A Key Role for Prefrontocortical Small Conductance Calcium-Activated Potassium Channels in Stress Adaptation and Rapid Antidepressant Response.
Cereb Cortex
; 30(3): 1559-1572, 2020 03 14.
Article
em En
| MEDLINE
| ID: mdl-31504265
ABSTRACT
The muscarinic acetylcholine receptor antagonist scopolamine elicits rapid antidepressant activity, but its underlying mechanism is not fully understood. In a chronic stress model, a single low-dose administration of scopolamine reversed depressive-like reactivity. This antidepressant-like effect was mediated via a muscarinic M1 receptor-SKC pathway because it was mimicked by intra-medial prefrontal cortex (intra-mPFC) infusions of scopolamine, of the M1 antagonist pirenzepine or of the SKC antagonist apamin, but not by the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine. Extracellular and whole-cell recordings revealed that scopolamine and ketamine attenuate the SKC-mediated action potential hyperpolarization current and rapidly enhance mPFC neuronal excitability within the therapeutically relevant time window. The SKC agonist 1-EBIO abrogated scopolamine-induced antidepressant activity at a dose that completely suppressed burst firing activity. Scopolamine also induced a slow-onset activation of raphe serotonergic neurons, which in turn was dependent on mPFC-induced neuroplasticity or excitatory input, since mPFC transection abolished this effect. These early behavioral and mPFC activational effects of scopolamine did not appear to depend on prefrontocortical brain-derived neurotrophic factor and serotonin-1A activity, classically linked to SSRIs, and suggest a novel mechanism associated with antidepressant response onset through SKC-mediated regulation of activity-dependent plasticity.
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Base de dados:
MEDLINE
Assunto principal:
Estresse Fisiológico
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Canais de Potássio Ativados por Cálcio de Condutância Baixa
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Antidepressivos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article