Cortical and raphe GABA_A, AMPA receptors and glial GLT-1 glutamate transporter contribute to the sustained antidepressant activity of ketamine

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>At sub-anaesthetic doses, ketamine, a non competitive N-methyl-d-aspartate (NMDA) receptor antagonist, has demonstrated remarkable and rapid antidepressant (AD) efficacy in patients with treatment-resistant depression (TRD). However, its mechanism of action of ketamine is not fully understood. Since comorbid depression and anxiety disorders often occur, GABAergic/inhibitory and glutamatergic/excitatory drug treatments may be co-administered in these patients. Information regarding this combination is critical to establish efficacy or treatment restrictions to maximize translation from animal models to TRD patients, effectiveness and safety. To assess the specific role of excitatory/inhibitory neurotransmission in the medial prefrontal cortex-raphe nuclei (mPFC-DRN) circuit in the sustained antidepressant-like activity (AD) of ketamine (at t24h post dose), AMPA-R antagonist (intra-DRN) and GABA<jats:sub>A</jats:sub>-R agonist (intra-mPFC) were co-administered with ketamine (intra-mPFC). Twenty-four hours later, responses in the forced swim test (FST) and neurochemical consequences on extracellular mPFC glutamate, GABA and 5-HT levels were measured in BALB/cJ mice. Intra-DRN NBQX prevented the sustained AD-like activity of ketamine evidenced by decreases in FST swimming duration and blunted cortical 5-HT<jats:sub>ext</jats:sub> and Glu<jats:sub>ext.</jats:sub> Intra-mPFC muscimol blocked ketamine AD-like activity and its effects on cortical 5-HT<jats:sub>ext</jats:sub>. Moreover, a selective glutamate transporter GLT-1 inhibitor, dihydrokainic acid (DHK) locally perfused into the mPFC produced an AD-like activity at t24h associated with robust increases in mPFC 5-HT<jats:sub>ext</jats:sub>, Glu<jats:sub>ext</jats:sub> and GABA<jats:sub>ext</jats:sub>. Thus, the sustained AD-like activity of ketamine is triggered by AMPA-R activation in the DRN and 5-HT - glutamate release in the mPFC, but limited by GABA<jats:sub>A</jats:sub>-R activation - GABA release in the mPFC. The local blockade of GLT-1 in the mPFC also mimics the rapid responses of ketamine, thus highlighting the role of neuronal-glial adaptation in these effects. These results also suggests the need to test for the concomitant prescription of ketamine and BZD to see whether its sustained antidepressant activity is maintained in TRD patients.</jats:p>

Positive effects of running exercise on astrocytes in the medial prefrontal cortex in an animal model of depression

“…It has been confirmed that deficiencies in glutamate transport function in astrocytes may be an important pathological factor leading to the occurrence or persistence of depressive symptoms (Aizawa et al., 2020; Tordera et al., 2011). Some experimental evidence has demonstrated that antidepressant drugs can affect the expression levels of glial‐specific glutamate (Nangaku et al., 2021; Pham et al., 2020; Song et al., 2010). Furthermore, drugs targeting glutamate neurotransmission are hot candidates for novel antidepressant drugs (Lener et al., 2017).…”

Agarwood essential oil inhalation exerts antianxiety and antidepressant effects via the regulation of Glu/GABA system homeostasis

“…Anxiety-like responses are accompanied by abnormal synaptic transmission, which results in an imbalance of excitatory/inhibitory (E/I) neurotransmission (10). GABA and its receptors serve an important role in regulating anxiety and depression (11). Moreover, the various receptors of GABA and Glu are potential therapeutic targets for anxiety and depression (12,13).…”