LOSARTAN BLOCKS DIAZEPAM AND ETHANOL EFFECTS ON AIR RIGHTING

We had previously discovered that both diazepam (DZ) and ethanol inhib ited long-term potentiation (LTP) in medial perforant path-dentate gra nule cell synapses and the inhibition was mediated by angiotensin II ( Ang II) because it could be blocked by pretreatment with losartan, an Ang II AT(1) receptor antagonist. In addition, we had shown that ethan ol intoxicating effects on air righting can be significantly reduced b y losartan. Therefore, the purpose of the present study was to determi ne the effects of DZ, 1 and 2 mg/kg IP, on air righting and also the e ffectiveness of losartan, 1, 5, 10, 15, and 20 mg/kg IF, in blocking t he impairment. Also, we examined the effects of losartan pretreatment on the intoxicating effects of 1 g/kg ethanol PO, a dose we had not st udied previously. Low doses of ethanol, 1 g/kg, and DZ, 1 mg/kg, appea r to be equivalent in the impairment of air righting; and the effects of both drugs were blocked by losartan, in a dose-dependent way. The i mpairment of air righting due to the larger dose of DZ, 2 mg/kg, was a lso blocked in a dose-dependent way by losartan; however, even combine d large doses of both losartan, 20 mg/kg, and PD 123,319, 20 mg/kg, an Ang II AT(2) receptor antagonist, were unable to completely block the initial impairment following the first 15 min after administration. R esults can be interpreted in terms of low-dose anxiolytic effects of b oth drugs and a mild sedation due to the high dose of DZ. The role of the hippocampus in air righting is still not clear and further explana tion will depend upon future research. (C) 1998 Elsevier Science Inc.