Effect of centrally acting drugs on the uptake of γ‐aminobutyric acid (GABA) by slices of rat cerebral cortex
Open Access
- 1 February 1973
- journal article
- Published by Wiley in British Journal of Pharmacology
- Vol. 47 (2), 229-239
- https://doi.org/10.1111/j.1476-5381.1973.tb08320.x
Abstract
1 The effects of centrally acting drugs on the uptake of 3H-γ-aminobutyric acid (GABA) by slices of rat cerebral cortex have been studied. 2 Many centrally acting drugs at concentrations of 0·1–1·0 mm significantly inhibited the uptake of 3H-GABA by cortical slices, but the only classes of drugs in which all members consistently produced inhibition of uptake were the phenothiazines, tricyclic antidepressants, and butyrophenones. 3 The receptor blocking drugs; phentolamine, propranolol, thymoxamine, mepyramine, and diphenhydramine at concentrations of 0–5–1 mm also significantly reduced the uptake of 3H-GABA. However, atropine, hexamethonium and (+)-tubocurarine had little effect on the uptake of 3H-GABA by cortical slices. 4 Centrally acting drugs, which did not significantly inhibit 3H-GABA uptake, included barbiturates, local anaesthetics, hallucinogens, monoamine oxidase inhibitors, anticonvulsants, and convulsants (except picrotoxin). 5 Chlorpromazine, prochlorperazine, l-2,4,diaminobutyric acid, desmethylimipramine, and iprindole inhibited the uptake of 3H-GABA by 50% (IC50) at concentrations of 30–100 μm. The most potent inhibitor of 3H-GABA uptake was p-chloromercuriphenylsulphonate (IC50 = 18 μM). 6 With the exception of l-2,4,diaminobutyric acid, an outstanding characteristic of these drugs was their complete lack of specificity. Thus at the IC50 for GABA, p-chloromercuriphenylsulphonate, chlorpromazine, prochlorperazine, iprindole, desmethylimipramine, apomorphine and diphenylhydramine also inhibited the uptake of radioactive glycine, alanine, noradrenaline, and 5-hydroxytryptamine. The uptake of the latter two compounds was often inhibited to a greater extent than GABA, glycine and alanine. 7 Kinetic analysis indicated that the inhibition of 3H-GABA by p-chloromercuriphenylsulphonate, chlorpromazine, and desmethylimipramine was non-competitive. l-2,4,Diaminobutyric acid reduced the uptake of 3H-GABA by a ‘mixed’ type of inhibition. 8 The present results do not support the suggestion that some centrally acting drugs may produce their effects by reducing the uptake of GABA in the brain after its release from inhibitory nerve terminals. Conceivably, the design of compounds which interfere effectively with the mechanisms of GABA operated synapses may lead to the introduction of whole new groups of centrally acting drugs.Keywords
This publication has 23 references indexed in Scilit:
- A comparison of the inhibitory activities of iprindole and imipramine on the uptake of 5-hydroxytryptamine and noradrenaline in brain slicesLife Sciences, 1971
- GLYCINE UPTAKE IN RAT CENTRAL NERVOUS SYSTEM SLICES AND HOMOGENATES: EVIDENCE FOR DIFFERENT UPTAKE SYSTEMS IN SPINAL CORD AND CEREBRAL CORTEXJournal of Neurochemistry, 1971
- GABA UPTAKE IN RAT CENTRAL NERVOUS SYSTEM: COMPARISON OF UPTAKE IN SLICES AND HOMOGENATES AND THE EFFECTS OF SOME INHIBITORSJournal of Neurochemistry, 1971
- FACTORS THAT AFFECT THE BINDING AND UPTAKE OF GABA BY BRAIN TISSUE1Journal of Neurochemistry, 1971
- Localizing 3H-GABA in Nerve Terminals of Rat Cerebral Cortex by Electron Microscopic AutoradiographyNature, 1971
- CNS at the Cellular Level: Identity of Transmitter AgentsAnnual Review of Physiology, 1970
- SUBCELLULAR DISTRIBUTION OF ENDOGENOUS AND [3H] γ‐AMINOBUTYRIC ACID IN RAT CEREBRAL CORTEXJournal of Neurochemistry, 1969
- THE UPTAKE OF [3H]GABA BY SLICES OF RAT CEREBRAL CORTEXJournal of Neurochemistry, 1968
- THE METABOLISM OF γ‐AMINOBUTYRIC ACID (GABA) IN THE LOBSTER NERVOUS SYSTEM–UPTAKE OF GABA IN NERVE‐MUSCLE PREPARATIONS1Journal of Neurochemistry, 1968
- OCCLUSION AND METABOLISM OF γ‐AMINOBUTYRIC ACID BY BRAIN TISSUE*Journal of Neurochemistry, 1958