THE ROLE OF GABA-A AND MITOCHONDRIAL DIAZEPAM-BINDING INHIBITOR RECEPTORS ON THE EFFECTS OF NEUROSTEROIDS ON FOOD-INTAKE IN MICE

The present studies were undertaken to investigate the neuroactive ste roidal modulation of feeding behavior and possible involvement of gamm a-aminobutyric acid type-A (GABA-A) and mitochondrial diazepam binding inhibitor (DBI) receptors (MDR) in food-deprived male mice. Allopregn anolone (0.5-2 mg/kg), a neurosteroid, progesterone (1-10 mg/kg), a ne urosteroid precursor, and 4'-chlordiazepam (0.25-1 mg/kg), a specific high affinity MDR agonist, produced a dose-dependent hyperphagic effec ts. In contrast, neurosteroids pregnenolone sulfate (PS) (1-10 mg/kg) and dehydroepiandrosterone sulfate (DHEAS) (1-10 mg/kg) produced a hyp ophagic effect, in a dose-dependent manner. The allopregnanolone-, pro gesterone- and 4'-chlordiazepam-induced hyperphagic effect was blocked by picrotoxin (1 mg/kg), a GABA-A chloride channel antagonist, but no t by flumazenil (2 mg/kg), a benzodiazepine (BZD) antagonist. The 4'-c hlordiazepam-induced hyperphagic effect was prevented by pretreatment with PK11195 (2 mg/kg), a selective partial MDR antagonist. The hypoph agic effect of DHEAS(10 mg/kg) was reversed by dizocilpine (10 mu g/kg ), an NMDA receptor antagonist, but resistant to muscimol (0.1 mg/kg), a selective GABA-A receptor agonist. In contrast, the PS (10 mg/kg)-i nduced hypophagic response was resistant to dizocilpine, but sensitive to muscimol (0.1 mg/kg). Both the sulfated neurosteroids PS and DHEAS also reversed the hyperphagic effect of allopregnanolone. In addition , the BZD agonist triazolam (0.05-0.25 mg/kg) also produced a flumazen il- and picrotoxin-sensitive hyperphagic effects, thereby suggesting t he changes in feeding behavior by neurosteroids represent GABA-A recep tor mediated hyperphagic action. Although the possible antistress or a nxiolytic actions of neurosteroids may confound the hyperphagia, behav ioral effects observed were specific to food because the mice were ado pted to the test environment and diet, and of a possible variation bet ween various neurosteroids in the extent to which antistress or anxiol ytic effect produced at hyperphagic doses. The hyperphagic effects of progesterone and 4'-chlordiazepam resembled that of neurosteroid allop regnanolone. Therefore, the effect of progesterone may be imputed to i ts metabolism to allopregnanolone, while the 4'-chlordiazepam-induced hyperphagic response is related to its MDR-stimulated neurosteroidogen esis and subsequent modulation of GABA-A receptors. The hypophagic res ponse following DHEAS may, at least partly, involve an NMDA receptor m echanism. However, PS-induced hypophagia may be mediated by GABA-A or other receptor systems. These data suggest a pivotal role for GABA-A a nd mitochondrial DBI receptors in the hyperphagic effects of neuroster oids and reinforces a role for endogenous neurosteroids in regulating feeding behavior. Future studies may lead to the development of neuros teroid-based anorectic/hyperphagic agents for therapeutic use.