Prefrontal control of cognitive functions critically depends upon glutamatergic transmission and N-methyl D-aspartate (NMDA) receptors, the activity of which is regulated by dopamine. Yet whether the NMDA receptor coagonist d-serine is implicated in the dopamine–glutamate dialogue in the prefrontal cortex (PFC) and other brain areas remains unexplored. Here, using electrophysiological recordings, we show that d-serine is required for the fine-tuning of glutamatergic neurotransmission, neuronal excitability, and synaptic plasticity in the PFC through the actions of dopamine at D₁ and D₃ receptors. Using in vivo microdialysis, we show that D₁ and D₃ receptors exert a respective facilitatory and inhibitory influence on extracellular levels and activity of d-serine in the PFC, with actions expressed primarily via the cAMP/protein kinase A (PKA) signaling cascade. Further, using functional magnetic resonance imaging (fMRI) and behavioral assessment, we show that d-serine is required for the potentiation of cognition by D₃R blockade as revealed in a test of novel object recognition memory. Collectively, these results unveil a key role for d-serine in the dopaminergic neuromodulation of glutamatergic transmission and PFC activity, findings with clear relevance to the pathogenesis and treatment of diverse brain disorders involving alterations in dopamine–glutamate cross-talk. Significance Dopamine and glutamate in the prefrontal cortex are important substrates of higher cognitive functions, which are impaired in neuropsychiatric disorders. As regards glutamatergic pathways, a role for the NMDA receptor coagonist d-serine has been highlighted, yet its relationship to dopaminergic transmission remains unclear. In this study, we reveal that d-serine plays a pivotal role in the modulation by dopamine of NMDA receptor activity and cognitive performance in the prefrontal cortex. Comprehensive evidence for this interaction is provided at the synaptic, neuronal, network, and behavioral levels. These observations are of relevance to the pathophysiology and treatment of cognitive impairment in numerous disorders involving disruption of the frontocortical dialogue between dopamine and glutamate.

To test for the relative contributions of the dopaminergic and serotoninergic systems in the striatum to the effects of d‐fenfluramine, an indirect serotonin receptor agonist, we assessed the expression of Fos/Jun proteins induced by d‐fenfluramine given alone or in the presence of dopaminergic or serotoninergic agents. To determine the neuronal targets of d‐fenfluramine in the striatum, we identified the phenotypes of striatal neurons in which d‐fenfluramine induced Fos expression. Our results demonstrated that d‐fenfluramine evokes nuclear expression of Fos/Jun B proteins in the striatum, and that the Fos expression was dose‐dependent and accompanied by transient induction of c‐fos mRNA. Fos expression was blocked by p‐chloroamphetamine, a serotoninergic neurotoxin. Pretreatment with SCH 23390, a D₁‐dopamine receptor antagonist, led to a marked decrease in Fos/Jun B expression in the caudoputamen, but not in the cortex, whereas pretreatment with methiothepin, a nonselective serotonin 5‐HT₁ receptor antagonist, blocked Fos expression completely in the cortex and only partially in the caudoputamen. The expression of Fos/Jun B in the striatum occurred mainly in dynorphin‐containing neurons and in a subpopulation of striatal interneurons that exhibited NADPH‐diaphorase activity. Most of the enkephalin‐containing neurons of the striatum did not show Fos/Jun B staining. These results suggest that the mechanism by which d‐fenfluramine induces c‐fos and jun B expression in the rat caudoputamen depends at least in part on activation of the dopaminergic system by serotonin.

Background: It is unclear whether olfactory deficits improve after remission in depressed patients. Therefore, we aimed to assess in drug-free patients the olfactory performance of patients with major depressive episodes (MDE) and its change after antidepressant treatment.Methods: In the DEP-ARREST-CLIN study, 69 drug-free patients with a current MDE in the context of major depressive disorder (MDD) were assessed for their olfactory performances and depression severity, before and after 1 (M1) and 3 (M3) months of venlafaxine antidepressant treatment. They were compared to 32 age- and sex-matched healthy controls (HCs). Olfaction was assessed with a psychophysical test, the Sniffin’ Sticks test (Threshold: T score; Discrimination: D score; Identification: I score; total score: T + D + I = TDI score) and Pleasantness (pleasantness score: p score; neutral score: N score; unpleasantness score: U score).Results: As compared to HCs, depressed patients had lower TDI olfactory scores [mean (s.d.) 30.0(4.5) v. 33.3(4.2), p < 0.001], T scores [5.6(2.6) v. 7.4(2.6), p < 0.01], p scores [7.5(3.0) v. 9.8(2.8), p < 0.001)] and higher N scores [3.5(2.6) v. 2.1(1.8), p < 0.01]. T, p and N scores at baseline were independent from depression and anhedonia severity. After venlafaxine treatment, significant increases of T scores [M1: 7.0(2.6) and M3: 6.8(3.1), p < 0.01] and p scores [M1: 8.1(3.0) and M3: 8.4(3.3), p < 0.05] were evidenced, in remitters only (T: p < 0.01; P: p < 0.01). Olfaction improvement was mediated by depression improvement.Conclusions: The olfactory signature of MDE is restored after venlafaxine treatment. This olfaction improvement is mediated by depression improvement.

We investigated the mechanisms underlying the effects of the antidepressant fluoxetine on behavior and adult hippocampal neurogenesis (AHN). After confirming our earlier report that the signaling molecule β‐arrestin‐2 (β‐Arr2) is required for the antidepressant‐like effects of fluoxetine, we found that the effects of fluoxetine on proliferation of neural progenitors and survival of adult‐born granule cells are absent in the β‐Arr2 knockout (KO) mice. To our surprise, fluoxetine induced a dramatic upregulation of the number of doublecortin (DCX)‐expressing cells in the β‐Arr2 KO mice, indicating that this marker can be increased even though AHN is not. We discovered two other conditions where a complex relationship occurs between the number of DCX‐expressing cells compared to levels of AHN: a chronic antidepressant model where DCX is upregulated and an inflammation model where DCX is downregulated. We concluded that assessing the number of DCX‐expressing cells alone to quantify levels of AHN can be complex and that caution should be applied when label retention techniques are unavailable.