam antibiotic, ceftriaxone, attenuated hydrocodone-induced downregulation of GLT-1 as well as cystine/glutamate antiporter (xCT) expression in central reward brain regions. In this study, we investigated the effects of escalating doses of morphine and tested the efficacy of novel synthetic non-antibiotic drug, MC-100093, and ceftriaxone in attenuating the effects of morphine exposure in the expression of GLT-1, xCT, and neuroinflammatory factors (IL-6 and TGF-ß) in the nucleus accumbens (NAc). This study also investigated the effects of morphine and beta-lactams in locomotor activity, spontaneous alternation percentage (SAP) and number of entries in Y maze since opioids have effects in locomotor sensitization. Mice were exposed to moderate dose of morphine (20 mg/kg, i.p.) on days 1, 3, 5, 7, and a higher dose of morphine (150 mg/kg, i.p.) on day 9, and these mice were then behaviorally tested and euthanized on Day 10. Western blot analysis showed that exposure to morphine downregulated GLT-1 and xCT expression in the NAc, and both MC-100093 and ceftriaxone attenuated these effects. In addition, morphine exposure increased IL-6 mRNA and TGF-ß mRNA expression, and MC-100093 and ceftriaxone attenuated only the effect on IL-6 mRNA expression in the NAc. Furthermore, morphine exposure induced an increase in distance travelled, and MC-100093 and ceftriaxone attenuated this effect. In addition, morphine exposure decreased the SAP and increased the number of arm entries in Y maze, however, neither MC-100093 nor ceftriaxone showed any attenuating effect. Our findings demonstrated for the first time that MC-100093 and ceftriaxone attenuated morphine-induced downregulation of GLT-1 and xCT expression, and morphine-induced increase in neuroinflammatory factor, IL-6, as well as hyperactivity. These findings revealed the beneficial therapeutic effects of MC-100093 and ceftriaxone against the effects of exposure to escalated doses of morphine.

Multiple exposure to methylmercury aggravates DNA damage in the BTBR T + Itpr3 tf/J autistic mouse model: The role of DNA repair efficiency.

Environmental and genetic factors have been recognized to play major roles in the pathogenesis of autism. Here we examined the BTBR T+Itpr3tf/J (BTBR) mice's susceptibility, an autistic model, to the genotoxic effects and DNA repair dysregulation of methylmercury. Micronuclei formation and oxidative DNA damage were analyzed using the micronucleus/fluorescence in situ hybridization test and modified comet assay, respectively. The results showed higher centromeric-positive micronuclei and oxidative DNA damage in BTBR mice exposed to methylmercury than the unexposed mice, which indicates that mutagenesis aggravated in BTBR mice after methylmercury exposure. Lipid peroxides in BTBR mice were significantly elevated, with a decrease in reduced/oxidized glutathione ratio after methylmercury exposure, indicating an augmenting oxidant-antioxidant imbalance. The expression of several genes involved in DNA repair was markedly altered in BTBR mice after methylmercury exposure as evaluated via PCR array and RT-PCR analyses. Declining of the antioxidant defense and dysregulation in DNA repair process after methylmercury exposure may explain the aggravated genotoxic susceptibility of BTBR mice. Thus, autistic individuals exposed to methylmercury must be under regular medical follow-up through standard timetabled medical laboratory inquiry to allow for early recognition of any mutagenic changes. Additionally, strategies that elevate cellular antioxidants/DNA repair efficiency may counteract methylmercury-induced genotoxicity.