Two Distinct Interactions of Barbiturates and Chlormethiazole with the GABAA Receptor Complex in Rat Cuneate Nucleus in Vitro

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 1983 Oct 1

PMID 6317133

Citations 18

Authors

N L Harrison

M A Simmonds

Affiliations

Soon will be listed here.

Abstract

Some pharmacological properties of the GABAA receptor complex in the rat cuneate nucleus slice have been assessed from depolarization responses to the gamma-aminobutyric acid (GABA) analogue muscimol and antagonism of the responses by bicuculline and picrotoxin. Responses to muscimol were potentiated by the following drugs, in descending order of potency with regard to the concentrations required in the Krebs medium: (+/-)-5-(1,3-dimethylbutyl)-5-ethylbarbituric acid [+/-)-DMBB) = (+/-)-quinalbarbitone = (+/-)-pentobarbitone greater than (+/-)-methyl-phenobarbitone = (-)-methylphenobarbitone greater than butobarbitone = chlormethiazole greater than phenobarbitone greater than barbitone = (+)-methylphenobarbitone. Primidone and phenylethylmalonamide were inactive. Calculation of the concentrations likely to be present in membrane lipids for equal potentiations of muscimol revealed little difference between quinalbarbitone, pentobarbitone, phenobarbitone and barbitone. The effect of picrotoxin as a muscimol antagonist was selectively reduced only by DMBB, chlormethiazole, phenobarbitone and (-)-methylphenobarbitone in concentrations that caused only a modest potentiation of muscimol. It is suggested that a specific site of action in the GABAA receptor complex is involved in the reduction of picrotoxin effect and that this may be relevant to the anticonvulsant properties of chlormethiazole, phenobarbitone and (-)-methylphenobarbitone. The potentiation of muscimol by chlormethiazole and the barbiturates in general involves a distinctly different site that is less selective and this may underlie the hypnotic properties of these drugs.

Citing Articles

Contrasting actions of a convulsant barbiturate and its anticonvulsant enantiomer on the α1 β3 γ2L GABAA receptor account for their in vivo effects.

Desai R, Savechenkov P, Zolkowska D, Ge R, Rogawski M, Bruzik K J Physiol. 2015; 593(22):4943-61.

PMID: 26378885 PMC: 4650410. DOI: 10.1113/JP270971.

Activity of chlormethiazole at human recombinant GABA(A) and NMDA receptors.

Usala M, Thompson S, Whiting P, Wafford K Br J Pharmacol. 2003; 140(6):1045-50.

PMID: 14530209 PMC: 1574126. DOI: 10.1038/sj.bjp.0705540.

On the regulation of ischaemia-induced glutamate efflux from rat cortex by GABA; in vitro studies with GABA, clomethiazole and pentobarbitone.

Nelson R, Green A, Lambert D, Hainsworth A Br J Pharmacol. 2000; 130(5):1124-30.

PMID: 10882398 PMC: 1572159. DOI: 10.1038/sj.bjp.0703398.

Striatal dopamine release in vivo following neurotoxic doses of methamphetamine and effect of the neuroprotective drugs, chlormethiazole and dizocilpine.

Baldwin H, Colado M, Murray T, de Souza R, Green A Br J Pharmacol. 1993; 108(3):590-6.

PMID: 8467354 PMC: 1908047. DOI: 10.1111/j.1476-5381.1993.tb12847.x.

Chlormethiazole attenuates the derangement of sensory evoked potential (SEP) induced by ICV administration of NMDA.

Thoren P, Sjolander M Psychopharmacology (Berl). 1993; 111(2):256-8.

PMID: 7870961 DOI: 10.1007/BF02245534.

References

Downes H, Perry R, Ostlund R, Karler R . A study of the excitatory effects of barbiturates. J Pharmacol Exp Ther. 1970; 175(3):692-9. View

Seeman P . The membrane actions of anesthetics and tranquilizers. Pharmacol Rev. 1972; 24(4):583-655. View

Harvey P, Higenbottam T, Loh L . Chlormethiazole in treatment of status epilepticus. Br Med J. 1975; 2(5971):603-5. PMC: 1673503. DOI: 10.1136/bmj.2.5971.603. View

Nicoll R . Pentobarbital: action on frog motoneurons. Brain Res. 1975; 96(1):119-23. DOI: 10.1016/0006-8993(75)90582-x. View

Ransom B, Barker J . Pentobarbital selectively enhances GABA-mediated post-synaptic inhibition in tissue cultured mouse spinal neurons. Brain Res. 1976; 114(3):530-5. DOI: 10.1016/0006-8993(76)90977-x. View

Choi D, Farb D, Fischbach G . Chlordiazepoxide selectively augments GABA action in spinal cord cell cultures. Nature. 1977; 269(5626):342-4. DOI: 10.1038/269342a0. View

MacDonald R, Barker J . Benzodiazepines specifically modulate GABA-mediated postsynaptic inhibition in cultured mammalian neurones. Nature. 1978; 271(5645):563-4. DOI: 10.1038/271563a0. View

Bowery N, Dray A . Reversal of the action of amino acid antagonists by barbiturates and other hypnotic drugs. Br J Pharmacol. 1978; 63(1):197-215. PMC: 1668297. DOI: 10.1111/j.1476-5381.1978.tb07790.x. View

Brown D, Constanti A . Interaction of pentobarbitone and gamma-aminobutyric acid on mammalian sympathetic ganglion cells. Br J Pharmacol. 1978; 63(1):217-24. PMC: 1668292. DOI: 10.1111/j.1476-5381.1978.tb07791.x. View

10.

Ticku M, Ban M, Olsen R . Binding of [3H]alpha-dihydropicrotoxinin, a gamma-aminobutyric acid synaptic antagonist, to rat brain membranes. Mol Pharmacol. 1978; 14(3):391-402. View

11.

Simmonds M . Presynaptic actions of gamma-aminobutyric acid and some antagonists in a slice preparation of cuneate nucleus. Br J Pharmacol. 1978; 63(3):495-502. PMC: 1668104. DOI: 10.1111/j.1476-5381.1978.tb07803.x. View

12.

Barker J, Ransom B . Pentobarbitone pharmacology of mammalian central neurones grown in tissue culture. J Physiol. 1978; 280:355-72. PMC: 1282663. DOI: 10.1113/jphysiol.1978.sp012388. View

13.

Schlosser W, Franco S . Modification of GABA-mediated depolarization of the cat ganglion by pentobarbital and two benzodiazepines. Neuropharmacology. 1979; 18(4):377-81. DOI: 10.1016/0028-3908(79)90145-x. View

14.

Raines A, Blake G, Richardson B, Gilbert M . Differential selectivity of several barbiturates on experimental seizures and neurotoxicity in the mouse. Epilepsia. 1979; 20(2):105-13. DOI: 10.1111/j.1528-1157.1979.tb04783.x. View

15.

Huang L, Barker J . Pentobarbital: stereospecific actions of (+) and (-) isomers revealed on cultured mammalian neurons. Science. 1980; 207(4427):195-7. DOI: 10.1126/science.7350656. View

16.

Simmonds M . Evidence that bicuculline and picrotoxin act at separate sites to antagonize gamma-aminobutyric acid in rat cuneate nucleus. Neuropharmacology. 1980; 19(1):39-45. DOI: 10.1016/0028-3908(80)90164-1. View

17.

Barker J, McBurney R . Phenobarbitone modulation of postsynaptic GABA receptor function on cultured mammalian neurons. Proc R Soc Lond B Biol Sci. 1979; 206(1164):319-27. DOI: 10.1098/rspb.1979.0108. View

18.

Briggs R, Castleden C, Kraft C . Improved hypnotic treatment using chlormethiazole and temazepam. Br Med J. 1980; 280(6214):601-4. PMC: 1600728. DOI: 10.1136/bmj.280.6214.601. View

19.

Schulz D, Macdonald R . Barbiturate enhancement of GABA-mediated inhibition and activation of chloride ion conductance: correlation with anticonvulsant and anesthetic actions. Brain Res. 1981; 209(1):177-88. DOI: 10.1016/0006-8993(81)91179-3. View

20.

Simmonds M . Distinction between the effects of barbiturates, benzodiazepines and phenytoin on responses to gamma-aminobutyric acid receptor activation and antagonism by bicuculline and picrotoxin. Br J Pharmacol. 1981; 73(3):739-47. PMC: 2071690. DOI: 10.1111/j.1476-5381.1981.tb16810.x. View