The neurobiology of depression and antidepressant action

Willner, Paul; Scheel-Krüger, Jørgen; Belzung, Catherine

doi:10.1016/j.neubiorev.2012.12.007

Cited by 428 publications

(351 citation statements)

References 646 publications

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“…Depressed patients and animal models of depression frequently display a deregulated neuroinflammatory response (Shelton et al, 2011;Sukoff Rizzo et al, 2012), resulting in increased production of pro-inflammatory cytokines that alter neurotransmitter metabolism and neural plasticity (Willner et al, 2013). It was interesting to observe here that fluoxetine reduced the expression of IL6-signaling and of TNF signaling-related molecules.…”

Section: Ad-specific Transcriptional Changesmentioning

confidence: 66%

“…Strikingly, a high percentage of patients treated with the currently available therapies do not show full remission (Lang and Borgwardt, 2013) and present treatment resistance (Blier and Blondeau, 2011). Although the pathophysiology of depression is still incompletely understood, dysregulation of monoaminergic systems, neuroplasticity, and immunological responses (Villanueva, 2013;Willner et al, 2013) are considered to contribute to the disease. In addition, alterations in dendritic plasticity and cytogenesis in the hippocampal dentate gyrus (DG) are observed in the brains of animal models of depression and depressed patients (Lucassen et al, 2014;Pittenger and Duman, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Differential and Converging Molecular Mechanisms of Antidepressants’ Action in the Hippocampal Dentate Gyrus

Patrício

Mateus‐Pinheiro

Irmler

et al. 2014

Neuropsychopharmacol

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Major depression is a highly prevalent, multidimensional disorder. Although several classes of antidepressants (ADs) are currently available, treatment efficacy is limited, and relapse rates are high; thus, there is a need to find better therapeutic strategies. Neuroplastic changes in brain regions such as the hippocampal dentate gyrus (DG) accompany depression and its amelioration with ADs. In this study, the unpredictable chronic mild stress (uCMS) rat model of depression was used to determine the molecular mediators of chronic stress and the targets of four ADs with different pharmacological profiles (fluoxetine, imipramine, tianeptine, and agomelatine) in the hippocampal DG. All ADs, except agomelatine, reversed the depression-like behavior and neuroplastic changes produced by uCMS. Chronic stress induced significant molecular changes that were generally reversed by fluoxetine, imipramine, and tianeptine. Fluoxetine primarily acted on neurons to reduce the expression of pro-inflammatory response genes and increased a set of genes involved in cell metabolism. Similarities were found between the molecular actions and targets of imipramine and tianeptine that activated pathways related to cellular protection. Agomelatine presented a unique profile, with pronounced effects on genes related to Rho-GTPase-related pathways in oligodendrocytes and neurons. These differential molecular signatures of ADs studied contribute to our understanding of the processes implicated in the onset and treatment of depression-like symptoms.

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Section: Ad-specific Transcriptional Changesmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Differential and Converging Molecular Mechanisms of Antidepressants’ Action in the Hippocampal Dentate Gyrus

Patrício

Mateus‐Pinheiro

Irmler

et al. 2014

Neuropsychopharmacol

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“…Third, learned safety signals exert protective effects on animal models of depression comparable with those obtained by adult antidepressant treatment (36), suggesting that serotonergic mechanisms contribute to these repair effects. Collectively, these findings show that 5-HT is involved in the pathophysiology of depression, its treatment, and resolution (39)(40)(41)(42)(43)(44). For these reasons, we provide a life span view of 5-HT's role in the initiation and rescue of depression.…”

Section: Significancementioning

confidence: 77%

“…First, increasing 5-HT in depressed patients decreases depression symptoms and its neural correlates (4,39,40). Second, 5-HT is implicated in initiating the developmental trajectory associated with later life depression vulnerability (41)(42)(43).…”

Section: Significancementioning

confidence: 99%

Enduring good memories of infant trauma: Rescue of adult neurobehavioral deficits via amygdala serotonin and corticosterone interaction

Rincón-Cortés

Barr

Mouly

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Children form a strong attachment to their caregiver-even when that caretaker is abusive. Paradoxically, despite the trauma experienced within this relationship, the child develops a preference for trauma-linked cues-a phenomenon known as trauma bonding. Although infant trauma compromises neurobehavioral development, the mechanisms underlying the interaction between infant trauma bonding (i.e., learned preference for trauma cues) and the long-term effects of trauma (i.e., depressive-like behavior, amygdala dysfunction) are unknown. We modeled infant trauma bonding by using odor-shock conditioning in rat pups, which engages the attachment system and produces a life-long preference for the odor that was paired with shock. In adulthood, this trauma-linked odor rescues depressive-like behavior and amygdala dysfunction, reduces corticosterone (CORT) levels, and exerts repair-related changes at the molecular level. Amygdala microarray after rescue implicates serotonin (5-HT) and glucocorticoids (GCs), and a causal role was verified through microinfusions. Blocking amygdala 5-HT eliminates the rescue effect; increasing amygdala 5-HT and blocking systemic CORT mimics it. Our findings suggest that infant trauma cues share properties with antidepressants and safety signals and provide insight into mechanisms by which infant trauma memories remain powerful throughout life.E arly-life trauma is associated with compromised neurobehavioral development and vulnerability to later-life psychiatric disorders like depression (1-5). Long-lasting effects of infant trauma relevant to depression include disruptions in social behavior, alterations in the serotonin (5-HT) system, and amygdala dysfunction (2, 5-8), which have been replicated by animal models (9-15). Paradoxically, trauma-linked cues-even those associated with abusive attachment-can elicit strong attraction and feelings of comfort in humans (16,17). Furthermore, a lifelong attraction to trauma-linked cues has also been demonstrated in rodent models of infant trauma, which suggests that sensory cues learned during infancy alter adult behaviors and amygdala activity (12,18,19).To explore the enduring effects of infant trauma and the mechanisms underlying their modulation by infant trauma-linked cues, we used an odor-learning paradigm during the sensitive period for attachment learning in rat pups, postnatal (PN) days 8-12, which is characterized by rapid and robust odor-preference learning that extends to aversive stimuli (14,(20)(21)(22). Specifically, we used infant olfactory classical conditioning in which a novel peppermint odor is paired with a mild shock (0.5 mA, 1s) to produce a preferred odor that functions behaviorally as a maternal odor and results in neural activation comparable with that induced by natural maternal odor (20,(23)(24)(25). During the sensitive period, low endogenous levels of corticosterone (CORT) and attenuated shock-induced CORT release prevent the infant amygdala from exhibiting the learning-induced plasticity required for avoidance learning (1...

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“…Antidepressants can target almost all components of the monoaminergic system to induce their pharmacological actions (15,16).Most genetic studies have considered set of functional polymorphisms relevant to monoaminergic neurotransmissionin depression (17)(18)(19). The ARs, consisting of β, α 1 , and α 2 receptors, are the cellular mediators of noradrenergic neurotransmission.…”

Section: Introductionmentioning

confidence: 99%

Beta Adrenoceptor Polymorphism and Clinical Response to Sertraline in Major Depressive Patients

et al. 2017

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-Purpose: The adrenoceptor family, as one of the main contributors in regulating the noradrenergic system, has been studied in involvement of depression and its treatment. A functional polymorphism of G1165C on beta adrenoceptor (βAR) enhances post receptor signalling and is assumed to be involved in pharmacotherapy of depression. The aim of the present study was to discern the influence of G1165C polymorphism in the β1AR gene on individual differences in response to sertraline. Methods: One hundred newly diagnosed patients completed 6 weeks of sertraline treatment. Response to treatment was defined as a 50% decrease in Hamilton Rating Scale for depression (HRSD). Results: The patients who carried CC genotype responded five times more to sertraline comparing with other variants (P=0.005; OR=5.7; 95%CI=1.4-23.9). Moreover, carriers of C allele responded three times more to sertraline than patients with the G allele (P=0.001; OR= 3.3; 95%CI= 1.72-6.50). Conclusion:In conclusion, our results support the hypothesis that genetic variation of β1AR might influence clinical response to sertraline.

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The neurobiology of depression and antidepressant action

Cited by 428 publications

References 646 publications

Differential and Converging Molecular Mechanisms of Antidepressants’ Action in the Hippocampal Dentate Gyrus

Differential and Converging Molecular Mechanisms of Antidepressants’ Action in the Hippocampal Dentate Gyrus

Enduring good memories of infant trauma: Rescue of adult neurobehavioral deficits via amygdala serotonin and corticosterone interaction

Beta Adrenoceptor Polymorphism and Clinical Response to Sertraline in Major Depressive Patients

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