Differential effects of α7 nicotinic receptor agonist PHA-543613 on spatial memory performance of rats in two distinct pharmacological dementia models

Abstract The aim of the present study was to compare the cognitive enhancer potential of a recently identified highly selective α7 nicotinic receptor agonist PHA-543613 in scopolamine induced cholinergic and in MK-801 induced glutamatergic transient amnesia models in adult male Wistar rats. Spontaneous alternation paradigm in the T-maze was used as it is considered a reliable measure of spatial working memory and as T-maze performance is highly dependent on the functioning of the hippocampus and the prefrontal cortex. Scopolamine (0.5 mg/kg) and MK-801 (0.1 mg/kg) caused similar decrease of alternation rate and increased locomotion. Prior administration of PHA-543613 (1 or 3 mg/kg) dose dependently and completely reversed scopolamine induced impairment of alternation. However, PHA-543613 had lower efficacy in the MK-801 induced transient amnesia model, as the pharmacologically induced memory deficit was only partially reversed and an inverted U-shaped dose-response was found. PHA-543613 did not modulate either scopolamine or MK-801 induced increased locomotor activity or decreased choice latency. Results suggest that the α7 nicotinic receptor agonist had better efficacy to alleviate working memory deficits of rats caused by cholinergic receptor dysfunction, when NMDA receptors were not primarily targeted. On the other hand, the same memory enhancer strategy through α7 cholinergic receptors was apparently less effective when glutamatergic transmission (via NMDARs) was directly impaired by MK-801 treatment. The present results provide data supporting the need of parallel comprehensive testing of novel drug-candidates for cognitive impairment in distinct preclinical models of memory deficits.