Nootropic agents or
cognitive enhancers are purported to improve mental functions such as cognition, memory, or attention. The aim of our study was to determine the effects of two possible
cognitive enhancers,
huperzine A and
IDRA 21, in normal young adult monkeys performing a visual memory task of varying degrees of difficulty.
Huperzine A is a reversible
acetylcholinesterase (AChE) inhibitor, its administration results in regionally specific increases in
acetylcholine levels in the brain. In human clinical trials,
Huperzine A resulted in cognitive improvement in patients with mild to moderate form of
Alzheimer's disease (AD) showing its potential as a palliative agent in the treatment of AD.
IDRA 21 is a positive allosteric modulator of
glutamate AMPA receptors. It increases excitatory synaptic strength by attenuating rapid desensitization of
AMPA receptors and may thus have beneficial
therapeutic effects to ameliorate
memory deficits in patients with
cognitive impairments, including AD. The present study evaluated the effects of the two drugs in normal, intact, young adult monkeys to determine whether they can result in cognitive enhancement in a system that is presumably functioning optimally. Six young pigtail macaques (Macaca nemestrina) were trained on delayed non-matching-to-sample task, a measure of visual recognition memory, up to criterion of 90% correct responses on each of the four delays (10s, 30s, 60s, and 90s). They were then tested on two versions of the task: Task 1 included the four delays intermixed within a session and the monkeys performed it with the accuracy of 90%. Task 2 included, in each of 24 trials, a list of six objects presented in succession. Two objects from the list were then presented for choice paired with novel objects and following two of the four delays intermixed within a session. This task with a higher mnemonic demand yielded an average performance of 64% correct.
Oral administration of
huperzine A did not significantly affect the monkeys' performance on either task. However, a significant negative correlation was found between the baseline performance on each delay and the change in performance under
huperzine A, suggesting that under conditions in which the subjects were performing poorly (55-69%), the
drug resulted in improved performance, whereas no improvement was obtained when the baseline was close to 90%. In fact, when the subjects were performing very well,
huperzine A tended to reduce the performance accuracy, indicating that in a system that functions optimally, the increased availability of
acetylcholine does not improve performance or memory, especially when the animals are close to the maximum performance. In contrast,
oral administration of
IDRA 21 significantly improved performance on Task 2, especially on the longest delay. This finding supports the potential use of this
drug in treatment of cognitive and
memory disorders. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.