Hans Flohr has developed two distinct lines of argument (Flohr 1995a, 1995b) to support his hypothesis: (1) a philosophical argument, based on the idea that NMDA receptor activity is capable of forming "representational states" in the brain, and (2) an argument which claims that all general anesthetics ultimately inhibit NMDA receptor activity, and hence NMDA receptor activity must be essential for consciousness. We will leave the philosophical argument to the philosophers, although we are bound to say that we find the arguments for and against far from compelling. The argument based on experimental evidence, however, is tantalizing.
There is no doubt that ketamine causes loss of consciousness at high enough doses. There is also good evidence that it acts predominantly on NMDA receptors (although there remains some doubt that this is its only important target) (Hirota and Lambert 1996). Thus one probably can safely conclude that the normal functioning of NMDA receptors is necessary for consciousness. But of course the normal functioning of all sorts of molecular and cellular systems must be necessary for consciousness. Flohr's hypothesis is far more specific, and interesting, because it states that the normal functioning of NMDA receptors is directly responsible for consciousness. It therefore follows that drugs like etomi-date, which, as discussed above, almost certainly act via GABAA receptors, must indirectly inhibit NMDA receptor activity. This is certainly easy to imagine, and there is some experimental evidence that supports this view (as discussed in chapter 16 ). If we suppose, as seems reasonable, that the normal firing of a certain subset of neurons in the brain is necessary for consciousness, and these neurons contain NMDA receptors, then obviously anesthetics that act by blocking NMDA receptors would act directly on these neurons, among others. Anesthetics that acted via GABAA receptors, on the other hand, could do so either because these receptors were present on the same neurons, or because they inhibited another set of neurons which then inhibited the critical "consciousness neurons.''
There is, however, the difficult question of whether the state of unconsciousness induced by ketamine is the same as that induced by etomi-date. Both drugs certainly cause unconsciousness (using the simplest of criteria), but the pharmacological profiles of ketamine and etomidate differ in a number of important ways. For example, ketamine induces powerful psychotomimetic effects (Bowdle et al. 1998) and is a potent analgesic (Marshall et al. 1996). Indeed, these properties seem characteristic of several NMDA antagonists. Etomidate, however, does not have these properties (Marshall et al. 1996). If etomidate acts by ultimately inhibiting NMDA receptors, why does it not produce analgesia? The answer could lie in the different distributions of NMDA and GABAA receptors in the brain and spinal cord, or on neuronal connectivity.
Unfortunately, these sorts of explanations open up a slippery slope of special pleading arguments that make the hypothesis less and less appealing because, we feel, they could be used to explain away almost any experimental result that challenged the theory. Overall, then, our view is that one of the apparent strengths of this interesting idea is also one of its weaknesses— namely, that it is capable of explaining almost everything. Nonetheless, Flohr's ideas are certainly of sufficient interest to justify serious attempts to design experiments that may provide definitive tests of his NMDA hypothesis.
Anis, N. A., Berry, S. C., Burton, N. R., and Lodge, D. (1983). The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate. British Journal of Pharmacology 79: 565-575. Becker, K. E., Jr. (1978). Plasma levels of thiopental necessary for anesthesia. Anesthesiology 49: 192-196. Belelli, D., Lambert, J. J., Peters, J. A., Wafford, K., and Whiting, P. J. (1997). The interaction of the general anesthetic etomidate with the y-aminobutyric acid type A receptor is influenced by a single amino acid. Proceedings of the National Academy of Sciences USA 94: 11031-11036.
Bowdle, T. A., et al. (1998). Psychedelic effects of ketamine in healthy volunteers: Relationship to steady-state plasma concentrations. Anesthesiology 88: 82-88. Brockmeyer, D. M., and Kendig, J. J. (1995). Selective effects of ketamine on amino acid-mediated pathways in neonatal rat spinal cord. British Journal of Anaesthesia 74: 79-84.
Flohr, H. (1995a). An information processing theory of anaesthesia. Neuropsychologia 33: 1169-1180. Flohr, H. (1995b). Sensations and brain processes. Behavioural Brain Research 71: 157-161. Franks, N. P., and Lieb, W. R. (1978). Where do general anaesthetics act? Nature 274: 339-342. Franks, N. P., and Lieb, W. R. (1982). Molecular mechanisms of general anaesthesia. Nature 300: 487493.
Franks, N. P., and Lieb, W. R. (1984). Do general anaesthetics act by competitive binding to specific receptors? Nature 310: 599-601. Franks, N. P., and Lieb, W. R. (1987). What is the molecular nature of general anaesthetic target sites? Trends Pharmacological Sciences 8: 169-174. Franks, N. P., and Lieb, W. R. (1993). Selective actions of volatile general anaesthetics at molecular and cellular levels. British Journal of Anaesthesia 71: 65-86.
Franks, N. P., and Lieb, W. R. (1994). Molecular and cellular mechanisms of general anaesthesia. Nature 367: 607-614.
Gustafsson, L. L., Ebling, W. F., Osaki, E., and Stan-ski, D. R. (1996). Quantitation of depth of thiopental anesthesia in the rat. Anesthesiology 84: 415-427.
Hall, A. C., Lieb, W. R., and Franks, N. P. (1994). Insensitivity of P-type calcium channels to inhalational and intravenous general anesthetics. Anesthesiology 81: 117-123.
Hirota, K., and Lambert, D. G. (1996). Ketamine: Its mechanism(s) of action and unusual clinical uses. British Journal of Anaesthesia 77: 441-444. Hung, O. R., Varvel, J. R., Shafer, S. L., and Stanski, D. R. (1992). Thiopental pharmacodynamics. II. Quantitation of clinical and electroencephalographic depth of anesthesia. Anesthesiology 77: 237-244. Lodge, D., Anis, N. A., and Burton, N. R. (1982). Effects of optical isomers of ketamine on excitation of cat and rat spinal neurones by amino acids and ace-tylcholine. Neuroscience Letters 29: 281-286. MacDonald, J. F., Miljkovic, Z., and Pennefather, P. (1987). Use-dependent block of excitatory amino acid currents in cultured neurons by ketamine. Journal of Neurophysiology 58: 251-266.
Marshall, B. E., and Longnecker, D. E. (1996). General Anesthetics. In J. G. Hardman et al., eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed., 307-330. New York: McGraw-Hill.
Rang, H. P., Dale, M. M., and Ritter, J. M. (1995). Pharmacology, 3rd ed. Edinburgh: Churchill Livingstone.
Ryder, S., Way, W. L., and Trevor, A. J. (1978). Comparative pharmacology of the optical isomers of ketamine in mice. European Journal of Pharmacology 49: 15-23.
Tomlin, S. L., Jenkins, A., Lieb, W. R., and Franks, N. P. (1998). Stereoselective effects of etomidate optical isomers on gamma-aminobutyric acid type A receptors and animals. Anesthesiology 88: 708-817. Violet, J. M., Downie, D. L., Nakisa, R. C., Lieb, W. R., and Franks, N. P. (1997). Differential sensitivities of mammalian neuronal and muscle nicotinic ace-tylcholine receptors to general anesthetics. Anesthesiol-ogy 86: 866-874.
White, P. F., et al. (1985). Comparative pharmacology of the ketamine isomers. Studies in volunteers. British Journal of Anaesthesia 57: 197-203. Zeilhofer, H. U., Swandulla, D., Geisslinger, G., and Brune, K. (1992). Differential effects of ketamine enantiomers on NMDA receptor currents in cultured neurons. European Journal of Pharmacology 213: 155158.
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