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

Abstract

Many theories of memory polate that processing of information outlasts the earning situation and involves several different physiological substrates. If such physiologically distinct mecanism or stages of memory do in fact exist, they should be differentially affected by particular experimental manipulations. Accordingly, a selective improvement of the processes underlying short-term memory should be detectable only while the information is encoded in the shortterm mode, and a selective influence on long-term memory should be detectable only from the moment when memory is based on the long-term trace. Our comparative study of the time course of the effects of the cholinergic agonist arecoline, the -aminobutyric acid type B receptor antagonist CGP 36742, the angiotensin-converting enzyme inhibitor captopril, and the nootropic oxiracetam, four substances with completely different primary sites of action, show that the memoryenhancing effects consistently come into evidence no sooner than 16-24 h after the learning trial. On the one hand, this finding suggests that all these substances act by way of the same type of mechanism; on the other hand, it demonstrates that the substrate modulated by the compounds forms the basis of memory only after 16-24 h. From the observation that animals also show clear signs of retention during the first 16 h-i.e., before the effects of the substances are measurable-it can be inferred that retention during this time is mediated by other mechanisms that are not influenced by any of the substances.The group of preparations already found to display memoryenhancing effects in experimental learning situations is surprisingly large. Even more surprising is the fact that the primary pharmacological sites of action of these substances are very heterogeneous. 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. Indeed, it is often implicitly assumed that the facilitatory effects occurred concomitantly with the initial learning itself, demonstrable at short retention intervals. By making a comparative study o...

Effects of ethanol and GABAB drugs on working memory in C57BL/6J and DBA/2J mice

“…GABA B receptors are present in significant concentrations within the hippocampus (for review, see Bowery 1989). Baclofen has been reported to disrupt working memory (Nakagawa and Takashima 1997;Romanides et al 1999) and GABA B receptor antagonists have been reported to have no effect on working memory, or to improve memory performance (Mondadori et al 1994;Brucato et al 1996;Pittaluga et al 2001). As GABA B drugs or ethanol can alter working memory, and GABA B drugs can modify ethanol's effects on motor function, the first goal of this experiment was to determine if ethanol, or the GABA B drugs baclofen or phaclofen administered alone, could alter working memory performance in mice.…”

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

“…For discussion of potential mechanisms and levels of interaction see, e.g. Mondadori et al (1992aMondadori et al ( , b, 1994. The conclusion that the memory impairment is brought about by mechanisms different from those responsible for the memory facilitation is additionally supported by the observation that memory facilitation induced by low doses of CGP 37849 only becomes experimentally detectable t6-20h after the learning test, whereas memory impairment is almost immediately discernible (Mondadori et al, in preparation).…”

“…These observations are entirely consistent with results deriving from investigations on other compounds. It has been shown, for example, that the memory improving effect of the cholinergic agonist arecoline, the GABAB antagonist CGP 36742, the nootropic oxiracetam and the ACE inhibitor captopril only emerged after a delay of 16-20 h (Mondadori et al 1994) whereas the memory impairing effects of phenobarbitone, diazepam, MK 801 and scopolamine were almost immediately detectable (Mondadori et al, in preparation).…”

Pharmacokinetic comparisons of S-oxiracetam and R-oxiracetam in beagle dogs

“…As a nootropic agent, oxiracetam can improve both learning and memory processes and is used in the treatment of various cognitive disorders (1)(2)(3)(4). ORT is a chiral drug; at present, the form of ORT used in clinical treatment is a racemate (Fig.…”