The Effect of Long-Term Intranasal Serotonin Treatment on Metabolic Parameters and Hormonal Signaling in Rats with High-Fat Diet/Low-Dose Streptozotocin-Induced Type 2 Diabetes

Derkach, K. V.; Бондарева, В. М.; Chistyakova, O. V.; Berstein, Lev M.; Ao, Shpakov

doi:10.1155/2015/245459

Cited by 59 publications

(34 citation statements)

References 99 publications

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“…Given the beneficial role of the serotonin (5-HT) system in the enhancement of brain plasticity (Quesseveur et al, 2013), the possibility that deficits in 5-HT neurotransmission underlie the comorbidity between T2D/IR and depression, has been raised. Consistent with this hypothesis, decreased levels of tryptophan were detected in the CNS of patients with T2D (Kloiber et al, 2010;Herrera-Marquez et al, 2011) or in rodents fed an HFD (Kim et al, 2013;Derkach et al, 2015). Using intracerebral microdialysis, we showed that mice fed an HFD displayed lower basal hippocampal extracellular 5-HT concentrations (Zemdegs et al, 2016).…”

Section: Introductionsupporting

confidence: 70%

Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids

et al. 2019

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Epidemiological studies indicate that insulin resistance (IR), a hallmark of type 2 diabetes, is associated with an increased risk of major depression. Here, we demonstrated that male mice fed a high-fat diet (HFD) exhibited peripheral metabolic impairments reminiscent of IR accompanied by elevated circulating levels of branched-chain amino acids (BCAAs), whereas both parameters were normalized by chronic treatment with metformin (Met). Given the role of BCAAs in the regulation of tryptophan influx into the brain, we then explored the activity of the serotonin (5-HT) system. Our results indicated that HFD-fed mice displayed impairment in the electrical activity of dorsal raphe 5-HT neurons, attenuated hippocampal extracellular 5-HT concentrations and anxiety, one of the most visible and early symptoms of depression. On the contrary, Met stimulated 5-HT neurons excitability and 5-HT neurotransmission while hindering HFD-induced anxiety. Met also promoted antidepressant-like activities as observed with fluoxetine. In light of these data, we designed a modified HFD in which BCAA dietary supply was reduced by half. Deficiency in BCAAs failed to reverse HFD-induced metabolic impairments while producing antidepressant-like activity and enhancing the behavioral response to fluoxetine. Our results suggest that Met may act by decreasing circulating BCAAs levels to favor serotonergic neurotransmission in the hippocampus and promote antidepressant-like effects in mice fed an HFD. These findings also lead us to envision that a diet poor in BCAAs, provided either alone or as add-on therapy to conventional antidepressant drugs, could help to relieve depressive symptoms in patients with metabolic comorbidities.Insulin resistance in humans is associated with increased risk of anxiodepressive disorders. Such a relationship has been also found in rodents fed a high-fat diet (HFD). To determine whether insulin-sensitizing strategies induce anxiolytic-and/or antidepressant-like activities and to investigate the underlying mechanisms, we tested the effects of metformin, an oral antidiabetic drug, in mice fed an HFD. Metformin reduced levels of circulating branched-chain amino acids, which regulate tryptophan uptake within the brain. Moreover, metformin increased hippocampal serotonergic neurotransmission while promoting anxiolytic-and antidepressant-like effects. Moreover, a diet poor in these amino acids produced similar beneficial behavioral property. Collectively, these results suggest that metformin could be used as add-on therapy to a conventional antidepressant for the comorbidity between metabolic and mental disorders.

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Section: Introductionsupporting

confidence: 70%

Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids

et al. 2019

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“…We found no significant difference between male and female rats ( Figure 4d). Female rats are reported to be no more variable than male rats across diverse traits relevant to neuroscience studies (Becker, Prendergast, & Liang, 2016), and female rats have been used for studies involving intranasal administration (Derkach, Bondareva, Chistyakova, Berstein, & Shpakov, 2015;Kumar et al, 2018). Thus, we used female rats for the subsequent intranasal administration studies.…”

Section: Compliance With Requirements For Studies Using Animalsmentioning

confidence: 99%

Intranasal administration of a stapled relaxin‐3 mimetic has anxiolytic‐ and antidepressant‐like activity in rats

Marwari

Poulsen

Shih

et al. 2019

British J Pharmacology

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Background and PurposeDepression and anxiety are common causes of disability, and innovative tools and potential pharmacological targets are actively sought for prevention and treatment. Therapeutic strategies targeting the relaxin‐3 peptide or its primary endogenous receptor, RXFP3, for the treatment of major depression and anxiety disorders have been limited by a lack of compounds with drug‐like properties. We proposed that a hydrocarbon‐stapled mimetic of relaxin‐3, when administered intranasally, might be uniquely applicable to the treatment of these disorders.Experimental ApproachWe designed a series of hydrocarbon‐stapled relaxin‐3 mimetics and identified the most potent compound using in vitro receptor binding and activation assays. Further, we assessed the effect of intranasal delivery of relaxin‐3 and the lead stapled mimetic in rat models of anxiety and depression.Key ResultsWe developed an i,i+7 stapled relaxin‐3 mimetic that manifested a stabilized α‐helical structure, proteolytic resistance, and confirmed agonist activity in receptor binding and activation in vitro assays. The stapled peptide agonist enhanced food intake after intracerebral infusion in rats, confirming in vivo activity. We showed that intranasal delivery of the lead i,i+7 stapled peptide or relaxin‐3 had orexigenic effects in rats, indicating a potential clinically translatable route of delivery. Further, intranasal administration of the lead i,i+7 stapled peptide exerted anxiolytic and antidepressant‐like activity in anxiety‐ and depression‐related behaviour paradigms.Conclusions and ImplicationsOur preclinical findings demonstrate that targeting the relaxin‐3/RXFP3 receptor system via intranasal delivery of an i,i+7 stapled relaxin‐3 mimetic may represent an effective treatment approach for depression, anxiety, and related neuropsychiatric disorders.

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“…Indirect evidence, however, is in favour of an attenuation of serotonergic tone because decreased levels of free tryptophan were detected in the CNS of patients with T2DM (Kloiber et al, 2010;Herrera-Marquez et al, 2011). Accordingly, a significant decrease in plasma or brain levels of 5-HT has been reported in rodents after prolonged HFD exposure (Kim et al, 2013;Derkach et al, 2015), but these neurochemical changes have never been confirmed using in vivo microdialysis.…”

Section: Introductionmentioning

confidence: 99%

High‐fat diet‐induced metabolic disorders impairs 5‐HT function and anxiety‐like behavior in mice

Zemdegs

Quesseveur

Jarriault

et al. 2015

British J Pharmacology

139

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BACKGROUND AND PURPOSEThe link between type 2 diabetes mellitus (T2DM) and depression is bidirectional. However, the possibility that metabolic disorders may elicit anxiogenic-like/depressive-like symptoms or alter the efficacy of antidepressant drugs remains poorly documented. This study explored the influence of T2DM on emotionality and proposed a therapeutic strategy that might be used in depressed diabetic patients. EXPERIMENTAL APPROACHMice were fed a high-fat diet (HFD) and subjected to a full comprehensive metabolic and behavioural analysis to establish correlations between metabolic and psychiatric disorders. In vivo intra-hippocampal microdialysis was also applied to propose a mechanism underpinning the phenotype of mice fed the HFD. Finally, we tested whether chronic administration of the selective 5-HT reuptake inhibitor escitalopram or HFD withdrawal could reverse HFD-induced metabolic and behavioural anomalies. KEY RESULTSThe increased body weight, hyperglycaemia and impaired glucose tolerance in response to HFD were correlated with anxiogeniclike/depressive-like symptoms. Moreover, this phenotype was associated with decreased extracellular 5-HT levels in the hippocampus which may result from increased sensitivity of the dorsal raphe 5-HT 1A autoreceptor. Interestingly, the beneficial effect of prolonged administration of escitalopram was abolished in HFD-fed mice. On the contrary, HFD withdrawal completely reversed metabolic impairments and positively changed symptoms of anxiety, although some behavioural anomalies persisted. CONCLUSIONS AND IMPLICATIONSOur data provide clear-cut evidence that both pathologies are finely correlated and associated with impaired 5-HT mediated neurotransmission in the hippocampus. Further experiments are warranted to define the most adequate strategy for the treatment of such co-morbidity. LINKED ARTICLES

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The Effect of Long-Term Intranasal Serotonin Treatment on Metabolic Parameters and Hormonal Signaling in Rats with High-Fat Diet/Low-Dose Streptozotocin-Induced Type 2 Diabetes

Cited by 59 publications

References 99 publications

Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids

Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids

Intranasal administration of a stapled relaxin‐3 mimetic has anxiolytic‐ and antidepressant‐like activity in rats

High‐fat diet‐induced metabolic disorders impairs 5‐HT function and anxiety‐like behavior in mice

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