Peripheral administration of lactate produces antidepressant-like effects.
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ABSTRACT:
SUBMITTER: Carrard A
PROVIDER: S-EPMC5794873 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In addition to its role as metabolic substrate that can sustain neuronal function and viability, emerging evidence supports a role for l-lactate as an intercellular signaling molecule involved in synaptic plasticity. Clinical and basic research studies have shown that major depression and chronic stress are associated with alterations in structural and functional plasticity. These findings led us to investigate the role of l-lactate as a potential novel antidepressant. Here we show that peripheral administration of l-lactate produces antidepressant-like effects in different animal models of depression that respond to acute and chronic antidepressant treatment. The antidepressant-like effects of l-lactate are associated with increases in hippocampal lactate levels and with changes in the expression of target genes involved in serotonin receptor trafficking, astrocyte functions, neurogenesis, nitric oxide synthesis and cAMP signaling. Further elucidation of the mechanisms underlying the antidepressant effects of l-lactate may help to identify novel therapeutic targets for the treatment of depression.
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Project description:Recent clinical studies demonstrate that serum levels of brain-derived neurotrophic factor (BDNF) are significantly decreased in patients with major depressive disorder (MDD) and that antidepressant treatments reverse this effect, indicating that serum BDNF is a biomarker of MDD. These findings raise the possibility that serum BDNF may also have effects on neuronal activity and behavior, but the functional significance of altered serum BDNF is unknown. To address this issue, we determined the influence of peripheral BDNF administration on depression- and anxiety-like behavior, including the forced swim test (FST), chronic unpredictable stress (CUS)/anhedonia, novelty-induced hypophagia (NIH) test, and elevated-plus maze (EPM). Furthermore, we examined adult hippocampal neurogenesis as well as hippocampal and striatal expression of BDNF, extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB), in order to determine whether peripherally administered BDNF produces antidepressant-like cellular responses in the brain. Peripheral BDNF administration increased mobility in the FST, attenuated the effects of CUS on sucrose consumption, decreased latency in the NIH test, and increased time spent in the open arms of an EPM. Moreover, adult hippocampal neurogenesis was increased after chronic, peripheral BDNF administration. We also found that BDNF levels as well as expression of pCREB and pERK were elevated in the hippocampus of adult mice receiving peripheral BDNF. Taken together, these results indicate that peripheral/serum BDNF may not only represent a biomarker of MDD, but also have functional consequences on molecular signaling substrates, neurogenesis, and behavior.
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Project description:Opiates have been used historically for the treatment of depression. Renewed interest in the use of opiates as antidepressants has focused on the development of kappa opioid receptor (κ-receptor) antagonists. Buprenorphine acts as a partial µ-opioid receptor agonist and a κ-receptor antagonist. By combining buprenorphine with the opioid antagonist naltrexone, the activation of µ-opioid receptors will be reduced and the κ-antagonist properties enhanced. We have established that a combination dose of buprenorphine (1 mg/kg) with naltrexone (1 mg/kg) functions as a short-acting κ-antagonist in the mouse tail withdrawal test. Furthermore, this dose combination is neither rewarding nor aversive in the conditioned place preference paradigm, and is without significant locomotor effects. We have shown for the first time that systemic co-administration of buprenorphine (1 mg/kg) with naltrexone (1 mg/kg) in CD-1 mice produced an antidepressant-like response in behaviours in both the forced swim test and novelty induced hypophagia task. Behaviours in the elevated plus maze and light dark box were not significantly altered by treatment with buprenorphine alone, or in combination with naltrexone. We propose that the combination of buprenorphine with naltrexone represents a novel, and potentially a readily translatable approach, to the treatment of depression.
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Project description:Research suggests that dysfunctional glutamatergic signalling may contribute to depression, a debilitating mood disorder affecting millions of individuals worldwide. Ketamine, a N-methyl-D-aspartate (NMDA) receptor antagonist, exerts rapid antidepressant effects in approximately 70% of patients. Glutamate evokes the release of D-serine from astrocytes and neurons, which then acts as a co-agonist and binds at the glycine site on the NR1 subunit of NMDA receptors. Several studies have implicated glial deficits as one of the underlying facets of the neurobiology of depression. The present study tested the hypothesis that D-serine modulates behaviours related to depression. The behavioural effects of a single, acute D-serine administration were examined in several rodent tests of antidepressant-like effects, including the forced swim test (FST), the female urine sniffing test (FUST) following serotonin depletion, and the learned helplessness (LH) paradigm. D-serine significantly reduced immobility in the FST without affecting general motor function. Both D-serine and ketamine significantly rescued sexual reward-seeking deficits caused by serotonin depletion in the FUST. Finally, D-serine reversed LH behaviour, as measured by escape latency, number of escapes, and percentage of mice developing LH. Mice lacking NR1 expression in forebrain excitatory neurons exhibited a depression-like phenotype in the same behavioural tests, and did not respond to D-serine treatment. These findings suggest that D-serine produces antidepressant-like effects and support the notion of complex glutamatergic dysfunction in depression. It is unclear whether D-serine has a convergent influence on downstream synaptic plasticity cascades that may yield a similar therapeutic profile to NMDA antagonists like ketamine.
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Project description:A brief burst-suppressing isoflurane anesthesia has been shown to rapidly alleviate symptoms of depression in a subset of patients, but the neurobiological basis of these observations remains obscure. We show that a single isoflurane anesthesia produces antidepressant-like behavioural effects in the learned helplessness paradigm and regulates molecular events implicated in the mechanism of action of rapid-acting antidepressant ketamine: activation of brain-derived neurotrophic factor (BDNF) receptor TrkB, facilitation of mammalian target of rapamycin (mTOR) signaling pathway and inhibition of glycogen synthase kinase 3? (GSK3?). Moreover, isoflurane affected neuronal plasticity by facilitating long-term potentiation in the hippocampus. We also found that isoflurane increased activity of the parvalbumin interneurons, and facilitated GABAergic transmission in wild type mice but not in transgenic mice with reduced TrkB expression in parvalbumin interneurons. Our findings strengthen the role of TrkB signaling in the antidepressant responses and encourage further evaluation of isoflurane as a rapid-acting antidepressant devoid of the psychotomimetic effects and abuse potential of ketamine.
| S-EPMC5552878 | biostudies-other
Project description:Major depressive disorder and related illnesses are globally prevalent, with a significant risk for suicidality if untreated. Antidepressant drugs that are currently prescribed do not benefit 30% of treated individuals. Furthermore, there is a delay of 3 or more weeks before a reduction in symptoms. Results from preclinical studies have indicated an important role for trophic factors in regulating behavior. Erythropoietin (Epo), which is widely prescribed for anemia, has been shown to produce robust neurotrophic actions in the CNS. Although Epo's antidepressant activity has been successfully demonstrated in multiple clinical trials, the inherent ability to elevate RBC counts and other hematological parameters preclude its development as a mainstream CNS drug. A chemically engineered derivative, carbamoylated Epo (Cepo) has no hematological activity, but retains the neurotrophic actions of Epo. Cepo is therefore an attractive candidate to be tested as an antidepressant.ObjectiveTo evaluate the antidepressant properties of Cepo in established antidepressant-responsive rodent behavioral assays.MethodsAdult male and female BALB/c mice were used for this study. Cepo (30 ?grams/ kg BWT) or vehicle (PBS) was administered intraperitoneally for 4?days before the test of novelty induced hypophagia and subsequently at five hours before testing in forced swim test (FST), tail suspension test (TST) and open field test (OFT). To obtain mechanistic insight we examined the phosphorylation of the transcription factor cAMP response element binding protein (CREB).ResultsAdministration of Cepo at 30 ?grams/ kg BWT, for 4?days produced significant reduction in latency to consume a palatable drink in a novel environment in male and female mice. Male BALB/c mice had a significant reduction in immobility in both tail suspension and forced swim tests, and female mice exhibited lower immobility in the forced swim test.
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Project description:Some antidepressant agents generate differential benefit based on gender. Blocking cholinergic muscarinic receptors using scopolamine produces robust and rapid antidepressant effects in males and females combined. This study evaluated if males and females differ in the antidepressant response magnitude following scopolamine administration. A total of 52 male and female outpatients meeting criteria for recurrent major depressive or bipolar disorder participated in a double-blind, randomized, placebo-controlled, crossover clinical trial involving seven i.v. infusions of placebo or scopolamine (4??g/kg). Following a single-blind placebo lead-in, participants entered either a placebo-block/scopolamine-block or a scopolamine-block/placebo-block sequence. Each block included three sessions. Clinical ratings were acquired before each infusion and included the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAM-A). A treatment group × block interaction (F=21.0, p<0.001) was observed in MADRS scores across gender, and the reduction was significant by the evaluation following the first scopolamine administration (F=8.4, p=0.006). The treatment group × block interaction was also significant in males (F=3.8, p=0.043) and females (F=35.6, p<0.001) separately. A block × gender interaction (F=7.4, p=0.009) indicated that the response magnitude was larger in women. The treatment × block interaction was significant for the HAM-A across gender (F=12.0, p<0.001), and was significant for females (F=24.9, p<0.001) but not for males (F=1.3, p=0.30). When comparing the baseline block to study end, the block × gender interaction (F=12.6, p=0.001) showed that the antianxiety response was greater in women. Men and women show a rapid antidepressant response following scopolamine, but the magnitude of response is larger in women than in men.
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Project description:Preclinical studies demonstrate that rapid acting antidepressants, including ketamine require stimulation of mTORC1 signaling. This pathway is regulated by neuronal activity, endocrine and metabolic signals, notably the amino acid leucine, which activates mTORC1 signaling via binding to the upstream regulator sestrin. Here, we examined the antidepressant actions of NV-5138, a novel highly selective small molecule modulator of sestrin that penetrates the blood brain barrier. The results demonstrate that a single dose of NV-5138 produced rapid and long-lasting antidepressant effects, and rapidly reversed anhedonia caused by chronic stress exposure. The antidepressant actions of NV-5138 required BDNF release as the behavioral responses are blocked by infusion of a BDNF neutralizing antibody into the medial prefrontal cortex (mPFC) or in mice with a knock-in of a BDNF polymorphism that blocks activity dependent BDNF release. NV-5138 administration also rapidly increased synapse number and function in the mPFC, and reversed the synaptic deficits caused by chronic stress. Together, the results demonstrate that NV-5138 produced rapid synaptic and antidepressant behavioral responses via activation of the mTORC1 pathway and BDNF signaling, indicating that pharmacological modulation of sestrin is a novel approach for development of rapid acting antidepressants.
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Project description:Depression is a common mood disorder characterized by a range of clinical symptoms, including prolonged low mood and diminished interest. Although many clinical and animal studies have provided significant insights into the pathophysiology of depression, current treatment strategies are not sufficient to manage this disorder. It has been suggested that connexin (Cx)-based hemichannels are candidates for depression intervention by modifying the state of neuroinflammation. In this study, we investigated the antidepressant-like effect of a recently discovered selective Cx hemichannel inhibitor, a small organic molecule called D4. We first showed that D4 reduced hemichannel activity following systemic inflammation after LPS injections. Next, we found that D4 treatment prevented LPS-induced inflammatory response and depressive-like behaviors. These behavioral effects were accompanied by reduced astrocytic activation and hemichannel activity in depressive-like mice induced by repeated low-dose LPS challenges. D4 treatment also reverses depressive-like symptoms in mice subjected to chronic restraint stress (CRS). To test whether D4 broadly affected neural activity, we measured c-Fos expression in depression-related brain regions and found a reduction in c-Fos+ cells in different brain regions. D4 significantly normalized CRS-induced hypoactivation in several brain regions, including the hippocampus, entorhinal cortex, and lateral septum. Together, these results indicate that blocking Cx hemichannels using D4 can normalize neuronal activity and reduce depressive-like symptoms in mice by reducing neuroinflammation. Our work provides evidence of the antidepressant-like effect of D4 and supports glial Cx hemichannels as potential therapeutic targets for depression.
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