Losartan blocks diazepam and ethanol effects on air righting

We had previously discovered that both diazepam (DZ) and ethanol inhibited long-term potentiation (LTP) in medial perforant path-dentate granule cell synapses and the inhibition was mediated by angiotensin II (Ang II) because it could be blocked by pretreatment with losartan, an Ang II AT1 receptor antagonist. In addition, we had shown that ethanol intoxicating effects on air righting can be significantly reduced by losartan. Therefore, the purpose of the present study was to determine the effects of DZ, 1 and 2 mg/kg i.p., on air righting and also the effectiveness of losartan, 1, 5, 10, 15, and 20 mg/kg i.p., in blocking the impairment. Also, we examined the effects of losartan pretreatment on the intoxicating effects of 1 g/kg ethanol PO, a dose we had not studied previously. Low doses of ethanol, 1 g/kg, and DZ, 1 mg/kg, appear 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 impairment of air righting due to the larger dose of DZ, 2 mg/kg, was also blocked in a dose-dependent way by losartan; however, even combined large doses of both losartan, 20 mg/kg, and PD 123,319, 20 mg/kg, an Ang II AT2 receptor antagonist, were unable to completely block the initial impairment following the first 15 min after administration. Results can be interpreted in terms of low-dose anxiolytic effects of both 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 explanation will depend upon future research.