Medial PFC AMPA receptor and BDNF signaling are required for the rapid and sustained antidepressant-like effects of 5-HT1A receptor stimulation

• Published in: Neuropsychopharmacology (New York, N.Y.) N.Y.), 2020-09, Vol.45 (10), p.1725-1734
• Main Authors: Fukumoto Kenichi, Fogaça Manoela V, Rong-Jian, Liu, Duman, Catharine H, Xiao-Yuan, Li, Chaki Shigeyuki, Duman, Ronald S
• Format: Article
• Language: English
• Subjects: 8-Hydroxy-2-(di-n-propylamino)tetralin; Antidepressants; Brain-derived neurotrophic factor; Glutamic acid receptors; Ketamine; Mental depression; N-Methyl-D-aspartic acid receptors; Phosphorylation; Prefrontal cortex; Receptor mechanisms; Serotonin; Serotonin S1 receptors; TOR protein; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/s41386-020-0705-0

We previously reported that the serotonergic system is important for the antidepressant-like effects of ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist, which produces rapid and long-lasting antidepressant effects in patients with major depressive disorder (MDD). In particular, selective stimulation of the 5-HT1A receptor in the medial prefrontal cortex (mPFC), as opposed to the somatic 5-HT1A autoreceptor, has been shown to play a critical role in the antidepressant-like actions of ketamine. However, the detailed mechanisms underlying mPFC 5-HT1A receptor-mediated antidepressant-like effects are not fully understood. Here we examined the involvement of the glutamate AMPA receptor and brain-derived neurotrophic factor (BDNF) in the antidepressant-like effects of 5-HT1A receptor activation in the mPFC. The results show that intra-mPFC infusion of the 5-HT1A receptor agonist 8-OH-DPAT induces rapid and long-lasting antidepressant-like effects in the forced swim, novelty-suppressed feeding, female urine sniffing, and chronic unpredictable stress tests. In addition, the results demonstrate that the antidepressant-like effects of intra-mPFC infusion of 8-OH-DPAT are blocked by co-infusion of an AMPA receptor antagonist or an anti-BDNF neutralizing antibody. In addition, mPFC infusion of 8-OH-DPAT increased the phosphorylation of signaling proteins downstream of BDNF, including mTOR, ERK, 4EBP1, and p70S6K. Finally, selective stimulation of the 5-HT1A receptor increased levels of synaptic proteins and synaptic function in the mPFC. Collectively, these results indicate that selective stimulation of 5-HT1A receptor in the mPFC exerts rapid and sustained antidepressant-like effects via activation of AMPA receptor/BDNF/mTOR signaling in mice, which subsequently increase synaptic function in the mPFC, and provide evidence for the 5-HT1A receptor as a target for the treatment of MDD.