Aminobutyric Acid Receptors
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Commentary Absinthe and ␥-aminobutyric acid receptors Richard W. Olsen* Department of Molecular and Medical Pharmacology, University of California School of Medicine, Los Angeles, CA 90095-1735 bsinthe is an emerald-green liqueur style led to a negative reaction and major Athat achieved fantastic popularity at support for prohibition in France and the close of the 19th century. It was asso- elsewhere. One can see the negative side ciated with the Bohemian lifestyle and was of absinthe drinking in many of the poems credited with the inspiration of famous written about it and the pictures drawn artists and poets (1, 2). Because of its about it, as in Degas (Fig. 1). The ‘‘mad- widespread abuse and the associated tox- ness in a bottle,’’ i.e., absinthe, was doubly icity of its content of oil of wormwood, attacked for its reputation for inducing absinthe was made illegal in most coun- insane and criminal acts, as well as con- tries in the 1910s. The most likely ingre- vulsions and other toxicity (2). However, dient responsible for toxicity is believed to statistics showed that in France in 1907, be the terpenoid ␣-thujone (1–4). Oil of only about 1/40th of the inmates of insane wormwood has convulsant activity as well asylums were absinthe drinkers, and many as activity in killing worms and insects (5). of those would actually drink anything The mechanism of action of thujone has alcoholic (2). remained speculative until now. In a re- Finally, military and civilian leaders cent issue of PNAS, Hold et al. (6) pro- entering into World War I discouraged vided evidence that thujone acts as a alcohol abuse and absinthe in support of ␥ -aminobutyric acid type A (GABAA) the war effort. Absinthe was outlawed in receptor chloride channel blocker, much most countries in 1910–1915, and all like the plant convulsant picrotoxin, and alcohol became illegal shortly after in related synthetic analogs. many. Pernod, an anise-flavored, green- Absinthe use is ritualistic, involving a colored analog of absinthe lacking the oil special glass and perforated spoon and of wormwood, has remained available. Fig. 1. L’Absinthe, E. Degas. COMMENTARY adding cold water by pouring it over Absinthe can still be purchased in certain sugar cubes, at which time the liqueur lands, including Czechoslovakia, and you thujone (Fig. 2), and its only pharmaco- turns white because of precipitation of can make your own with readily available logical action listed in the Merck index is alcohol-soluble herbal ingredients. Its and legal ingredients (check the web). ‘‘convulsant’’ (8). Many naturally occur- magical powers worshiped by the masses, Absinthe was widely regarded as im- ring and synthetic convulsive agents are absinthe became the national drink of parting pharmacological effects beyond blockers of GABA-mediated inhibition France in the late 19th century, with those of alcohol alone, such as stimulating (9, 10). The prototypic GABA channel workers and artists alike awaiting l’heure the imagination and aphrodisiac action, as verte, 5–7 p.m., when they all headed for well as producing hallucinations. Except blocker picrotoxinin (Fig. 2) is isolated the cafes of Paris for their glass of ab- for the toxicity, there is little research from plants of the moonseed family, sinthe, drinking 36–221 million liters per evidence supporting this view and more Menispermaceae, and its close relatives year around 1910 (1, 2). In 1906, Paris study is needed. tutin and coriamyrtin, from the New had 33,330 bars (and drink sellers) for As noted, oil of wormwood had an- Zealand tutu plant Coriaria arborea (11, 2,601,000 people, compared with 17,000 cient herbal medicinal uses, primarily for 12), known as a ‘‘loco weed’’ that caused bakers. Alcohol was a major economic digestion (5). It is an extract of the occasional poisonings in cows, and even force. The major supplier was the Swiss common European woody bush, the in people. factory Pernod, established in 1787, and wormwood plant, Artemisia absinthium. The senior author of this thujone re- the original French connection was prob- Other members of the Artemisia genus port, Dr. John Casida, has synthesized and ably in Algeria. include sagebrush. The natural product studied a major category of synthetic po- Many Parisians adopted the Bohemian thujone is found in plants of the Thuja tent neurotoxic chemicals (13), the cage lifestyle in the Belle Epoque, among them genus, which is arborvitae and cedar. convulsants (Fig. 2), which were discov- many creative artists and writers. De Mus- They are in the conifer family Cupressa- ered to be noncompetitive GABAA recep- set was so often hung over from absinthe cae, which also includes Juniperus (the tor antagonists acting at the picrotoxinin that his students found him to ‘‘absinthe source of gin), and nutmeg; the related site (13–15). One of these drugs, t-butyl himself too much from his lectures.’’ Tsuga genus is hemlock (a well-known bicylcophosphorothionate (TBPS), is a Beaudelaire was an habitual user of ab- poison). major research tool used to assay GABA sinthe. Verlaine abused absinthe in a self- The newly noted connection with receptors by radioligand binding (16). destructive overindulgence, in the midst of GABAA receptor channel antagonism Synthetic butyrolactones with convulsant a homosexual affair with Rimbaud. Other should not be surprising in light of pre- big fans included Zola, Oscar Wilde, Gau- vious observations. The major pharma- gin, Toulouse-Lautrec, van Gogh, and Pi- cological effect of oil of wormwood is See companion article on page 3826 in issue 8 of volume 97. casso. But the wild and destructive life- seizures (2). The active agent (1, 7) is *E-mail: [email protected]. PNAS ͉ April 25, 2000 ͉ vol. 97 ͉ no. 9 ͉ 4417–4418 Downloaded by guest on October 1, 2021 of evidence: (i) the symptoms of poisoning Now why would a drug with toxic and and protection by benzodiazepines and convulsant actions possibly be considered barbiturates resemble those of other pleasant or at least desirable? A specula- GABA blockers like picrotoxinin; (ii)a tion that thujone might behave in a man- strain of insects resistant to picrotoxin and ner similar to tetrahydrocannabinol, the GABA-blocking insecticides like dieldrin active ingredient of marijuana, was ruled is resistant to thujone; (iii) thujone com- out (22): thujone has a low affinity for petitively inhibits the binding of a radio- cannabinoid receptor binding sites but none of the pharmacological actions, such active cage convulsant to the picrotoxin/ as locomotor activity (open field test), convulsant site on GABA receptors in A immobility (ring stand test), and analgesia mammalian brain membranes; and (iv) (hot plate test). Thus cannabinoids, but thujone reversibly blocks GABAA recep- not thujone, are central nervous system tor chloride currents in mammalian neu- depressants, like a sleeping pill. Thujone, rons. These actions are shown not to be like picrotoxin, is excitatory on the brain caused by ethanol. In addition, the authors (analeptic). Such an agent may produce demonstrate the nature and activity of the mood elevation and antidepressant ef- major metabolites of thujone in mamma- fects. One may note the anxiogenic and Fig. 2. Chemical structures. lian brain and liver. They demonstrate that possibly alerting effect of GABA antago- ␣-thujone is 2.3 times more active than nists, as opposed to the anxiolytic, seda-  tive, but also amnestic effects of GABA- and anticonvulsant actions also have been -thujone in binding and that 7-hydroxy- ␣-thujone and dehydro-␣-thujone are enhancing drugs like benzodiazepines and described for the picrotoxinin site (17). In ␣ ethanol (9, 10, 23). Do not forget, how- addition, this drug target appears to be the toxic but not as potent as -thujone. It would have been nice to have additional ever, that in absinthe one is balancing the site of action of the experimental convul-  effect of thujone with the intoxicating, sant pentylenetetrazol (18) and numerous biological potencies for -thujone because it is more abundant than ␣-thujone in disinhibitory, and depressant effects of polychlorinated hydrocarbon insecticides, ethanol, not to mention those of the other ␣ wormwood and active in the binding test. including dieldrin (Fig. 2) and -endosul- herbal ingredients of oil of wormwood and If the two stereoisomers had differed in fan, mentioned in Hold et al. (6). This was others added to the myriad recipes for demonstrated independently by both Dr. activity it would have provided even stron- absinthe now in existence. Casida (19, 20) and another author of the ger evidence that the GABAA receptor is I will leave with this quote of Oscar report, Dr. Toshio Narahashi (21), who the drug target. It is possible or likely that Wilde about absinthe: ‘‘After the first has been a pioneer in mechanism studies both isomers have some activity. Likewise, glass, you see things as you wish they were. on many drugs and toxins. the high abundance of the metabolite After the second, you see them as they are The report of Hold et al. (6) convinc- 7-hydroxy thujone suggests the possibility not. Finally, you see things as they really ingly demonstrates that thujone acts as a that some of the pharmacological actions are, which is the most horrible thing in the GABAA receptor antagonist by four lines may ensue from this substance. world’’ (2). 1. Vogt, D. D. & Montagne, M. (1982) Int. J. Addict. 9. Macdonald, R. L. & Olsen R. W. (1994) Annu. 16. Squires, R. F., Casida, J. E., Richardson, M. & 17, 1015–1029. Rev. Neurosci. 17, 569–602. Saederup, E. (1983) Mol. Pharmacol. 23, 326–336. 2. Conrad, B. (1988) Absinthe: History in a Bottle 10. Olsen, R. W. & Gordey, M. (2000) in Handbook of 17. Klunk, W. E., Covey, D. F. & Ferrendelli, J.