All neurotransmitters may be involved in coma, with interactions between receptor-mediated and non-receptor-mediated functions.
2. A recent advance has added the cholinergic system to the list of the mechanisms. However, the important monoaminergic system has been relatively ignored. It seems unlikely that these neurotransmitters, with their inhibitory and excitatory functions, play no role in this process. Unfortunately, we lack evidence and even hypotheses. Blake et al. (1985) found that a combination of iron-chelators (the hydrophilic desferrioxamine and the hydrophobic prochlorperazine) induces coma in humans and rats; recent findings concerning iron and monoamine functions in free radical biology and medicine suggested to Smythies the intriguing hypothesis of an involvement of the monoaminergic system in the mechanisms of coma.
3. We have long been interested in the role of monoamine neurotransmitters in aging, stress and pathological conditions as oxidants and antioxidants, aside from their neurotransmitter functions (Liu & Mori 1993, 1994; Liu et al 1996, 1998; Mori et al. 1995). The monoamine neurotransmitter balance can be maintained by their double-edged characteristics. They can easily oxidize to form highly neurotoxic o-semiquinones, rendering them potentially neurotoxic. On the other hand, these monoamines are potent antioxidants which render them neuroprotective. The balance between these two is maintained by a very complex mechanism in which ascorbate, NO and the mechanisms that prevent formation of o-semiquinones may all play a role.
4. Based on these related findings, Smythies (1997) proposed a new idea about the interaction of catecholamines and glutamate as below. It is currently believed that neuromodulators exert their effects solely via their own specific receptors. However, catecholamines may produce some of their effects on other receptors by a spill-over effect (NMDA receptors on one cell can be stimulated in a similar way by glutamate released from axon terminals on neighboring cells, this is called the spill-over effect). In certain brain areas, the spines on the medium spiny output neurons have two contacts; one is a glutamatergic terminal on the spine and the other is an adjacent non-synaptic dopaminergic terminal en passage. These two terminals are only 1-2 mu apart. Thus, it seems possible that catecholamines from the en passage dopamine boutons (and possibly NE boutons in NE systems) modulate the redox status of the adjacent glutamatergic synapse by scavenging oxidants such as superoxide and hydroxyl radicals produced by hydrogen peroxide. Hydrogen peroxide can diffuse out of the post-synaptic neuron into the synaptic cleft and there, under certain conditions, can undergo conversion to superoxide and hydroxyl radicals. Edelman & Gally (1992) have suggested that hydrogen peroxide might have a modulatory role in synapses. There is also direct evidence that dopamine protects against glutamate neurotoxicity in striatal neurons (Amano et al. 1994). The involvement of the monoaminergic system and its interaction with the glutamate system in the mechanism of coma is simply another application of this idea.
5. The interaction of all CNS neurotransmitters in coma seems probable because any change in one type of neurotransmitter will affect the homeostasis of all other neurotransmitter systems, thus effect a change of physiological functions. In our studies of stress, we have found that the interaction of different systems (such as the hormone, neurotransmitter, and oxidant systems in the brain) play a critical role in modulating stress response (Liu & Mori 1999). The redox theory of the biochemical basis of learning suggested by Smythies (1999b,c) gives another good example of this. Not only does he suggest that the monoaminergic system participates in the coma mechanism, but he also suggests that the interaction between the dopamine and the glutamate systems plays an essential role in mediating loss of consciousness.
6. Another important point Smythies emphasizes is the possible role of endocytosis of receptors and their subsequent processing inside the post-synaptic neuron. This interesting idea depends on the hypothesis that the redox balance at the synapse is an important factor in the plasticity of the synapses (Smythies 1997).
7. I propose that some of the polypeptides, with neurotransmitter function, will be found to be involved in coma mechanisms because endocytosis is a general process for all the transmitters and their receptors, though the purposes of endocytosis may differ for different neurotransmitters and their receptors (Koenig & Edwardson 1997). The interaction between non-receptor-mediated and the receptor-mediated functions will likewise be involved in coma mechanisms because the two functions sometimes cannot be separated or distinguished. As we know, any structural change in cells and ion channels can cause feedback effects on receptors.
I thank Professor B. N. Ames for his comments and critical reading of the manuscript.
Amano, T., H. Ujihara, H. Matsubayashi, M. Sasa, T. Yokota, Y. Tamura, and A. Akaike. 1994. Dopamine-induced protection of striatal neurons against kainate receptor-mediated glutamate cytotoxicity in vitro. Brain Res 655: 61-9.
Blake, D. R., P. Winyard, J. Lunec, A. Williams, P. A. Good, S. J. Crewes, J. M. C. Gutteridge, D. Rowley, B. Halliwell, A. Cornish, and R. C. Hider. 1985. Cellular and ocular toxicity induced by desffioxamine. Quarterly J. Med. 56: 345-355.
Edelman, G. M., and J. A. Gally. Nitric oxide: linking space and time in the brain. 1992. Proc Natl Acad Sci U S A 89: 11651-2.
Koenig, J. A., and J. M. Edwardson. 1997. Endocytosis and recycling of G protein coupled receptors. Trends Pharmacol. Sci. 18: 276-287.
Liu, J., I. Yokoi, S. Doniger, H. Kabuto, H. C. Yeo, A. Mori, and B. N. Ames. 1998. Adrenalectomy causes oxidative damage and monoamine increase in the brain of rats and enhances immobilization stress-induced oxidative damage and neurotransmitter changes. Int. J. Stress Manag. 5: 39-56.
Liu, J., M. K. Shigenaga, A. Mori, and B. N. Ames. Free radicals and neurodegenerative diseases: stress and oxidative damage. 1996. In: Free Radicals in Brain Physiology and Disorders, edited by L. Packer, M. Hiramatsu and T. Yoshikawa. New York: Academic Press, p. 403-437.
Liu, J., and A. Mori. 1994. Involvement of reactive oxygen species in emotional stress: A hypothesis based on the immobilization stress-induced oxidative damage and antioxidant defense changes in rat brain, and the effect of antioxidant treatment with reduced glutathione. Int. J. Stress Manag. 1: 249-263.
Liu, J., and A. Mori. 1993. Monoamine metabolism provides an antioxidant defense in the brain against oxidant- and free radical-induced damage. Arch Biochem Biophys 302: 118-27.
Liu, J., and A. Mori. Stress, aging, and brain oxidative damage. Neurochem. Res. 24: 1479-1497.
Mori, A., I. Yokoi, J. Liu, and K. Mizukawa. Oxidative stress and brain damage as the pathogenesis of epilepsy. In: Oxidative Stress and Aging, edited by R. G. Cutler, L. Packer, J. Bertram and A. Mori. Switzerland: Birkhauser Verlag Basel, 1995, p. 309-317.
Smythies, J. 1999a. The biochemical basis of coma. PSYCOLOQUY 10(026) ftp://ftp.princeton.edu/pub/harnad/Psycoloquy/1999.volume.10/ psyc.99.10.026.coma-biochemistry.1.smythies http://www.cogsci.soton.ac.uk/cgi/psyc/newpsy?10.026
Smythies, J. 1999b. Redox mechanisms at the glutamate synapse and their significance: a review. Eur. J. Pharmacol. 370: 1-7
Smythies, J. 1999c. The neurochemical basis of learning and neurocomputation: the redox theory. Behav. Brain Res. 99: 1-6.
Smythies, J. 1997. The biochemical basis of synaptic plasticity and neurocomputation: a new theory. Proc R Soc Lond B Biol Sci 264: 575-9,