Glutamate: The Two-Edged Sword of Scholarship
By John V. Schloss, Ph.D.
The observation that glutamate builds up in the brains of students during study and contributes to exhaustion after periods of intensive scholarship caused considerable excitement.1 However, this came as no surprise to those of us who have studied the role of glutamate in the brain over the past three decades. Glutamate is the primary excitatory signaling molecule in the central nervous system (CNS) similar to the role that acetylcholine plays in the periphery. Since discovering glutamate’s primary role in the CNS during the 1950s, it has been shown to be essential to neuronal plasticity, neurotoxicity, learning, and memory.2 Excessive glutamate causes ‘excitotoxicity’, which in the extreme leads to the death of brain neurons. Release of glutamate following oxygen reperfusion of the anoxic brain is the underlying cause of neuronal death in stroke.
Alcohol inhibits the NMDA receptor, a key regulator of glutamate signaling in the brain. Moderate inhibition of the NMDA receptor by alcohol causes the anxiolytic effect or relaxation. Greater inhibition of the NMDA receptor leads to motor ataxia (falling down drunk), blackouts, and loss of memory during the period of inebriation. Other drugs that block the NMDA receptor, like ketamine (‘Special K’) and phencyclidine (PCP or ‘Angel Dust’), have similar pharmacology and collectively are known as dissociative anesthetics (you can feel the pain, but are not ‘in the body’ and do not necessarily respond). In the late 1990s, I led a group of investigators at the University of Kansas studying the mechanism of oxygen-induced seizures that occur during deep dives on compressed air.3-5 We discovered that molecular oxygen inhibits the conversion of the excitatory molecule, glutamate, into an inhibitory molecule of signal transduction, gamma-aminobutyrate (GABA).6,7 Further, we found that partial inhibition of NMDA receptors could prevent oxygen-induced seizures and other glutamate-related neurotoxicity.8-11 So, higher levels of oxygen should potentiate excitation (alertness and ultimately seizure), while lower levels of oxygen should promote relaxation (and impair learning). It has been known for more than two decades that in scholarship no pain means no gain. Without the effect of glutamate (and some neuronal death) there is no long-term learning.
REFERENCES
- Underwood E (2022) Mentally exhausted? Study blames buildup of key chemical in brain, Science doi: 10.1126/science.ade3733.
- Rezvani AH (2006) Involvement of the NMDA system in learning and memory. In: Levin ED, Buccafusco JJ, editors. Animal Models of Cognitive Impairment. Boca Raton, Florida. Chapter 4.
- Office of Naval Research, Hyperbaric Oxygen Toxicity: Mechanism and Therapy(N00014-03-1-0450), 2003-2004, Schloss JV, PI.
- Office of Naval Research, Hyperbaric Oxygen Toxicity: Mechanism and Therapy (N00014-00-1-01-02), 1999-2002, Schloss JV, PI.
- Office of Naval Research, Hyperbaric Oxygen Toxicity: Mechanism and Therapy (N00014-94-1-0457), 1994-1999, Schloss JV, PI.
- Abell LM, Schloss JV (1991) Oxygenase side reactions of acetolactate synthase and other carbanion-forming enzymes, Biochemistry 30:7883-7887.
- Davis K, Foos T, Wu JY, Schloss JV (2001) Oxygen-induced seizures and inhibition of human glutamate decarboxylase and porcine cysteine sulfinic acid decarboxylase by oxygen and nitric oxide, J. Biomed. Sci. 8:359-364.
- Nagendra SN, Faiman MD, Davis K, Wu JY, Newby X, Schloss JV (1997) Carbamoylation of brain glutamate receptors by a disulfiram metabolite, J Biol Chem 272:24247-24251.
- Liu G, Nagendra SN, Wu JY, Faiman MD, Schloss JV (1998) The fate of thiocarbamate sulfoxides in vitro and in vivo. In: Enzymatic Mechanisms, Eds., P. A. Frey and D. B. Northrop, IOS Press, Amsterdam, 107-115.
- Faiman M, Schloss JV, Wu JY (2000) Methods for Treatment of Glutamate Related Disorders, United States Patent Number 6,156,794.
- Schloss JV (2007) Therapeutic Compositions, United States Patent Number 7,250,401.
