PARTICIPATION OF MITOCHONDRIAL DIAZEPAM BINDING INHIBITOR RECEPTORS IN THE ANTICONFLICT, ANTINEOPHOBIC AND ANTICONVULSANT ACTION OF 2-ARYL-3-INDOLEACETAMIDE AND IMIDAZOPYRIDINE DERIVATIVES

The 2-hexyl-indoleacetamide derivative, FGIN-1-27 -di-n-hexyl-2-(4-flu orophenyl)indole-3-acetamide], and the imidazopyridine derivative, alp idem, both bind with high affinity to glial mitochondrial diazepam bin ding inhibitor receptors (MDR) and increase mitochondrial steroidogene sis. Although FGIN-1-27 is selective for the MDR, alpidem also binds t o the allosteric modulatory site of the gamma-aminobutyric acid(A) rec eptor where the benzodiazepines bind. FGIN-1-27 and alpidem, like the neurosteroid 3alpha,21-dehydroxy-5alpha-pregnane-20-one (THDOC), clona zepam and zolpidem (the direct allosteric modulators of gamma-aminobut yric acid(A) receptors) delay the onset of isoniazid and metrazol-indu ced convulsions. The anti-isoniazid convulsant action of FGIN-1-27 and alpidem, but not that of THDOC, is blocked by PK 11195. In contrast, flumazenil blocked completely the anticonvulsant action of clonazepam and zolpidem and partially blocked that of alpidem, but it did not aff ect the anticonvulsant action of THDOC and FGIN-1-27. Alpidem, like cl onazepam, zolpidem and diazepam, but not THDOC or FGIN-1-27, delay the onset of bicuculline-induced convulsions. In two animal models of anx iety, the neophobic behavior in the elevated plus maze test and the co nflict-punishment behavior in the Vogel conflict test, THDOC and FGIN- 1-27 elicited anxiolytic-like effects in a manner that is flumazenil i nsensitive, whereas alpidem elicited a similar anxiolytic effect, but is partially blocked by flumazenil. Whereas PK 11195 blocked the effec t of FGIN-1-27 and partially blocked alpidem, it did not affect THDOC in both animal models of anxiety. Because both alpidem and FGIN-1-27 b ind to MDR and stimulate mitochondrial steroid biosynthesis, the behav ioral effects of FGIN-1-27 and in part alpidem may be mediated via MDR -induced steroidogenesis.