Abstract
Acute alcohol administration to rats has in preliminary studies been reported to drastically increase the binding of the benzodiazepine (BZ) receptor antagonist [3H]flumazenil (Ro 15-1788) to central BZ receptors. In the present study the effect of acute alcohol ingestion on the disposition of [11C]flumazenil in the human brain and plasma was examined by positron emission tomography (PET) in four healthy volunteers. Neocortex, cerebellum and pons (reference region) were delineated using X-ray computerized tomography (CT). Alcohol did not increase either total radioactivity uptake or specific [11C]flumazenil binding in neocortex or cerebellum. However, alcohol had a small but significant effect on [11C]flumazenil in arterial blood. After alcohol the plasma radioactivity peak was higher, more narrow and occurred earlier than in the control experiments. The present experiments contradict the view that alcohol directly affects central BZ receptor binding in man. Thus the dramatic increase of flumazenil binding in rat brain reported previously could not be observed in the human brain.
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References
Allan AM, Harris RA (1986) Gamma-aminobutyric acid and alcohol actions: neurochemical studies of long sleep and short sleep mice. Life Sci 39:2005–2015
Bergström M, Boetius J, Eriksson L, Greitz T, Ribbe T, Widén L (1981) Head fixation device for reproducible position alignment in transmission CT and positron emission tomography. J Comput Assist Tomogr 5:136–141
Cole JO, Davis JM (1975) In: Antianxiety drugs. Freedman DX, Dyrud JE (eds) American handbook of psychiatry, vol 5. Basic Books, New York, pp 427–440
Davidoff RA (1973) Alcohol and presynaptic inhibition in a isolated spinal cord preparation. Arch Neurol 28:60–63
Davis WC, Ticku MK (1981) Ethanol enhances [3H]diazepam binding at the benzodiazepine-aminobutyric acid receptor-ionophore complex. Mol Pharmacol 20:287–298
Deutsch ST, Miller L, Greenblatt DJ, Do Luu M, Paul SM (1986) Alterations of benzodiazepine receptor binding in response to pentobarbital and ethanol as measured by in vivo labelling with [3H]Ro 15-1788. Soc Neurosci 12:658
Enna SJ (1981) GABA receptors pharmacology. Functional considerations. Biochem Pharmacol 30:907–913
Eriksson L, Holte S, Bohm S, Kesselberg M, Hovander B (1988) Automated blood sampling systems for positron emission tomography. IEEE Trans Nucl Sci 35:703–707
Freund G, Ballinger W (1988) Decrease of benzodiazepine receptors in frontal cortex of alcoholics. Alcohol 5:275–282
Frye GD, Breese GR (1982) GABAergic modulation of ethanol-induced motor impairment. J Pharmacol Exp Ther 223:750–756
Greenberg DA, Cooper EC, Gordon A, Diamond T (1984) Ethanol and the γ-aminobutyric acid-benzodiazepine receptor complex. J Neurochem 42:1062–1068
Halldin C, Stone-Elander S, Thorell J-O, Persson A, Sedvall G (1988) C-11 labelling of Ro 15-1788, in two different positions, and its main metabolite Ro 15-3890 for PET studies of benzodiazepine receptors. Appl Radiat Isotop 39:993–997
Huang S-C, Barrio JR, Phelps ME (1986) Neuroreceptor assay with positron emission tomography: equilibrium versus dynamic approaches. J Cereb Blood Flow Metab 6:515–521
James A, Roos M (1975) Minuit. Comput Physics Commun 10:343–367
Jones AW, Schubert J (1989) Computer-aided head space gas chromatography applied to blood-alcohol analysis: importance of online process control. J Forens Sci 34:1116–1127
Koob GF, Strecker RE, Bloom F (1980) Effects of naloxone and the anticonflict properties of alcohol and chlordiazepoxide. Subst Alcohol Actions Misuse 1:447–457
Liljequist S, Engel J (1982) Effects of GABAergic agonists and antagonists in various ethanol-induced behavioral changes. Psychopharmacology 78:71–75
Liljequist S, Engel JA (1984) The effect of GABA and benzodiazepine receptor antagonists on the anti-conflict actions of diazepam or ethanol. Pharmacol Biochem Behav 21:521–525
Liljequist S, Culp S, Tabakoff B (1986) Effect of ethanol on the binding of [35S]t-butylbicyclophosphorothionate to mouse brain membranes. Life Sci 38:1931–1939
Liljequist S, Culp S, Tabakoff B (1989) The effect of ethanol on [35S]-TBPS binding to mouse brain membranes in the presence of chloride. Pharmacol Toxicol 65:352–367
Litton J-E, Bergström M, Eriksson L, Bohm C, Blomqvist G, Kesselberg M (1984) Performance study of the PC-384 positron camera system for emission tomography of the brain. J Comput Assist Tomogr 8:74–87
Martz A, Deitrich RA, Harris RA (1983) Behavioral evidence for the involvement of gamma-aminobutyric acid in the actions of ethanol. Eur J Pharmacol 89:53–62
Mereu G, Gessa GL (1985) Low doses of ethanol inhibit the firing of neurons in the substantia nigra, pars reticulata: a GABAergic effect? Brain Ress Bull 360:325–330
Mintun MA, Raichle ME, Kilbourn MR, Wooten GF, Welch MJ (1984) A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography. Ann Neurol 15:217–227
Nestoros JN (1980) Ethanol specifically potentiates GABA-mediated neurotransmission in feline cerebral cortex. Science 209:708–710
Olsen RW, Bergman MO, Van Ness PC, Lummis SC, Watkins AE, Napias C, Greenlee (1981) γ-Aminobutyric acid receptor binding in mammalian brain. Mol Pharmacol 19:217–227
Persson A, Ehrin E, Farde L, Litton J-E, Mindus P, Sedvall G (1985) Imaging of 11-C-labelled Ro 15-1788 binding to benzodiazepine receptors in the human brain by positron emission tomography. J Psychiatry Res 19:609–622
Persson A, Pauli S, Halldin C, Stone-Elander S, Farde L, Sjögren I, Sedvall S (1989) Saturation analysis of specific [11C]flumazenil binding to the human neocortex using positron emission tomography. Hum Psychopharmacol 4:21–31
Ramanjaneyulu R, Ticku MK (1984) Binding characteristics and interactions of depressant drugs with [35S]t-butylbicyclophosphorothionate, a ligand that binds to the picrotoxin site. J Neurochem 42:221–229
Sieghart W (1989) Multiplicity of GABAA benzodiazepine receptors. TIPS 10:407–411
Squires RF, Casida JE, Richardson M, Saederup E (1983) [35S]t-butyl-bicyclophosphorothionate binds with high affinity to brainspecific sites coupled to γ-aminobutyric acid-A and ion recognition sites. Mol Pharmacol 23:326–336
Suzdak PD, Schwartz RD, Skolnick P, Paul SM (1986) Ethanol stimulates γ-aminobutyric acid receptor-mediated chloride transport in rat brain synaptoneurosomes. Proc Natl Acad Sci USA 83:4071–4075
Swahn C-G, Farde L, Halldin C, Sedvall G (1992) Ligand metabolites in plasma during PET-studies with the11C-labelled dopamine antagonists: raclopride, SCH 23390 and N-methylspiroperidol. Hum Psychopharmacol (submitted)
Thyagarajan R, Ticku MK (1985) The effects of in vitro and in vivo ethanol administration on the [35S]t-butylbicyclophosphorothionate binding in C57 mice. Brain Res Bull 15:343–345
Ticku MK, Lowrimore P, Lehoullier P (1986) Ethanol enhances GABA-induced36Cl influx in primary spinal cord cultured neurons. Brain Res Bull 17:123–126
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Pauli, S., Liljequist, S., Farde, L. et al. PET analysis of alcohol interaction with the brain disposition of [11C]flumazenil. Psychopharmacology 107, 180–185 (1992). https://doi.org/10.1007/BF02245135
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DOI: https://doi.org/10.1007/BF02245135