LAUSR

ABSTRACT Novel fast‐acting antidepressant strategies, such as ketamine and deep brain stimulation, enhance glutamatergic neurotransmission in medial prefrontal cortex (mPFC) regions via AMPA receptor (AMPA‐R) activation. We recently reported that the regionally‐selective blockade of the glial glutamate transporter‐1 (GLT‐1) by dihydrokainic acid (DHK) microinfusion in rat infralimbic cortex (IL), the most ventral part of the mPFC, evoked immediate (10min) antidepressant‐like responses, which involved AMPA‐R activation and were associated to increased serotonin (5‐hydroxytryptamine, 5‐HT) release. Given the reciprocal connectivity between the mPFC and the serotonergic dorsal raphe nucleus (DR), here we examined the serotoninergic mechanisms involved in the reported antidepressant‐like responses of DHK microinfusion. First, we show that antidepressant‐like responses evoked by IL application of DHK and citalopram are mediated by local 5‐HT1A receptors (5‐HT1A‐R), since they are cancelled by previous IL WAY100635 microinfusion. Second, IL DHK microinfusion increases excitatory inputs onto DR, as shown by an increased glutamate and 5‐HT release in DR and by a selective increase of c‐Fos expression in DR 5‐HT neurons, not occurring in putative GABAergic neurons. This view is also supported by an increased 5‐HT release in ventral hippocampus following IL DHK microinfusion. Interestingly, antidepressant‐like responses evoked by IL DHK lasted for 2h and could be prolonged for up to 24h by attenuating self‐inhibitory effects via 5‐HT1A autoreceptors. In contrast, the antidepressant‐like effects of S‐AMPA microinfusion in IL were short‐lasting. Together, our results further support a prominent role of the IL–DR pathway and of ascending 5‐HT pathways in mediating antidepressant‐like responses evoked by glutamatergic mechanisms. HIGHLIGHTSIL 5‐HT1A‐R mediate the antidepressant responses evoked by enhanced IL glutamate.Enhancing glutamate transmission in IL activates excitatory inputs onto 5‐HT neurons.This effect enhances forebrain 5‐HT release via IL‐DR reciprocal connectivity.GLT‐1 blockade in IL induces parallel changes in behavior and 5‐HT neurochemistry.