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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.

Acute selective serotonin reuptake inhibitors regulate the dorsal raphe nucleus causing amplification of terminal serotonin release