Are benzodiazepines GABA antagonists?

Kozhechkin, S. N.; Ostrovskaya, R. U.

doi:10.1038/269072a0

Cited by 54 publications

(8 citation statements)

References 9 publications

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“…Similar complex interactions of benzodiazepines have been reported in other studies. Thus benzodiazepines have been proposed on the one hand to mimic Dray & Straughan, 1976) or facilitate (Costa, Guidotti, Mao & Suria, 1975; Haefely, Kulczar, Mohler, Pieri, Polc & Schaffner, 1975;Choi Farb & Fischbach, 1977), and on the other to depress (Giihwiler, 1976;Steiner & Felix, 1976) the action of GABA or glycine, though the mimetic and antagonistic activities have been disputed (Haefely, Pieri, Polc & Schaffner, 1976;Curtis, Game & Lodge, 1976;Curtis, Lodge, Johnston & Brand, 1976;Hunt & Raynaud, 1977;Kozhechkin & Ostrovskaya, 1977). From the present data the benzodiazepines seem also to have the additional property of reversing the action of antagonists.…”

Section: Discussionmentioning

confidence: 68%

Reversal of the Action of Amino Acid Antagonists by Barbiturates and Other Hypnotic Drugs

Bowery

Dray

1978

British J Pharmacology

106

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1 The effects of pentobarbitone (PB) and other sedative/hypnotic drugs have been examined in relation to y-aminobutyric acid (GABA) in vitro on the superfused isolated superior cervical ganglion of the rat and in vivo on single units in the brain stem of the anaesthetized rat. 2 PB, and other barbiturates, depolarized the ganglion in a dose-dependent manner (threshold concentration 100-300 pM, cf. GABA depolarization threshold 1 lIM). The depolarization was reduced in the presence of the selective GABA antagonist (+ )-bicuculline methochloride (Bic). Other non-barbiturate sedatives e.g. chlordiazepoxide, amitriptyline, promethazine at concentrations up to 2mM produced no depolarization.3 PB, tested at concentrations up to 80 gM, produced variable effects on the dose-response curve to GABA. On most occasions a slight potentiation occurred in responses to low concentrations of GABA (below 10 JM) coupled with a depression in the responses to concentrations of GABA greater than 10 pM. 4 Superfusion with PB in the presence of Bic reversed the depression in the response to GABA produced by Bic. This reversal phenomenon occurred at concentrations of PB too low to depolarize the ganglion and was dependent not only on the concentration of PB but also on that of Bic. 5 The reversal potency within an homologous series of barbiturates increased with the size of the alkyl substituent (R2) at C5 on the barbiturate ring. The most potent occurred when the substituent contained 5 carbon atoms (pentobarbitone and amylobarbitone); above this, activity decreased. 6 PB reversed the effects of the other GABA antagonists, tetramethylenedisulphotetramine and isopropyl bicyclophosphate and also the non-selective antagonism produced by strychnine. A concomitant reduction by strychnine of responses to the cholinomimetic, carbachol, was not reversed by PB. 7 Non-barbiturate sedative/hypnotics also reversed the GABA antagonism produced by Bic. The benzodiazepines were effective at lower concentrations than PB (chlordiazepoxide threshold concentration 0.5 JIM, cf. PB 5 gM), however, they only produced a partial reversal even at concentrations much higher than the maximally effective concentration of PB. 8 The Bic reversal effect of chlordiazepoxide (and other benzodiazepines) lasted many hours after removal from the superfusion solution. By contrast the effect of PB lasted only 15-30min after its removal.* 9 Chlordiazepoxide (30 gM) applied in the absence of Bic did not affect the response to GABA but did reduce the depression produced by the subsequent application of Bic even though the chlordiazepoxide had been removed 40 min earlier. 10 In the rat brain stem in vivo PB, applied iontophoretically in amounts which neither decreased the spontaneous neuronal firing rate nor affected the response to GABA or glycine, reversed the GABA antagonism induced by iontophoretic application of Bic (in all 23 neurones tested). PB also reversed the antagonism produced by strychnine of responses to glycine although this was less readily observed (5 out...

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Section: Discussionmentioning

confidence: 68%

Reversal of the Action of Amino Acid Antagonists by Barbiturates and Other Hypnotic Drugs

Bowery

Dray

1978

British J Pharmacology

106

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“…physiological (Choi et al, 1977;Kozhechkin and Ostrovskaya, 1977;MacDonald and Barker, 1978;Polc et al, 1974) and biochemical (Costa et al, 1975;Costa and Guidotti, 1979) experiments to interfere with GABAergic transmission, have no effect on either L-glutamate-1-decarboxylase (EC 4.1.1.15;GAD) (Peritit et al, 1977) or 4-aminobutyrate: 2-oxoglutarate aminotransferase (EC 2.6.1.19; GABA-T) activity (Sawaya et al, 19751, on GABA levels, GABA uptake (Iversen and Johnston, 1971) or GABA release (Olsen et al, 1978). Moreover, a direct GABA-mimetic action of the benzodiazepines has been excluded because benzodiazepines (up to l t 4 M) added to brain synaptic membranes failed to displace CJHIGABA from high-affinity receptor sites (Snyder and Enna, 1975).…”

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confidence: 99%

The Use of Inhibitors of GABA‐Transaminase for the Determination of GABA Turnover in Mouse Brain Regions: An Evaluation of Aminooxyacetic Acid and Gabaculine

Bernasconi

Maître

Martin

et al. 1982

Journal of Neurochemistry

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The accumulation of γ‐aminobutyric acid (GABA) after inhibition of GABA‐T (4‐aminobutyrate: 2‐oxoglutamate aminotransferase, EC 2.6.1.19) by various doses of aminooxyacetic acid (AOAA) and gabaculine was studied in four different regions of the mouse brain. The dose‐response curve for GABA accumulation after treatment with AOAA was linear up to 10 mg/kg i.p., and then leveled off. The increase in GABA accumulation after gabaculine treatment was linear up to 100 mg/kg i.p. No further increase was observed with doses up to 300 mg/kg i.p. The selectivity of both GABA‐T inhibitors was assessed by measuring their effects on the content of free amino acids in mouse brain. Apart from the substantial increase in the GABA concentration, there were significant decreases in the content of glutamic acid, aspartic acid, alanine and glutamine, and an increase in ornithine content after administration of gabaculine. The same changes in amino acid content were observed after treatment with AOAA, but the level of lysine was also increased and the change in alanine level was biphasic. All these changes, however, were very small compared with the large increase in GABA level. A method for estimating the rate of the GABA turnover in vivo by measuring the initial rate of GABA accumulation after administration of AOAA or gabaculine is proposed, and the validity of the two techniques is discussed. The effect of diazepam on GABA levels and on the gabaculine‐induced accumulation of GABA was studied. The results obtained with diazepam show that this method can provide valuable insight into the effects of drugs on GABAergic mechanisms in vivo.

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“…Both diazepan and muscimol in nonsedative doses facilitate be havioral responses that are repressed by con ditioned fear (27,28) and increase the cata lepsy and analgesia induced by morphine (2,3). Diazepam and muscimol decrease the levels of cerebellar cGMP by activation of intracerebellar GABAergic mechanisms (1) and finally 1,4-benzodiazepines mimic the action o f GA BA in a number o f brain nuclei or cell cultures where GABAergic mechanisms are operative (5,8,10,11,17,18,20). These results which were obtained with the collaboration o f Dr. Brodie (1) led us to believe that 1,4-benzodiazepines enhance the action o f G A B A at postsynaptic receptors, because they modify a complex chain of events that participate in eliciting GABA responses.…”

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confidence: 99%

1,4-Benzodiazepines and Gamma-Aminobutyric Acid: Pharmacological and Biochemical Correlates

Guidotti¹,

Baraldi²,

Costa³

1979

Pharmacology

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The high affinity receptors or GABA present in brain interact with an endogenous thermostable inhibitor (GABA modulin) which allosterically modifies GABA binding sites. This is the type of GABA receptor that we term GABA₂ receptor in comparison to GABA₁ receptor which has low affinity for GABA and is not regulated by GABA modulin. The 1,4-benzodiazepines interact competitively with GABA modulin and thereby modify GABA₂ receptor binding. In contrast the occupancy of GABA receptor increases the affinity of 1,4-benzodiazepine receptors for their specific agonist. The GABA modulin and both GABA receptors are located on the membranes of C₆ and NB_2a cells. The NB_2a cell membranes also contain Cl^– ionophore, thus the complete receptor complex is present in the membranes of NB_2a cell clone. It was proposed that the inability of clonazepam to displace ³H-diazepam from specific binding sites characterizes the nonneuronal 1,4-benzodiazepine receptor. This characterization was shown to relate to the properties of other membrane components rather than to the characteristics of the specific benzodiazepine receptors.

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Are benzodiazepines GABA antagonists?

Cited by 54 publications

References 9 publications

Reversal of the Action of Amino Acid Antagonists by Barbiturates and Other Hypnotic Drugs

Reversal of the Action of Amino Acid Antagonists by Barbiturates and Other Hypnotic Drugs

The Use of Inhibitors of GABA‐Transaminase for the Determination of GABA Turnover in Mouse Brain Regions: An Evaluation of Aminooxyacetic Acid and Gabaculine

1,4-Benzodiazepines and Gamma-Aminobutyric Acid: Pharmacological and Biochemical Correlates

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