Influence of oxygenated fuel additives and their metabolites on γ-aminobutyric acidA (GABAA) receptor function in rat brain synaptoneurosomes

Joseph V. Martin, Sonal V. Iyer, Patrick J. McIlroy, M. Michael Iba

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8 Scopus citations


Experimental and occupational inhalational exposure to oxygenate fuel additives in reformulated gasoline has been reported to induce neurological symptoms (e.g., headache, nausea, dizziness). We reported previously that the ether additives (methyl-t-butyl ether (MTBE), t-amyl-methyl ether (TAME) and ethyl-t-butyl ether (ETBE)) and their metabolites (t-amyl alcohol (TAA), t-butyl alcohol (TBA) and ethanol) alter the binding of [3H]t- butylbicycloorthobenzoate ([3H]TBOB), a ligand for the γ-aminobutyric acidA (GABAA) receptor in rat brain membrane preparations. To more directly assess the effects of the ethers and their alcohol precursors on GABAA receptor function, the uptake of 36Cl- was measured in synaptoneurosomes, a preparation of closed membrane sacs comprised of pre- and postsynaptic membranes from adult rat cerebral cortex. Each of the compounds caused a concentration-dependent enhancement of muscimol-stimulated uptake of 36Cl-, which diminished with further increasing concentrations. The potency of the enhancement by the compounds was in the rank order: MTBE=TAME>TAA= ETBE>TBA>ethanol. The half-maximally effective concentration (EC 50) for the facilitation of muscimol-stimulated 36Cl - uptake ranged from 0.06 to 3mM, and that for the higher-dose inhibitory effect (IC50) ranged from 3 to 50mM. The facilitatory concentrations of the compounds are in the range of the blood concentrations reported in experimental animals after exposures known to induce CNS effects such as ataxia. The results suggest a potential role of the GABAA receptor in some of the reported neurotoxic effects of gasoline additives.

Original languageEnglish (US)
Pages (from-to)209-217
Number of pages9
JournalToxicology Letters
Issue number3
StatePublished - Mar 7 2004

All Science Journal Classification (ASJC) codes

  • Toxicology


  • Ethyl-t-butyl ether (ETBE)
  • Methyl-t-butyl ether (MTBE)
  • Oxygenates
  • t-Amyl alcohol (TAA)
  • t-Amyl-methyl ether (TAME)
  • t-Butyl alcohol (TBA)
  • γ-Aminobutyric acid (GABA)

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