Diazepam enhancement of low affinity GABA binding to rat brain membranes

Skerritt, John H.; Willow, Max; Johnston, Graham A.R.

doi:10.1016/0304-3940(82)90365-2

Cited by 161 publications

(38 citation statements)

References 11 publications

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“…47 Basically, the benzodiazepines potentiate the action of the inhibitory neurotransmitter γ-aminobutyric acid at its receptors. [48][49][50][51] In the cholinergic nervous system, diazepam probably decreases the synaptic release of ACh. 52 The main consequence of the action of benzodiazepines in CNS is hyperpolarization of neurons which makes them significantly less susceptible to cholinergically-induced depolarization.…”

Section: Treatment Of Organophosphate Poisoningmentioning

confidence: 99%

Unequal Efficacy of Pyridinium Oximes in Acute Organophosphate Poisoning

Antonijević¹,

Stojiljković²

2007

Clinical Medicine & Research

215

159

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Section: Treatment Of Organophosphate Poisoningmentioning

confidence: 99%

Unequal Efficacy of Pyridinium Oximes in Acute Organophosphate Poisoning

Antonijević¹,

Stojiljković²

2007

Clinical Medicine & Research

215

159

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“…BZs enhance binding to the low-affinity, but not the high-affinity GABA site (Skerritt et al, 1982;Skerritt & Johnston, 1983). Regional distributions of binding to the various components of the GABA receptor complex also suggest that it is the low-affinity GABA receptor to which BZ receptors are coupled (Olsen et al, 1990).…”

Section: Gabaa Receptormentioning

confidence: 99%

Changes in benzodiazepine‐GABA receptor coupling in an accumbens‐habenula circuit after chronic diazepam treatment

Brett

Pratt

1995

British J Pharmacology

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4 In general, the patterns of binding produced by the two different treatment routes were very similar. However, SR 95531 binding was lower in certain hippocampal fields in the i.p. treated animals compared to the rats implanted with silastic capsules. 5 It is concluded that repeated administration of diazepam evokes changes in benzodiazepine and GABA receptor coupling, and to a lesser extent changes in low affinity GABA binding, in certain interrelated brain structures of which an accumbens-habenula circuit is a central feature. These changes occur soon after the initiation of diazepam treatment, suggesting that they are unlikely to account for tolerance to the anxiolytic effects of diazepam but may trigger and/or accompany other critical neurochemical events.

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“…BZ and GABA receptors interact at the molecular level and probably co-exist as a functional unit in the neuronal membrane (Olsen, 1982). The GABA receptor is of the low affinity variety (Skerritt et al, 1982;Krogsgaard-Larsen et al, 1984). The affinity ofthe BZ receptor for its ligand is increased in the presence of GABA (see Brmstrup & Nielsen, 1983).…”

Section: Introductionmentioning

confidence: 99%

“…The converse, i.e. that BZs cause an increase in the affinity of the GABA receptor, probably occurs, but is less well documented (Olsen, 1982; but see Skerritt et al, 1982;Brmstrup & Nielsen, 1983;.…”

Section: Introductionmentioning

confidence: 99%

Electrophysiological studies in cultured mouse CNS neurones of the actions of an agonist and an inverse agonist at the benzodiazepine receptor

Jensen¹,

Lambert²

1986

British J Pharmacology

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1 The action ofagents which bind with the benzodiazepine (BZ) receptor has been investigated by use of intracellular recordings from dissociated mouse neurones grown in tissue culture. 2 The agents tested were midazolam (an agonist at the BZ receptor) and methyl 6,7-dimethoxy-4-ethyl-p-carboline-3-carboxylate (DMCM -an inverse agonist at the BZ receptor). These were applied to the neurone under study by one of the following methods: iontophoresis; pressure application of known concentrations from blunt pipettes; directly in the perfusing medium. 3 On only very few occasions did midazolam or DMCM have a direct effect on the membrane potential (EM) or conductance (GM) ofthe impaled neurone. For the neurones where direct effects were present, there was no consistent pattern of response. Neither substance affected the threshold for action potential generation.4 The effect of midazolam and DMCM on responses evoked by iontophoretic application of yaminobutyric acid (GABA) was also investigated. Three parameters were used to quantify GABA responses: the depolarization (VGABA); the increase in GM (&GABA) measured with constant current pulses; using voltage clamp, the GABA current (IGABA)-5 The GABA response should be quantified by a parameter which is linearly related to the number of GABA-operated channels which are conducting at any instant. VGABA does not fulfil this criterion. &GABA is an appropriate parameter, but is difficult to determine for large responses where the membrane is nearly short circuited. IGABA measured during voltage clamp fulfils this criterion. 6 Midazolam (> 10-6 M) reliably potentiated GABA responses with a parallel shift to the left of the dose-response curve. This is in agreement with biochemical studies where BZs increase the affinity of the GABA receptor for its ligand. 7 The effect of DMCM on GABA responses was more variable. In the majority of cases GABA responses were reduced by DMCM. The threshold dose for this depression was usually around 10-6 M, but was sometimes as low as 10-8 M. Dose-response curves of IGABA or gGABA showed the inhibition to be of a non-competitive nature. The maximum inhibition achieved was around 70%. 8 For a given neurone, and at doses which did not necessarily cause a reduction of the response to GABA, DMCM could antagonize the potentiating action of midazolam on GABA responses. A possible interpretation is that more than one BZ site per receptor complex must be occupied by a BZ agonist (or inverse agonist) before the functional changes for the complex as a whole can occur.9 Desensitization to GABA was increased by midazolam.

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Diazepam enhancement of low affinity GABA binding to rat brain membranes

Cited by 161 publications

References 11 publications

Unequal Efficacy of Pyridinium Oximes in Acute Organophosphate Poisoning

Unequal Efficacy of Pyridinium Oximes in Acute Organophosphate Poisoning

Changes in benzodiazepine‐GABA receptor coupling in an accumbens‐habenula circuit after chronic diazepam treatment

Electrophysiological studies in cultured mouse CNS neurones of the actions of an agonist and an inverse agonist at the benzodiazepine receptor

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