Impaired retention by angiotensin II mediated by the AT1 receptor.
ABSTRACT We demonstrated previously that hippocampal dentate gyrus neurons were sensitive to angiotensin II (AII) and recently discovered that AII applied directly to the dentate gyrus inhibited granule cell long-term potentiation induction and that the inhibition is mediated by the AT1 receptor and can be blocked by losartan, a specific AT1 antagonist. The purpose of the present study was to examine the effects of AII administered directly to the dentate gyrus, 1, 5, 50, 150, and 300 ng, on the retention of an inhibitory shock avoidance response and to determine if the resultant impairment of retention can be blocked by losartan. A total of 12 groups of rats in three experiments were studied. Three independent repetitions of 5 ng AII administered bilaterally to the dentate gyrus demonstrate a clear impairment of retention under these experimental conditions and that the impairment can be effectively prevented by pretreatment with 20 mg/kg of losartan IP.
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ABSTRACT: Results of a previous study showed that angiotensin II (AII) inhibited the induction of long-term potentiation (LTP) in hippocampal granule cells in response to dorsomedial perforant path stimulation in urethane-anesthetized rats. The results of present experiments demonstrate a dose-dependent inhibition of LTP induction under the same conditions due to ethanol (EtOH) administered by stomach tube and diazepam (DZ) injected IP. The inhibition of LTP induction by EtOH and DZ can be blocked by saralasin (SAR) applied directly to the dorsal hippocampus and by lorsartan (DuP 753) administered IP. Lorsartan or a metabolite crosses the blood-brain barrier because it also blocks the inhibition of LTP induction due to AII administration directly into the dorsal hippocampus. Lorsartan is a competitive antagonist of the AT1 subtype AII receptor. Therefore, the AII and the EtOH and DZ inhibition of LTP induction are mediated by the AII subtype receptor AT1. AIII and the AT2 antagonist PD123319 did not produce any significant effects. These in vivo effects can be reproduced in brain slices and therefore cannot be attributed to other factors, such as the urethane. In addition, electrical stimulation of the lateral hypothalamus (LH) inhibits LTP induction, and the inhibition can be blocked by SAR. These data on LH stimulation indicate that LH AII-containing neurons send axons into the hippocampus that inhibit the induction of LTP. These results not only provide new information on a neurotransmitter involved in the amnesic effects of benzodiazepines and ethanol-induced memory blackouts, but also testable hypotheses concerning recent observations that angiotensin converting enzyme (ACE) inhibitors elevate mood and improve certain cognitive processes in the elderly.Pharmacology Biochemistry and Behavior 07/1993; 45(2):455-64. · 2.61 Impact Factor
- 5 11/2004; Academic Press.
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ABSTRACT: Results of a previous study showed that ethanol inhibition of hippocampal long-term potentiation (LTP) induction was mediated by angiotensin II (AII) and the AT1 subtype receptor because it was blocked by losartan, a specific AT1 antagonist. Because LTP is an important hippocampal function involved in the memory process and other behaviors, it is possible that losartan might block some of the directly observable ethanol-induced changes in rat behavior. Results demonstrate that losartan can effectively block some of the intoxicating effects of low doses of ethanol, 2 g/kg PO or IP. However, even a high dose of losartan 20 mg/kg IP, did not reduce significantly any of the intoxicating effects of the higher dose of 4 g/kg administered by gavage. Higher doses of ethanol might be more difficult to block because of a direct effect on the post synaptic membrane.Alcohol 01/1994; 11(4):343-6. · 2.26 Impact Factor