Air righting: role of the NMDA receptor channel and hippocampal LTP.

Air righting results in an animal turning over when it is dropped from a height in an inverted position. In the rat, air righting is a complex set of movements that depends only on an intact labyrinth and the normal vestibular input. Visual modulation of air righting does not develop until adulthood; and the ability to estimate the time to impact requires bilateral visual cues and indicates that air righting is a complex set of perceptually controlled movements and learning. The general purpose of this study was to determine the role of the NMDA receptor-ion channel on air righting and hippocampal LTP. Specifically: to measure the effects of various doses of CPP, an NMDA receptor antagonist, and MK-801, an ion channel blocker, on (a) air righting and (b) hippocampal LTP induction in medial perforant path-granule cell synapses. The following doses were used: CPP-0, 1, 5, and 10 mg/kg i.p.; MK-801-0. 0, 0.05, 0.1, 0.2, 0.3, 0.4, and 0.5 mg/kg i.p. Data were analyzed by appropriate ANOVAs and post hoc tests. Results were significant and demonstrate dose-dependent impairment of air righting and inhibition of LTP for both CPP and MK-801, implicating the role of the NMDA receptor and Na(+)/K(+)/Ca(2)+ channel in these effects. Air righting is a complex behavior and appears to be dependent upon NMDA mediated hippocampal LTP.

Nicotine blocks ethanol and diazepam impairment of air righting and ethanol impairment of maze performance.

Results of our previous research in rats demonstrate the following: (a) Angiotensin II (Ang II) inhibits long term potentiation (LTP) in dentate granule cell-perforant path synapses and that this inhibition can be blocked by losartan, an Ang II AT1 receptor antagonist; (b) both ethanol and diazepam inhibit LTP induction and this inhibition can be blocked by losartan; (c) impairment of air righting by ethanol and diazepam (DZ) and eight-arm radial maze performance by ethanol can be blocked by pretreatment with losartan: (d) inhibition of dentate granule cell LTP by Ang II can also be prevented by pretreatment with nicotine. Therefore, it seemed reasonable to hypothesize that ethanol and diazepam impairment of air righting and maze performance might also be blocked by pretreatment with nicotine. The purpose of the present study was to determine the effects of nicotine 0.1, 0.2, 0.3, and 0.4 mg/kg subcutaneously (SC) on 2.0 g/kg ethanol per os (PO) and 1.0 and 2.0 mg/kg DZ intraperitoneally (i.p.) induced impairment of air righting; and to determine if the impaired maze performance due to 2.0 g/kg ethanol PO could be prevented by pretreatment with 0.4 mg/kg of nicotine, SC. Results confirm the hypothesis that moderate doses of ethanol, 2.0 g/kg PO, and DZ, 1.0 mg/kg i.p. impair air righting and that the impairment can be prevented by pretreatment with nicotine SC. Nicotine was not effective in blocking the 2.0 mg/kg DZ impairment of air righting. Nicotine, 0.4 mg/kg SC, prevented the impaired maze performance induced by 2.0 g/kg ethanol PO.

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.

Losartan improves the performance of ethanol-intoxicated rats in an eight-arm radial maze.

Results of previous research demonstrate that angiotensin II (Ang II) inhibits long-term potentiation (LTP) in medial perforant path-dentate gyrus granule cells and that the inhibition is mediated by the AT1 receptor because it can be blocked by losartan, a specific AT1 receptor antagonist. Ang II impairment of retention and ethanol inhibition of LTP can both be blocked by pretreatment with losartan. Because losartan pretreatment also prevents ethanol intoxication measured in terms of the aerial righting reflex, the purpose of the present study was to assess the effects of 2.0 g/kg ethanol administered by gavage on performance in an eight-arm radial maze, and then to determine the effectiveness of losartan in reducing the impairment of the learning and memory process. Results confirmed the general hypothesis that ethanol-induced cognitive deficits are mediated by Ang II and the AT1 receptor and that the impairment can be reduced by pretreatment with losartan.

Angiotensin II antagonists block ethanol effects on the aerial righting reflex.

The purpose of the present study was to determine the effects of an angiotensin II (AII) AT1 antagonist, losartan 10, 15, and 20 mg/kg IP, and the AII AT2 antagonist, PD 123319, 20 mg/kg IP on ethanol (EtOH) intoxication as measured by the aerial righting reflex in male rats. EtOH (25%), 2.0 g/kg, was administered by stomach tube under mild metaphane anesthesia and the aerial righting reflex was determined at 30-min intervals for 3.5 h. The AII antagonists were administered IP 2 h before the EtOH. There were six groups of 10 rats each: EtOH alone, 10, 15, or 20 mg/kg losartan plus ethanol, 20 mg/kg losartan plus 20 mg/kg PD 123319 plus EtOH, and 20 mg/kg losartan alone. Data were analyzed by a two-way ANOVA with repeated measures on one factor, time. Results show a clear intoxicating effect of ethanol on the aerial righting reflex that was blocked significantly by losartan in a dose-dependent way. Losartan alone had no observable effect. The administration of both antagonists, losartan and PD 123319 injected IP in two different sites, completely blocked the EtOH effect on the aerial righting reflex. The involvement of AII in the mediation of EtOH intoxication effects on the aerial righting reflex supports results of our previous studies on the effects of EtOH on open field behavior, AII impairment of the retention of an inhibitory shock avoidance response, and AII inhibition of hippocampal granule cell long-term potentiation, all of which can be blocked by losartan.