Early-life stress induces emotional and molecular alterations in female mice that are partially reversed by cannabidiol

Martín‐Sánchez, Ana; González-Pardo, Héctor; Alegre-Zurano, Laia; Castro‐Zavala, Adriana; López-Taboada, Isabel; Valverde, Olga; Conejo, Nélida M.

doi:10.1016/j.pnpbp.2021.110508

Cited by 15 publications

(10 citation statements)

References 94 publications

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“…These results are consistent with one previous study that found antidepressant-like effects of CBD across males of two different genetic models of depression [Wistar Kyoto (WKY) and Flinders Sensitive Line (FSL) rats], while CBD had antidepressant-like effects in females of only one genetic model (WKY rats) [ 74 ]. However, one single-sex study did find an antidepressant-like effect (reduced immobility time in the tail suspension test) of CBD in early-life stressed female mice [ 75 ]. As noted in a recent scoping review [ 36 ], there are no published human trials of CBD for the treatment of depression, though there are at least three currently registered trials.…”

Section: Discussionmentioning

confidence: 99%

Sex Differences in the Neuropsychiatric Effects and Pharmacokinetics of Cannabidiol: A Scoping Review

2022

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Cannabidiol (CBD) is a non-intoxicating cannabinoid compound with diverse molecular targets and potential therapeutic effects, including effects relevant to the treatment of psychiatric disorders. In this scoping review, we sought to determine the extent to which sex and gender have been considered as potential moderators of the neuropsychiatric effects and pharmacokinetics of CBD. In this case, 300 articles were screened, retrieved from searches in PubMed/Medline, Scopus, Google Scholar, PsycInfo and CINAHL, though only 12 met our eligibility criteria: eight studies in preclinical models and four studies in humans. Among the preclinical studies, three suggested that sex may influence long-term effects of gestational or adolescent exposure to CBD; two found no impact of sex on CBD modulation of addiction-relevant effects of Δ⁹-tetrahydrocannabinol (THC); two found antidepressant-like effects of CBD in males only; and one found greater plasma and liver CBD concentrations in females compared to males. Among the human studies, two found no sex difference in CBD pharmacokinetics in patient samples, one found greater plasma CBD concentrations in healthy females compared to males, and one found no evidence of sex differences in the effects of CBD on responses to trauma recall in patients with post-traumatic stress disorder (PTSD). No studies were identified that considered the role of gender in CBD treatment effects. We discuss potential implications and current limitations of the existing literature.

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Section: Discussionmentioning

confidence: 99%

Sex Differences in the Neuropsychiatric Effects and Pharmacokinetics of Cannabidiol: A Scoping Review

2022

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“…On PW 2, each mouse was individually suspended from the tip of the tail, 50 cm above a bench top for 6 minutes. This test allows measuring total immobility time, reflecting despair-like behaviour 32 which in turn can be indicative of a depressive-like behaviour.…”

Section: Tail Suspension Testmentioning

confidence: 99%

A novel mouse model of postpartum depression and the neurobiological effects of fast-acting antidepressant treatments

García-Baos

Ferreres-Alvarez

Gallego-Landin

et al. 2022

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Postpartum depression (PPD) is a severe psychiatric disorder that affects up to 15% of mothers and impairs mother-infant bonding with devastating consequences on the child development and the mother health. Several studies indicate a possible dysregulation of glutamatergic and GABAergic signalling in the corticolimbic system, as well as a downregulation of the allopregnanolone levels in serum of PPD patients. Although brexanolone, an allopregnanolone-based treatment, has recently emerged as fundamental PPD treatment, there is scarce evidence on its neurobiological action mechanism. Moreover, ketamine appears to be a promising antidepressant treatment preventing PPD, nevertheless whether it might be a more effective than allopregnanolone for some patients remain unknown. Therefore, the present study is aimed to evaluate the depressive-like phenotype of postpartum females undergoing maternal separation with early weaning (MSEW) protocol, as well as to compare the effectiveness of ketamine and allopregnanolone treatments. MSEW dams show increased despair-like behaviour, anhedonia and disrupted maternal behaviour. Moreover, lower allopregnanolone serum levels, reduction of vesicular transporters for GABA (VGAT) and glutamate (VGLUT1) in the infralimbic cortex, as well as decreased hippocampal cellular proliferation are found in MSEW females. As for the antidepressant treatments, both drugs prevent despair-like behaviour, whereas only ketamine reverts anhedonia present in MSEW females. In addition, both treatments induce pro-neurogenic effects in the dorsal hippocampus but only allopregnanolone increases the VGAT and VGLUT1, without altering the excitatory/inhibitory ratio. Altogether, we propose a new mice model that recapitulates the core symptomatology and alterations in glutamatergic and GABAergic systems shown in PPD patients, which allows us to investigate the therapeutic mechanisms of allopregnanolone and ketamine.

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“…Furthermore, both mTOR signaling (262,(267)(268)(269) and mitochondrial function (270)(271)(272)(273)(274)(275) are essential for synaptic signaling, function and plasticity. In fact, preclinical data suggest that ELS impairs neuronal metabolism and synaptic plasticity via mTOR-dependent mechanisms (276,277). The interplay between mitochondrial metabolism and microglial activation is also essential to regulate neuronal apoptosis, synaptic pruning and myelination during neurodevelopment (221,225,278).…”

Section: From Mal To Neurophysiology Neurochemistry and Behavior: A M...mentioning

confidence: 99%

A Molecular Framework for Autistic Experiences: Mitochondrial Allostatic Load as A Mediator between Autism and Psychopathology

Mahony¹,

O’Ryan²

2022

Preprint

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Molecular autism research is evolving towards a biopsychosocial framework that is more informed by autistic experiences. In this context, research aims are moving away from correcting external autistic behaviors and towards alleviating internal distress. Autism Spectrum Conditions (ASCs) are associated with high rates of depression, suicidality and other comorbid psychopathologies, but this relationship is poorly understood. Here, we integrate emerging characterizations of internal autistic experiences within a molecular framework to yield insight into the prevalence of psychopathology in ASC. We demonstrate that descriptions of social camouflaging and autistic burnout resonate closely with the accepted definitions for early life stress (ELS) and chronic adolescent stress (CAS). We propose that social camouflaging could be considered a distinct form of CAS that contributes to allostatic overload, culminating in a pathophysiological state that is experienced as autistic burnout. Autistic burnout is thought to contribute to psychopathology via psychological and physiological mechanisms, but these remain largely unexplored by molecular researchers. Building on converging fields in molecular neuroscience, we discuss the substantial evidence implicating mitochondrial dysfunction in ASC to propose a novel role for mitochondrial allostatic load in the relationship between autism and psychopathology. An interplay between mitochondrial, neuroimmune and neuroendocrine signaling is increasingly implicated in stress-related psychopathologies, and these molecular players are also associated with neurodevelopmental, neurophysiological and neurochemical aspects of ASC etiology. Together, this suggests an increased exposure and underlying molecular susceptibility to ELS that increases the risk of psychopathology in ASC. This article describes an integrative framework shaped by autistic experiences that highlights novel avenues for molecular research into mechanisms that directly affect the quality of life and well-being of autistic individuals. Moreover, this framework emphasizes the need for increased access to diagnoses, accommodations, and resources to improve mental health outcomes in autism.

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Early-life stress induces emotional and molecular alterations in female mice that are partially reversed by cannabidiol

Cited by 15 publications

References 94 publications

Sex Differences in the Neuropsychiatric Effects and Pharmacokinetics of Cannabidiol: A Scoping Review

Sex Differences in the Neuropsychiatric Effects and Pharmacokinetics of Cannabidiol: A Scoping Review

A novel mouse model of postpartum depression and the neurobiological effects of fast-acting antidepressant treatments

A Molecular Framework for Autistic Experiences: Mitochondrial Allostatic Load as A Mediator between Autism and Psychopathology

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