Oxytocin mitigated the depressive-like behaviors of maternal separation stress through modulating mitochondrial function and neuroinflammation

Dong

Intl J of Devlp Neuroscience

et al. 2017

There is little research on the effects of adolescent administration of antidepressants on behavioural function and inflammation in early-life stressed adult mice. Using maternal separation (MS), a paradigm of early adversity, we investigated the effects of adolescent (PND 33-54) escitalopram (ES; 10mg/kg) exposure on depression- and anxiety-like behaviours and the levels of inflammatory cytokines (interleukin [IL]-1β, tumor necrosis factor [TNF]-α, and IL-10) in the ventral hippocampus (HPV), prefrontal cortex (PFC), and serum in adult (PND 61) male offspring mice. The results showed that MS has no effect on locomotor activity, but increased depression-like behaviours in the saccharin preference test and increased anxiety-like behaviours in the social preference and elevated plus maze tests. MS increased the levels of IL-1β in the HPV, PFC, and serum, while decreasing the level of IL-10 in the HPV. Furthermore, adolescent ES treatment inhibited these depression- and anxiety-like behaviours, decreased the levels of IL-1β, and increased the level of IL-10 in the HPV. The results also showed that there are no effects of chronic escitalopram administration on normal behaviour in control mice. Taken together, the current data provide experimental evidence that MS increases depression and anxiety levels in adult male offspring. Additionally, the findings support the idea that early pharmacological intervention with ES may be an effective treatment for reducing the behavioral abnormalities induced by early adversity and regulating the underlying inflammatory mechanisms involved.

Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 94%

Adolescent escitalopram prevents the effects of maternal separation on depression‐ and anxiety‐like behaviours and regulates the levels of inflammatory cytokines in adult male mice

Dong

Intl J of Devlp Neuroscience

et al. 2017

“…In addition, the authors demonstrated that OXT could reduce LPS-induced activation both in primary microglia and in microglial cell lines [127]. Recently, Amini-Khoei et al (2017) demonstrated that intracerebral administration of OXT reduced pro-inflammatory gene expression related to microglia activity, including TNF-α, IL-1β, and TLR4, in the HIP of adult animals exposed to MS [128]. In a double-hit model using a low-protein diet to induce perinatal brain damage followed by postnatal injections of IL-1β during early life, the accompanying administration of the OXT receptor agonist carbetocin was found to prevent microglial activation and reduce the effects of the low-protein diet and IL-1β injections on genes associated with microglial activation throughout the brain [45].…”

Section: Early Preventative Interventionsmentioning

confidence: 99%

Microglial Function in the Effects of Early-Life Stress on Brain and Behavioral Development

Catale

Gironda

Iacono

et al. 2020

JCM

The putative effects of early-life stress (ELS) on later behavior and neurobiology have been widely investigated. Recently, microglia have been implicated in mediating some of the effects of ELS on behavior. In this review, findings from preclinical and clinical literature with a specific focus on microglial alterations induced by the exposure to ELS (i.e., exposure to behavioral stressors or environmental agents and infection) are summarized. These studies were utilized to interpret changes in developmental trajectories based on the time at which the stress occurred, as well as the paradigm used. ELS and microglial alterations were found to be associated with a wide array of deficits including cognitive performance, memory, reward processing, and processing of social stimuli. Four general conclusions emerged: (1) ELS interferes with microglial developmental programs, including their proliferation and death and their phagocytic activity; (2) this can affect neuronal and non-neuronal developmental processes, which are dynamic during development and for which microglial activity is instrumental; (3) the effects are extremely dependent on the time point at which the investigation is carried out; and (4) both pre- and postnatal ELS can prime microglial reactivity, indicating a long-lasting alteration, which has been implicated in behavioral abnormalities later in life.

“…The 33 triples consisted of the subset of those pairs that have been used to augment SSRI action clinically or experimentally (in 1 case), combined with a third substance that was either Oxytocin (a hormone), Antalarmin (a CRF1 receptor antagonist), or Olanzapine (an antipsychotic). These 3 substances were selected due to recent preliminary evidence suggesting that Oxytocin, Antalarmin, and Olanzapine could potentially have antidepressant effects either by themselves or in combination with another antidepressant (Amini-Khoei et al, 2017;Björkholm et al, 2015;Scantamburlo et al, 2015;Thomas et al, 2017).…”

Section: Predicting the Efficacy Of Drug And Hormone Combinationsmentioning

confidence: 99%

Computational Analysis of Therapeutic Neuroadaptation to Chronic Antidepressant in a Model of the Monoaminergic Neurotransmitter and Stress Hormone Systems

Camacho

Vijitbenjaronk

Anastasio³

2019

Preprint

The clinical practice of selective serotonin reuptake inhibitor (SSRI) augmentation relies heavily on clinical judgment and trial-and-error. Unfortunately, the drug combinations prescribed today fail to provide relief for all treatment-resistant depressed patients. In order to identify potentially more effective treatments, we developed a computational model of the monoaminergic neurotransmitter and stress-steroid systems that neuroadapts to chronic administration of combinations of antidepressant drugs and hormones by adjusting the strengths of its transmittersystem components (TSCs). We used the model to screen 60 chronically administered drug/hormone pairs and triples, and identified as potentially therapeutic those combinations that raised the monoamines (serotonin, norepinephrine, and dopamine) but lowered cortisol following neuroadaptation in the model. We also evaluated the contributions of individual and pairs of TSCs to therapeutic neuroadaptation with chronic SSRI using sensitivity, correlation, and linear temporal-logic analyses. All three approaches found that therapeutic neuroadaptation to chronic SSRI is an overdetermined process that depends on multiple TSCs, providing a potential explanation for the clinical finding that no single antidepressant regimen alleviates depressive symptoms in all patients. (Dinan, 1996;Ma and Morilak, 2005;Ziegler et al., 1999), while cortisol can alter expression of proteins involved in monoaminergic synaptic transmission, including serotonergic receptors, monoamine synthesis enzymes, and monoamine oxidase (MAO) (Hucklebridge et al., 1998;McAllister-Williams et al., 2007;Nexon et al., 2011).Here we represent the major interactions between the monoaminergic neurotransmitter systems and the HPA axis in a computational model that we refer to as the Monoamine-Stress model (MS-model). It extends our previously published computational model of the monoaminergic neurotransmitter system but differs in its structure, training procedure, and analysis (Camacho and Anastasio, 2017). Specifically, the MS-model takes the form of a recurrent network in order to use a more efficient learning procedure to train its more extensive representations of neurobiological interactions, and to conform to a larger set of experimental observations. Acute administration of substances (such as drugs or hormones) has been observed to alter neuronal activity levels, and chronic (days to weeks) substance exposure can lead to adaptive changes in neurons that move their activity levels back toward their original levels (Blier and De Montigny, 1987;Turrigiano, 2008Turrigiano, , 1999. We simulated neuroadaptive changes by allowing a subset of transmitter system components (TSCs, mainly proteins such as neurotransmitter or neurohormone receptors or transporters) to adjust their strengths (corresponding to factors such as expression levels, sensitivities, and synaptic locations) incrementally up or down. TSC-strength configurations that restored the activities of DR, LC, VTA, and PVN back toward normative b...