Role of 5-HT1A Receptor Stimulation in the Medial Prefrontal Cortex in the Sustained Antidepressant Effects of Ketamine

Abstract

BackgroundWe previously reported that serotonergic transmission plays an important role in antidepressant effects of ketamine. However, detailed mechanisms have not been elucidated. Among the serotonin receptor subtypes, the serotonin1A receptor in the medial prefrontal cortex has an important role in depression. Here, we investigated the role of the medial prefrontal cortex serotonin1A receptor and its signaling mechanism in the antidepressant effects of ketamine.MethodsThe role of serotonin1A receptor-mediated signaling mechanism (phosphoinositide-3 kinase/Akt) in the medial prefrontal cortex was examined in the mouse forced swimming test and western blotting.ResultsKetamine exerted antidepressant effects that lasted for 24 hours, and the sustained antidepressant effects were attenuated by intra-medial prefrontal cortex injection of a serotonin1A receptor antagonist, WAY100635. The sustained antidepressant effects were mimicked by intra- medial prefrontal cortex, but not systemic, administration of a serotonin1A receptor agonist, (±)-8-hydroxy-2-dipropylaminotetralin hydrobromide (8-OH-DPAT). The sustained antidepressant effects of ketamine and 8-OH-DPAT were abrogated by intra- medial prefrontal cortex injection of a phosphoinositide-3 kinase inhibitor. Ketamine increased the phosphorylation of Akt in the medial prefrontal cortex at 60 minutes after administration, which was blocked by a serotonin1A receptor antagonist and a phosphoinositide-3 kinase inhibitor. Furthermore, the sustained antidepressant effects of ketamine and 8-OH-DPAT were attenuated by pretreatment of intra-medial prefrontal cortex injection of a mechanistic target of rapamycin complex-1 inhibitor.ConclusionsThese results indicate that selective stimulation of the medial prefrontal cortex serotonin1A receptor and subsequent activation of the phosphoinositide-3 kinase/Akt/mechanistic target of rapamycin complex-1 pathway may be necessary for ketamine to exert the sustained antidepressant effects, and that this mechanism could be targeted to develop a novel and effective approach for treating depression.

Serotonin Signaling Trough Prelimbic 5-HT1A Receptors Modulates CSDS-Induced Behavioral Changes in Adult Female Voles

“…After 3 days of recovery, each vole with normal activity received microinjections of either saline/200 nL, 0.03-μg 8-OH-DPAT/200 nL, 0.3-μg 8-OH-DPAT/200 nL, 3-μg 8-OH-DPAT/200 nL, and 0.4-μg WAY-100635/200 nL (n=8 animals per group). The 5-HT 1A R agonist 8-OH-DPAT (Sigma-Aldrich) (0.03 μg, 0.3 μg, or 3 μg in 200 nL) and the 5-HT 1A R antagonist WAY-100635 (Sigma-Aldrich) (0.4 μg in 200 nL) were dissolved in saline, and doses were chosen based on effective doses used in previous studies (Cooper et al, 2008; Fukumoto et al, 2018) with little modification, based on their effects on mandarin voles in the preliminary experiment. The speed of injection was 0.1 μL/min for 1-minute per side.…”

“…The PrL is involved in regulating emotional responses (Petty et al, 1997; Broersen et al, 2000). In addition, stimulation of postsynaptic 5-HT1A heteroreceptors in the mPFC is involved in the response to antidepressants (Fukumoto et al, 2018), and suppressing the 5-HT1A heteroreceptors in the mPFC is reported to result in a depression-like phenotype (Garcia-Garcia et al, 2017). More importantly, sustained antidepressant effects are mimicked by intra-mPFC injection of a 5-HT 1A R agonist and attenuated by a 5-HT 1A R antagonist (Fukumoto et al, 2018).…”

“…In addition, stimulation of postsynaptic 5-HT1A heteroreceptors in the mPFC is involved in the response to antidepressants (Fukumoto et al, 2018), and suppressing the 5-HT1A heteroreceptors in the mPFC is reported to result in a depression-like phenotype (Garcia-Garcia et al, 2017). More importantly, sustained antidepressant effects are mimicked by intra-mPFC injection of a 5-HT 1A R agonist and attenuated by a 5-HT 1A R antagonist (Fukumoto et al, 2018). Nevertheless, 5-HT1A autoreceptors have consistently been shown to impact anxiety-like behavior (De Vry, 1995; Albert and Lemonde, 2004; Garcia-Garcia et al, 2014).…”

Genetic, epigenetic and posttranscriptional mechanisms for treatment of major depression: the 5-HT1A receptor gene as a paradigm

“…128 Thus, even in adulthood, chronic treatment with SSRIs may influence cortical neuroplasticity via 5-HT 1A signalling. In this regard, PFC 5-HT 1A receptor signalling to phosphatidyl-inositol 3'-kinase, implicated in the acute antidepressant actions of ketamine in mice, 129 is thought to trigger synaptic remodelling. 130 The 5-HT 1A signalling mechanisms to neuroplasticity-induced behavioural changes remain incompletely understood, as reviewed recently.…”

Classification and signaling characteristics of 5-HT receptors: toward the concept of 5-HT receptosomes

“…For example, they can activate Extracellular signal-Regulated Kinase (ERK)1/2 in the hypothalamus in a Calmodulin (CaM)-dependent manner, similar to what is observed in heterologous systems (Della Rocca et al, 1999;Turner et al, 2007), whereas they inhibit ERK1/2 phosphorylation in the hippocampus (Crane et al, 2007). In contrast, an activation of the Akt pathway has been demonstrated in the hippocampus and the medial prefrontal cortex (mPFC), where an activation of the mTOR (mammalian Target Of Rapamycin) has also been described (Cowen et al, 2005;Fukumoto et al, 2018aFukumoto et al, , 2018b).…”