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Fast-acting antidepressant-like effects of Reelin evaluated in the repeated-corticosterone chronic stress paradigm.

ABSTRACT: The present report examines the effects of repeated or single intrahippocampal Reelin infusions on measures of depressive-like behavior, cognition, and hippocampal neurogenesis in the repeated-corticosterone (CORT) paradigm. Rats received subcutaneous injections of CORT for 3 weeks and Reelin was infused through an inserted canula in the left hippocampus on days 7, 14, and 21, or only on day 21 of CORT injections. CORT increased immobility in the forced-swim test and impaired object-location memory. Notably, these effects were reversed by both repeated and single-Reelin infusions. CORT decreased both the number and complexity of doublecortin-labeled maturing newborn neurons in the dentate gyrus subgranular zone, and a single-Reelin infusion increased the number but not complexity of newborn neurons, while repeated Reelin infusions restored both. Injection of the AMPA antagonist CNQX blocked the rescue of the behavioral phenotype by Reelin but did completely block the effects of Reelin on hippocampal neurogenesis. Reelin is able to rescue the deficits in AMPA, NMDA, GABA_A receptors, mTOR and p-mTOR induced by CORT. These novel results demonstrate that a single intrahippocampal Reelin infusion into the dorsal hippocampus has fast-acting antidepressant-like effects, and that some of these effects may be at least partially independent of Reelin actions on hippocampal neurogenesis.

SUBMITTER: Brymer KJ

PROVIDER: S-EPMC7419539 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Newer antidepressants are needed for the many individuals with major depressive disorder (MDD) that do not respond adequately to treatment and because of a delay of weeks before the emergence of therapeutic effects. Recent evidence from clinical trials shows that the NMDA antagonist ketamine is a revolutionary novel antidepressant because it acts rapidly and is effective for treatment-resistant patients. A single infusion of ketamine alleviates depressive symptoms in treatment-resistant depressed patients within hours and these effects may be sustained for up to 2 weeks. Although the discovery of ketamine's effects has reshaped drug discovery for antidepressants, the psychotomimetic properties of this compound limit the use of this therapy to the most severely ill patients. In order to develop additional antidepressants like ketamine, adequate preclinical behavioral screening paradigms for fast-acting antidepressants need to be established and used to identify the underlying neural mechanisms. This review examines the preclinical literature attempting to model the antidepressant-like effects of ketamine. Acute administration of ketamine has produced effects in behavioral screens for antidepressants like the forced swim test, novelty suppression of feeding and in rodent models for depression. Protracted behavioral effects of ketamine have been reported to appear after a single treatment that last for days. This temporal pattern is similar to its clinical effects and may serve as a new animal paradigm for rapid antidepressant effects in humans. In addition, protracted changes in molecules mediating synaptic plasticity have been implicated in mediating the antidepressant-like behavioral effects of ketamine. Current preclinical studies are examining compounds with more specific pharmacological effects at glutamate receptors and synapses in order to develop additional rapidly acting antidepressants without the hallucinogenic side effects or abuse potential of ketamine.

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Fast-acting antidepressant-like effects of Reelin evaluated in the repeated-corticosterone chronic stress paradigm.

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