Pretreatment with aldosterone or corticosterone blocks the memory-enhancing effects of nimodipine, captopril, CGP 37 849, and strychnine in mice

Abstract

Oral pretreatment with aldosterone or corticosterone blocked the memory-enhancing effects of the calcium antagonist nimodipine, the ACE inhibitor captopril, the NMDA blocker CGP 37,849, and the glycine antagonist strychnine in a passive-avoidance test in mice. The memory-disturbing effects of phenobarbitone, diazepam, CGP 37,849 and scopolamine were not influenced by the hormonal pretreatment. These findings could indicate the involvement of a steroid-sensitive mechanism in drug-induced improvement of memory. In the light of clinical observations showing elevated cortisol levels in Alzheimer patients, the results might also explain why only a limited number of these patients respond to therapy with memory enhancers.

Delayed emergence of effects of memory-enhancing drugs: implications for the dynamics of long-term memory.

“…What already seems quite certain is that the delayed emergence of the drug-induced effects on memory applies only to memory improvement and to antibiotics: in a series of pilot experiments, we noted that the memory-disturbing effects of, e.g., diazepam, MK-801, and scopolamine, are immediately perceptible-i.e., after a retention interval of only 1 h-and remain stable thereafter. These amnestic effects also were not steroid sensitive (12).…”

“…In the context of the present findings, it is interesting to note that the amnesia produced by such antibiotics emerged after a certain time lag; however, by comparison with our results the delay was mostly found to be much shorter (e.g., see refs. [16][17][18][19][20] (12,13) and steroids are potent modulators of gene transcription (30,31).…”

“…Among others, the list includes cholinergic agonists at the muscarinic and nicotinic receptors (1,2); cholinesterase inhibitors such as physostigmine (3); calcium-channel blockers such as nimodipine (4); angiotensin-converting enzyme (ACE) inhibitors such as captopril (5); transmitters such as, e.g., norepinephrine (6); t-aminobutyric acid type B (GABAB) receptor blockers such as CGP 36742 (7); peptides such as vasopressin and corticotropin (8); glucose (9); and, not least, the large group of so-called nootropics including oxiracetam and piracetam (10,11). Despite their different primary sites of action, all of the above-mentioned substances have a similar effect in a simple one-trial passive avoidance task; if administered, e.g., 1 h before the learning trial, they improve the retention performance at retest 24 h later (12,13). At the time of retention testing, the changes induced by the substances have already been expressed at a stage generally reckoned to be in long-term memory, but it is not known when these changes occurred.…”

The memory-facilitating effects of the competitive NMDA-receptor antagonist CGP 37849 are steroid-sensitive, whereas its memory-impairing effects are not

“…The range of substances already tested includes the nootropics piracetam, oxiracetam, pramiracetam and aniracetam, the cholinomimetics arecoline, physostigmine and tacrine, the ACE inhibitor captopril, the calcium antagonist nimodipine, and the glycine antagonist strychnine (for review see Mondadori 1993). Steroid sensitivity appears to be confined to memory-enhancing effects: control experiments have shown that the disturbances of memory provoked by phenobarbitone, diazepam, scopolamine and C. Mondadori -J. Borkowski -C. Gentsch CIBA Pharmaceutical Research Department, CH-4002 Basel, Switzerland C. Mondadori (~) Marion Merell Dow Research Center, 16, Rue d' Ankara, F-67080 Strasbourg, France the two NMDA receptor antagonists MK 801 and CGP 37849 are not influenced by alterations in steroid levels (Mondadori et al 1992b). The latter findings merit particular attention in this context insofar as it has also been demonstrated that the facilitation of memory induced by low doses of the two NMDA-receptor blockers were steroid sensitive (Mondadori et al 1992b;Mondadori and Weiskrantz 1993).…”

“…Steroid sensitivity appears to be confined to memory-enhancing effects: control experiments have shown that the disturbances of memory provoked by phenobarbitone, diazepam, scopolamine and C. Mondadori -J. Borkowski -C. Gentsch CIBA Pharmaceutical Research Department, CH-4002 Basel, Switzerland C. Mondadori (~) Marion Merell Dow Research Center, 16, Rue d' Ankara, F-67080 Strasbourg, France the two NMDA receptor antagonists MK 801 and CGP 37849 are not influenced by alterations in steroid levels (Mondadori et al 1992b). The latter findings merit particular attention in this context insofar as it has also been demonstrated that the facilitation of memory induced by low doses of the two NMDA-receptor blockers were steroid sensitive (Mondadori et al 1992b;Mondadori and Weiskrantz 1993). The fact that NMDA-receptor blockers can facilitate or impair memory, depending on the particular learning task and the dose administered (Morris et al t986; Mondadori et al 1989;Venable and Kelly 1990), provided a new possibility.…”