Reversal of GABA-mediated inhibition of the electrically and potassium chloride evoked [3H]-GABA release from rat substantia nigra slices by DL-3-hydroxy-3-phenyl pentanamide.
The phenyl alcohol amides, DL-2-hydroxy-2-phenyl butyramide (CAS 52839-87-9), DL-3-hydroxy-3-phenyl pentanamide (CAS 131802-69-2, DL-HEPP) and DL-4-hydroxy-4-phenyl hexanamide (CAS 67880-30-2) and their fluorine and chlorine analogs, at a concentration of 100 micromol/L, did not displace [3H]-gamma-aminobutyric acid ([3H]-GABA, CAS 108158-36-7) from GABAA receptors and only weakly displaced [3H]-GABA and [3H]-CGP62349 (CAS 186986-97-0), a GABAB receptor antagonist, from GABAB receptors in rat brain crude synaptic membranes. The electrically and potassium chloride (15 mmol/L) evoked [3H]-GABA release in the presence of DL-HEPP, GABA and GABAB receptor ligands from rat brain substantia nigra (SN) slices was studied. R-Baclofen (CAS 69308-37-8) (10 micromol/L), a GABAB receptor agonist, produced an inhibition of the electrically evoked [3H]-GABA release and this inhibition was blocked by CGP 55845A (CAS 149184-22-5) (10 micromol/L), a GABAB receptor antagonist, but was not affected by DL-HEPP (100 micromol/L). CGP 55845A (10 micromol/L) did not alter the electrically evoked [3H]-GABA release in the absence of baclofen. The addition of DL-HEPP (100 micromol/L) alone did not affect the electrically-evoked release of [3H]-GABA release control, but it was able to significantly reduce the inhibitory effect of GABA (CAS 56-12-2) (10 micromol/L) on [3H]-GABA release evoked both by electrical and potassium chloride stimulation, in the presence of tiagabine (CAS 115103-54-3) (10 micromol/L), a GABA uptake blocker. In three preliminary experiments, bicuculline (CAS 485-49-4) (10 micromol/L) and picrotoxinin (CAS 17617-45-7) (10 micromol/L), two GABAA antagonists, inhibited the electrically evoked release of [3H]-GABA from rat SN slices, and DL-HEPP (100 micromol/L) reversed this inhibition. The mechanism of action of DL-HEPP is not known but, it might act as a negative GABA modulator in rat brain slices.
Meza-Toledo
Sergio E
SE
Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas del Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala, México D. F., México. smezat@ipn.mx
Bowery
Norman G
NG
D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001565:Benzoates / Q000378:metabolism / Q000494:pharmacology; D003627:Data Interpretation, Statistical; D004558:Electric Stimulation; D018756:GABA Antagonists / Q000494:pharmacology*; D058787:GABA-A Receptor Antagonists; D058788:GABA-B Receptor Antagonists; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D009943:Organophosphorus Compounds / Q000378:metabolism / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D013570:Synaptic Membranes / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000502:physiology*
D000577:Amides; D001565:Benzoates; C114540:CGP 62349; C528796:DL-3-hydroxy-3-phenyl pentanamide; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D058788:GABA-B Receptor Antagonists; D008024:Ligands; D009943:Organophosphorus Compounds; D005680:gamma-Aminobutyric Acid; D011189:Potassium Chloride