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Acute selective serotonin reuptake inhibitors regulate the dorsal raphe nucleus causing amplification of terminal serotonin release
Author(s) -
Dankoski Elyse C.,
Carroll Susan,
Wightman Robert Mark
Publication year - 2016
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13528
Subject(s) - dorsal raphe nucleus , serotonin , raphe nuclei , serotonergic cell groups , serotonin uptake inhibitors , raphe , chemistry , terminal (telecommunication) , reuptake , reuptake inhibitor , pharmacology , neuroscience , serotonergic , biology , fluoxetine , computer science , biochemistry , computer network , receptor
Selective serotonin reuptake inhibitors ( SSRI s) were designed to treat depression by increasing serotonin levels throughout the brain via inhibition of clearance from the extracellular space. Although increases in serotonin levels are observed after acute SSRI exposure, 3–6 weeks of continuous use is required for relief from the symptoms of depression. Thus, it is now believed that plasticity in multiple brain systems that are downstream of serotonergic inputs contributes to the therapeutic efficacy of SSRI s. The onset of antidepressant effects also coincides with desensitization of somatodendritic serotonin autoreceptors in the dorsal raphe nucleus ( DRN ), suggesting that disrupting inhibitory feedback within the serotonin system may contribute to the therapeutic effects of SSRI s. Previously, we showed that chronic SSRI treatment caused a frequency‐dependent facilitation of serotonin signaling that persisted in the absence of uptake inhibition. In this work, we use in vivo fast‐scan cyclic voltammetry in mice to investigate a similar facilitation after a single treatment of the SSRI citalopram hydrobromide. Acute citalopram hydrobromide treatment resulted in frequency‐dependent increases of evoked serotonin release in the substantia nigra pars reticulata . These increases were independent of changes in uptake velocity, but required SERT expression. Using microinjections, we show that the frequency‐dependent enhancement in release is because of SERT inhibition in the DRN , demonstrating that SSRI s can enhance serotonin release by inhibiting uptake in a location distal to the terminal release site. The novel finding that SERT inhibition can disrupt modulatory mechanisms at the level of the DRN to facilitate serotonin release will help future studies investigate serotonin's role in depression and motivated behavior.In this work, stimulations of the dorsal raphe nucleus (DRN) evoke serotonin release that is recorded in the substantia nigra pars reticulata (SNpr) using in vivo fast‐scan cyclic voltammetry. Systemic administration of a selective serotonin reuptake inhibitor (SSRI) causes both an increase in t 1/2 and an increase in [5‐HT] max in the SNpr. Local application of SSRI to the DRN recapitulates the increase in [5‐HT] max observed in the SNpr without affecting uptake. Thus, SSRIs increase serotonin signaling via two distinct SERT‐mediated mechanisms.