Abstract

Ketamine and deep brain stimulation produce rapid antidepressant effects in humans and rodents. An increased AMPA receptor (AMPA-R) signaling in medial prefrontal cortex (mPFC) has been suggested to mediate these responses. However, little research has addressed the direct effects of enhancing glutamate tone or AMPA-R stimulation in mPFC subdivisions. The current study investigates the behavioral and neurochemical consequences of glutamate transporter-1 (GLT-1) blockade or s-AMPA microinfusion in the infralimbic (IL) and prelimbic (PrL) cortex. Owing to the connectivity between the mPFC and raphe nuclei, the role of serotonin is also explored. The bilateral microinfusion of the depolarizing agent veratridine into IL -but not PrL- of rats evoked immediate antidepressant-like responses. The same regional selectivity was observed after microinfusion of dihydrokainic acid (DHK), a selective inhibitor of GLT-1, present in astrocytes. The DHK-evoked antidepressant-like responses appear to be mediated by an AMPA-R-driven enhancement of serotonergic activity, as (i) they were prevented by NBQX 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium salt) and mimicked by s-AMPA; (ii) DHK and s-AMPA elevated similarly extracellular glutamate in IL and PrL, although extracellular 5-HT and c-fos expression in the midbrain dorsal raphe increased only when these agents were applied in IL; and (iii) DHK antidepressant-like responses were prevented by 5-HT synthesis inhibition and mimicked by citalopram microinfusion in IL. These results indicate that an acute increase of glutamatergic neurotransmission selectively in IL triggers immediate antidepressant-like responses in rats, likely mediated by the activation of IL–raphe pathways, which then results in a fast increase of serotonergic activity.

Highlights

  • Major depressive disorder is a leading cause of disability worldwide with a high socioeconomic impact.[1]

  • One-way analysis of variance (ANOVA) showed a significant effect of treatment on immobility (F3,23 = 4.117; P o0.05) and swimming behavior (F3,23 = 7.448; P o 0.01)

  • The present study shows that the regionally selective enhanceview, 5-HT depletion with pCPA prevented the antidepressant effects of infralimbic cortex (IL) dihydrokainic acid (DHK)

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Summary

Introduction

Major depressive disorder is a leading cause of disability worldwide with a high socioeconomic impact.[1]. The prefrontal cortex (PFC) has a crucial role in the pathophysiology and treatment of major depressive disorder. Neuroimaging studies reported on a reduced energy metabolism in the subgenual anterior cingulate cortex of major depressive disorder patients, associated with a glial loss.[8,9] Further studies indicated an increased activity of the adjacent Brodmann area 25, which was normalized after effective treatment including DBS.[4,10,11,12,13] In some contrast to the latter observations, subanesthetic doses of ketamine increased glucose metabolism in this area in healthy volunteers.[14,15,16]

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