The Hard Problem of Consciousness
All of the problems of consciousness are hard problems. The "hard problem of consciousnes" is the most difficult. It is a fundamental problem with profound implications.
The easier problem of consciousness is to understand neuronal correlates of consciousness (NCCs).
NCCs can demonstrate cause-effect relationships between neuronal activity and subjective experience. The hard problem remains unanswered:
How and why is subjective experienced produced?
Psychedelics, Mental Illness and Consciousness
The Czech psychiatrist Stanslav Grof (2008) has said that ". . . psychedelics, used responsibly and with proper caution, would be for psychiatry what the microscope is to the study of biology and medicine or the telescope for astronomy . . .”
Historical Thinking About Mental Illness
The discovery of LSD was important in developing the idea that brain chemistry might have something to do with thinking and behaviour.
The idea that mental disorders result from natural causes was suggested as early as 400 years BCE by Hippocrates. JLW Thudichum (1884) published A Treatise on the Chemical Constitution of the Brain, in which he stated:
"Many forms of insanity are unquestionably the external manifestations of the effects upon the brain-substance of poisons fermented within the body, just as. the mental aberrations accompanying chronic alcoholic intoxication are the accumulated effects of a relatively simple poison fermented out of the body. These poisons we shall, I have no doubt, be able to isolate after we know the normal chemistry to its uttermost detail. And then will come in their turn the crowning discoveries to which all our efforts must ultimately be directed, namety, the discoveries of the antidotes to the poisons, and to the fermenting causes and processes which produce them."
The empirical formula for LSD is C20H25N3O.
The PEA moiety is a common motif in nature. It makes up the backbone of the amino acids phenylalanine and tyrosine which are important biological prescursors of dopamine, epinephrine (adrenaline) and norepinephrine.
LSD also contains a conformationally restricted indole moiety. Indole is also a common structural motif in nature. It comprises the bulk of the essential amino acid tryptophan which is a biological precursor of the neurotransmitter serotonin.
In LSD, the benzene ring is shared by both the PEA and indole moieties.
Biosynthetically, the natural precursor to LSD derives from tryptophan. The PEA moiety results from the isoprenylation of tryptophan (Keller, 1999).
Monoamine Neurotransmitters
The monoamine hypothesis of schizophrenia was an attempt to explain schizophrenia in terms of monoamine neurotransmitter dysfunction (i.e. a "chemical imbalance" of neurotransmitters containing one amino group).
Dopamine (3,4-Dihydroxyphenethylamine)
Dopamine is involved in motivation and reward.
Some of the first biochemical hypothesis of schizophrenia were developed based on observations that the effects of mescaline resembled the symptomatology of schizophrenia to some extent (Osmond & Smythies, 1952). Osmond and Smythies postulated that a problem with epinephrine (adrenaline) metabolism led to the formation of a mescaline analogue in the brains of schizophrenics (Smythies, 1963).
Serotonin (5-HT; 5-Hydroxytryptamine)
Serotonin is a neurotransmitter involved in the regulation of appetite, mood and concentration.
Serotonin was discovered in 1948 and its structure was deduced in 1949. Serotonin's struture was satisfactorily confirmed when it was first sythesized in 1951 and shown to be identical to natural serotonin (Woolley & Shaw, 1954b).
Research into serotonin was pursued as a causative factor in schizophrenia due to LSD's serotonergic effects (Woolley & Shaw, 1954a).
LSD was first synthesized in 1938 by a Swiss chemist, Albert Hofmann (1906-2008). He wrote a book about his discovery: LSD My Problem Child. It is freely available from the Multidisciplinary Association for Psychedelic Studies (MAPS).
LSD belongs to a class of drugs known as psychedelics or hallucinogens.
Hallucinogens are then chemicals which in nontoxic doses produce changes in perception, in thought, and in mood, but which seldom produce mental confusion, memory loss, or disorientation for person, place, and time. These latter changes are characteristic of organic brain reactions following intoxications with alcohol, anesthetics, and other toxic drugs. (Hoffer & Osmond, p.v).
Hallucinogen is a misnomer for this class of drugs because the classical hallucinogens such as LSD, psilocin and mescaline, rarely cause actual hallucinations. Perceptual distortions are common and users typically retain insight that these distortions are due to the effect of a drug.
The serotonin hypothesis of schizophrenia was largely the result of the discovery of LSD which researchers described as producing a "model psychosis." There are significant differences between the endogenous psychoses we call schizophrenia and the 'symptoms' produced by LSD. The serotonin model could not explain the symptoms of schizophrenia and so was replaced by the dopamine hypothesis.
The serotonin hypothesis of schizophrenia has largely been discarded in favour of dopaminergic and glutamatergic explanations (Aghajanian & Marek, 2000). The classical psychedelic drugs do not produce a 'model psychosis' but interest in these drugs remains due to their potential use as therapeutic tools and tools to investigate consciousness.
Psilocin (4-Hydroxy-N,N-dimethyltryptamine)
The structure of psilocin is very similar to the structure of serotonin. In psilocin, the oxygen is shifted over one carbon and there are two methyl groups attached to the previously free amino nitrogen. Magic mushrooms also contain psilocybin which is rapidly converted to psilocin in vivo (Hasler et al., 1997).
Glutamic acid (2-Aminopentanedioic acid)
Receptors
Each neurotransmitter listed above has corresponding receptors to which they bind and act upon. For example, serotonin binds to serotonin receptors. There are often several different types and subtypes of each receptor.
Serotonin Receptors
There are 7 types (or families) of serotonin receptors. Each family is designated with a numerical subscript (e.g. 5-HT1, 5-HT2, etc). There are multiple subtypes of each family of serotonin receptors. For example, there are five subtypes of 5-HT1 receptors and each subtype is designated by a letter (e.g. 5-HT1A, 5-HT1B, 5-HT1C, etc). Pytliak et al., (2011) provide a brief overview of the different serotonin receptors and their functions.
All serotonin receptors except the 5-HT3 family are 7-transmembrane domain G-protein coupled receptors (GPCRs). These GPCRs feature 7 transmembrane helices.
5-HT3 receptors consist of 5 subunits around a central ligand-gated cation channel.
CITED WORKS
Aghajanian GK & Marek GJ (2000). Serotonin model of schizophrenia: emerging role of glutamate mechanisms. Brain Research Reviews. 31: 302-312.
Grof S. LSD Psychotherapy: The Healing Potential of Psychedelic Medicine. Ben Lomond, CA: Multidisciplinary Association for Psychedelic Studies, 2008.
Hanwell M, Curtis DE, Lonie DC, Vandermeersch T, Zurek E, & Hutchison GR (2012). Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. Journal of Cheminformatics. 4: 17.
Hasler F, Bourquin D, Brenneisen R, Bär T & Vollenweider FX (1997). Determination of psilocin and 4-hydroxyindole-3-acetic acid in plasma by HPLC-ECD and pharmacokinetic profiles of oral and intravenous psilocybin in man. Pharmaceutica Acta Helvetiae. 72: 175-184.
Hoffer A and Osmond H. The Hallucinogens. New York: Academic Press, 1967.
Keller U. Biosynthesis of Ergot Alkaloids. In: Křen V and Cvak L (Eds). Ergot: the genus Claviceps. Amsterdam: Harwood Academic Publishers, 1999. pp. 95 - 163.
Osmond H & Smythies J (1952). Schizophrenia: a new approach. J Mental Sci. 98: 309-15.
Pytliak M, Vargová V, Mechírová V, & Felsöci M (2011). Serotonin receptors-from molecular biology to clinical applications. Physiological Research. 60: 15 - 25.
Smythies JR (1963). Biochemistry of schizophrenia. Postgraduate Medical Journal. 39: 26 - 33.
Thudichum JLW. A Treatise on the Chemical Constitution of the Brain. London, Bailliere, Tindall and Cox, 1884.
Woolley DW & Shaw E (1954a). A biochemical and pharmacological suggestion about certain mental disorders. Proceedings of the National Academy of Sciences. 40: 228-231.
Woolley DW & Shaw E. (1954b). Some neurophysiological aspects of serotonin. British Medical Journal. 2: 122 - 126.
OTHER REFERENCES
Hofmann, Albert. LSD: My Problem Child. New York: Oxford University Press, 1980. Avalailable from Multidisciplinary Association for Psychedlic Studies (MAPS) - Free Books and Essays
About
Images were made using Avogadro (Hanwell et al. 2012) and the GNU Image Manipulation Program (GIMP).
Andrew Leyton
Ottawa, Canada
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