Differences of central mechanisms of the discriminative effects of benzodiazepines and barbiturates

Abstract

Our previous studies have shown that central-type benzodiazepine (BZD) receptors (CBR) and neurbsteroids capable of modulating GABAA receptor function are involved in the decrease of pentobarbital (PB)-induced sleep caused by social isolation stress in mice. In this study, to further clarify the mechanism underlying this decrease, we investigated the possible involvement of peripheraltype BZD receptors (PBR) which play an important role in neurosteroidogenesis in PB sleep in socially isolated mice. Socially isolated mice showed significantly shorter duration of PB-induced sleep than group-housed animals. When injected intracerebroventricularly (i.c.v.), FGIN-1–27 (FGIN, 25–100 nmol), a selective PBR agonist, and PK11195 (PK, 14–28 nmol), a PBR antagonist, and pregnenolone (PREG, 15–30 nmol), a neurosteroid precursor, dose-dependently normalized the PB sleep in isolated mice without having an effect on the group-housed animals. In contrast, pregnenolone sulfate (PS, 24 nmol), an endogenous neurosteroidal negative allosteric modulator of the GABAA receptor, reduced PB sleep in group-housed but not isolated mice. PS, at the same dose, significantly attenuated the effects of FGIN (100 nmol), PK (28 nmol) and PREG (30 nmol) in isolated mice, while FGIN (100 nmol), PK (28 nmol) and pregnenolone (30 nmol) significantly blocked the effect of PS (24 nmol) in group-housed mice. These results suggest that the PBR-mediated decrease in the genesis of neurosteroid(s) possessing a GABAA receptor agonistic profile is also partly involved in the down regulation of the GABAA receptor following long-term social isolation and contributes to the decrease of PB-induced sleep in isolation stressed mice.