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

Abstract

The retention performance of mice in a passive-avoidance task was facilitated by low doses (0.3 mg/kg) of the competitive NMDA-receptor blocker CGP 37849, but impaired by high doses (30 mg/kg). The facilitatory effect was selectively suppressed by elevation of the plasma levels of aldosterone or corticosterone, or by blockade of steroid biosynthesis or the mineralocorticoid receptors. The impairment of memory, on the other hand, was not steroid sensitive. Accordingly, the data are in line with the hypothesis that drug induced memory facilitation is dependent on steroid sensitive processes.

Synaptic Plasticity and Memory: An Evaluation of the Hypothesis

“…These findings embarrass but do not really challenge the SPM hypothesis because the effects are observed at doses too low to block LTP in vivo, and different mechanisms are likely to be involved in the antagonist-induced facilitation of learning. For instance, the facilitation of inhibitory avoidance by low doses of NMDA antagonists is sensitive to pretreatment by such steroids as aldosterone or corticosterone, whereas the impairment of inhibitory avoidance caused by high doses is steroid insensitive (Mondadori & Weiskrantz 1993, Mondadori et al 1996. Work with the noncompetitive antagonist memantine has led to counterintuitive findings by virtue of its rapid on-and off-channel blocking kinetics.…”

Renin-Angiotensin-Aldosterone System: The Forgotten Stress Hormone System: Relationship to Depression and Sleep

“…Because of this rationale, the direct eff ect of aldosterone on CNS activity has been widely neglected despite the fact that important examples have been reported. For example, aldosterone leads to a diminishing of mild NMDA receptor blockade-induced memory improvement [ 29 ] as well as the memory improving eff ects of angiotensinconverting enzyme inhibitors and the calcium antagonist nimodipine [ 30 ] in mice. Experimentally it has been demonstrated that MR-agonist administration leads to a suppression of cortisol in humans [ 31 ] , suggesting that under physiological conditions specifi c MR-action is possible and MRs are not completely occupied by cortisol.…”

Reversal of cycloheximide-induced memory disruption by AIT-082 (Neotrofin) is modulated by, but not dependent on, adrenal hormones

“…The first, as Mondadori (1995) has discussed, is that there is an interaction between GCmediated effects on cognition and cognitive enhancers. For instance, it is possible that elevated GC levels create a cognitive deficit that piracetam, tacrine, and other memory enhancers studied by Mondadori et al (1996) cannot overcome. According to the data presented here, AIT-082 would be able to overcome this deficit.…”

“…Evaluation of the effect of plasma corticosteroid on other memory enhancing agents by Mondadori and coworkers (Mondadori et al , 1996Mondadori and Weiskrantz 1993) demonstrated that, while only the NMDA antagonist CGP 37849 was inhibited by chemical adrenalectomy, memory enhancement induced by CGP 37849, the calcium channel antagonist nimodipine, the ACE inhibitor captopril, the glycine antagonist strychnine, and the cholinomimetics tacrine, physostigmine, and arecoline was inhibited by high serum levels of corticosterone in mice (Mondadori et al 1992a(Mondadori et al , 1992b. It has been suggested that inhibition by high corticosterone levels might be a general characteristic of all memoryenhancing agents and that inhibition of such agents by the increased cortisol levels seen in AD patients may explain why only a limited number of patients respond positively to currently available therapies (Mondadori 1993(Mondadori , 1995.…”