Memory enhancement: Supra-additive effect of subcutaneous cholinergic drug combinations in mice

Abstract

The amnesias characteristic of Alzheimer's disease and other age-related dementias are refractory to conventional pharmacotherapy. A recent treatment strategy is to combine present drugs to improve their memory enhancing effect. We used mice weakly trained on active avoidance in a T-maze to compare the effect of cholinergic drugs, given alone and in two-drug combinations, on retention test performance. All drugs were injected SC immediately after training. Memory retention was tested 1 week later. A dose-response curve was determined for each of four drugs (arecoline, edrophonium, oxotremorine, tacrine) and for each of the six possible two-drug combinations. Each drug and each combination improved retention test performance up to an optimal dose; the improvement decreased with further increases in dose. A striking reduction (66.2%-95.7%) in the optimal dose for enhanced retention was observed with these two-drug combinations.

Rolipram and Its Optical Isomers, Phosphodiesterase 4 Inhibitors, Attenuated the Scopolamine-Induced Impairments of Learning and Memory in Rats

“…An acetylcholinesterase inhibitor, tetrahydro-aminoacridine (THA), has been shown to improve these symptoms in patients with dementia (5-7). Based on these findings concerning the cholinergic systems, scopolamine, a mus carinic receptor antagonist, has been useful for the evalu ation of the effects of drugs on learning and memory deficits in animals and humans (9,10). We also have reported that scopolamine impaired the performance in the radial maze task and passive avoidance task, and cholinergic enhancers such as physostigmine and THA improved the deficits of memory performance (26).…”

“…In addition, the cholinesterase inhibitors are effective in treating Alzheimer's disease (3 6) and in experimental animals (7,8). Therefore, numerous animal models used in the search for potential nootropic agents are related to the modulation of acetylcholine systems (9,10). Recent studies indicated that the monoamines and the second messengers including adenosine 3'5'-cyclic monophos phate (cAMP) play critical roles in learning and memory (11).…”

Cellular Stress Responses, The Hormesis Paradigm, and Vitagenes: Novel Targets for Therapeutic Intervention in Neurodegenerative Disorders

“…This concept has been supported in a variety of studies on hormesis and drug interaction. Flood (173)(174)(175)(176) has demonstrated that the hormetic response for memory was bounded by the 30%-60% increase even when several drugs were used in combination that were designed to maximize memory outcome. This response magnitude constraint has been reported for immune stimulation, bacterial growth, increases in hair growth, plant growth, decrease in anxiety, decreases in tumor incidence, and numerous other endpoints (73).…”

Drug Influences on Learning and Memory in Aged Animals and Humans

“…Contrary to the effects of physostigmine, pretreatment with arecoline produced more consistent dose effects between the monkeys tested. Posttraining treatment with arecoline has also been shown to improve retention performance in aged mice trained in both one-trial inhibitory avoidance [Flood et al, 1982] and active avoidance [Flood et al, 1983[Flood et al, , 1984[Flood et al, , 1985. Pretraining treatment with oxotremorine, another cholinergic antagonist, has also been reported to improve performance when tested in aged monkeys [Bartus et al, 1983].…”