Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comment
. 2017 Apr 15;81(8):e61-e63.
doi: 10.1016/j.biopsych.2017.01.002.

What's the Buzz About Hydroxynorketamine? Is It the History, the Story, the Debate, or the Promise?

Chadi G Abdallah  1
Affiliations
Comment

What's the Buzz About Hydroxynorketamine? Is It the History, the Story, the Debate, or the Promise?

Chadi G Abdallah. Biol Psychiatry. .
No abstract available

PubMed Disclaimer

Figures

Figure 1
Figure 1. Glutamatergic Mechanisms Underlying the Effects of Rapid Acting Antidepressants (RAADs)
It is believed that the rapid increase of synaptogenesis, by modulating prefrontal and hippocampal glutamatergic synapses, is a convergent mechanistic pathway underlying the beneficial behavioral effects of RAADs. Ketamine and scopolamine have been shown to precipitate glutamate neurotransmission surge by blocking interneuronal N-methyl-D-aspartate (NMDA) or muscarinic acetylcholine (mACh) receptors, respectively, leading to inhibition of GABAergic input on glutamatergic neurons. This glutamate surge stimulates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and activity dependent release of brain derived neurotrophic factor (BDNF), which in turn stimulates mammalian target of rapamycin complex 1 (mTORC1) signaling and increases translation of synaptic proteins. LY341495 induces a glutamate neurotransmission surge presumably by blocking presynaptic metabotropic glutamate receptors (mGluR2/3). Rapastinel is believed to increase postsynaptic glutamate neurotransmission by exerting partial agonist properties on intrasynaptic NMDA receptors. Ketamine, traxoprodil, and Ro25-6981 were proposed to increase synaptogenesis by blocking NR2B-containing NMDA receptors activated by ambient glutamate. (2S,6S;2R,6R)-Hydroxynorketamine [a.k.a., Z-6-HNK] has been shown to increase glutamate transmission and elongation eukaryotic factor 2 (eEF2), however, the underlying pathways leading to these changes are not fully known. Alpha 7 nicotinic ACh (α7-nACh) receptors induce presynaptic glutamate release as well as increase ambient extrasynaptic glutamate by activating astrocytic glutamate release. Considering preliminary evidence of α7-nACh inhibition by (2S,6S;2R,6R)-HNK, future studies should examine whether the (2S,6S;2R,6R)-HNK induced increase in eEF2 is related to its effects on astrocytic α-7-nicotinic-ACh receptors.
See this image and copyright information in PMC

Comment on

References

    1. Skolnick P, Layer RT, Popik P, Nowak G, Paul IA, Trullas R. Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression. Pharmacopsychiatry. 1996;29:23–26. - PubMed
    1. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351–354. - PubMed
    1. Maeng S, Zarate CA, Jr, Du J, Schloesser RJ, McCammon J, Chen G, et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry. 2008;63:349–352. - PubMed
    1. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–964. - PMC - PubMed
    1. Abdallah CG, Adams TG, Kelmendi B, Esterlis I, Sanacora G, Krystal JH. Ketamine’s Mechanism of Action: A Path to Rapid-Acting Antidepressants. Depress Anxiety 2016 - PMC - PubMed

Publication types

LinkOut - more resources