The pathophysiology of major affective illness is poorly understood. However, several lines of preclinical and clinical evidence indicate that an enhancement of 5-HT-mediated neurotransmission might underlie the therapeutic effect of most antidepressant treatments. This net effect would, however, be obtained via different mechanisms. A better understanding of the neurobiological basis for the delayed onset of action of antidepressant treatments has led to the elaboration of strategies that could accelerate the antidepressant response. These strategies are discussed in this article by Pierre Blier and Claude de Montigny.
"3.6. Glial Modulation of IL-DBS-Induced Enhancement of the Spontaneous Activity of Presumed DRN 5-HT Neurons Classical antidepressants are well known to enhance serotoninergic neurotransmission, with a time course that is consistent with the onset of their therapeutic effects (Blier and de Montigny, 1994). In the present study, the firing activity of presumed 5-HT neurons was recorded in the dorsal raphe nucleus (DRN) before and/or after 1 h of stimulation of the IL-PFC (30 and 130 Hz, 150 μA bilaterally) in anesthetized rats (Fig. S3). "
[Show abstract][Hide abstract] ABSTRACT: Although deep brain stimulation (DBS) shows promising efficacy as a therapy for intractable depression, the neurobiological bases underlying its therapeutic action remain largely unknown. The present study was aimed at characterizing the effects of infralimbic prefrontal cortex (IL-PFC) DBS on several pre-clinical markers of the antidepressant-like response and at investigating putative non-neuronal mechanism underlying DBS action. We found that DBS induced an antidepressant-like response that was prevented by IL-PFC neuronal lesion and by adenosine A1 receptor antagonists including caffeine. Moreover, high frequency DBS induced a rapid increase of hippocampal mitosis and reversed the effects of stress on hippocampal synaptic metaplasticity. In addition, DBS increased spontaneous IL-PFC low-frequency oscillations and both raphe 5-HT firing activity and synaptogenesis. Unambiguously, a local glial lesion counteracted all these neurobiological effects of DBS. Further in vivo electrophysiological results revealed that this astrocytic modulation of DBS involved adenosine A1 receptors and K+ buffering system. Finally, a glial lesion within the site of stimulation failed to counteract the beneficial effects of low frequency (30 Hz) DBS. It is proposed that an unaltered neuronal–glial system constitutes a major prerequisite to optimize antidepressant DBS efficacy. It is also suggested that decreasing frequency could heighten antidepressant response of partial responders.
"Diverse genetic manipulations of 5-HT 1A receptor levels have confirmed the role of these receptors in anxiety-and depression-like phenotypes in mice (Heisler et al., 1998; Parks et al., 1998; Richardson-Jones et al., 2010; Ferres-Coy et al., 2013). It is widely accepted that the slow onset of the response to antidepressants is related to the progressive desensitization of the inhibitory effects mediated by activation of 5-HT 1A receptors onto 5-HT neurotransmission (Blier and de Montigny, 1994; Artigas et al., 1996). Also the behavioral response to antidepressants has been linked to increased neurogenesis, which is mediated by stimulation of 5-HT 1A receptors (Santarelli et al., 2003). "
"Imaging studies have shown hippocampal volume reduction in patients with depressive disorder, which correlates with disease duration (Koolschijn et al., 2009). Additionally, low levels of monoamines in such regions, and in particular that of 5-HT, have been related to the state of depression (Blier and de Montigny, 1994). Conversely, the increases on brain 5-HT levels are thought to be closely related to the antidepressant effect (Kitaichi et al., 2010). "
[Show abstract][Hide abstract] ABSTRACT: Atorvastatin is a statin largely used in the treatment of hypercholesterolemia and recently revealed as a neuroprotective agent. The antidepressant-like effect of acute atorvastatin treatment in mice has been previously demonstrated by our laboratory. The purpose of this study was to explore the contribution of the serotonergic system in the antidepressant-like effect of atorvastatin in mice. Data demonstrate that the serotonin (5-HT) depleting agent p-chlorophenylalanine methyl ester (PCPA, 100 mg/kg, i.p.) completely abolished atorvastatin (0.1 mg/kg, p.o.) antidepressant-like effect. Besides atorvastatin, fluoxetine (10 mg/kg, p.o.), a serotonin selective reuptake nhibitor (SSRI) was able to exert an antidepressant-like effect, but any of them changed 5-HT content in hippocampus or frontal cortex. The 5H-T1A (WAY100635, 0.1 mg/kg, s.c) or the 5-HT2A/2C (ketanserin, 5 mg/kg, s.c.) receptor antagonists prevented atorvastatin antidepressant-like effect. In addition, a combinatory antidepressant-like effect was observed when mice received the co-administration of sub-effective doses of atorvastatin (0.01 mg/kg, p.o.) and the SSRI fluoxetine (5 mg/kg, p.o.), paroxetine (0.1 mg/kg, p.o.) or sertraline (1 mg/kg, p.o.). Taken together, these results indicate that the antidepressant-like effect of atorvastatin depends on the serotonergic system modulation.
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