Differential Immediate and Sustained Memory Enhancing Effects of Alpha7 Nicotinic Receptor Agonists and Allosteric Modulators in Rats

The alpha 7 nicotinic acetylcholine receptor (nAChR) is a potential target for the treatment of cognitive deficits in patients with schizophrenia, ADHD and Alzheimer's disease. Here we test the hypothesis that upregulation of alpha 7 nAChR levels underlies the enhanced and sustained procognitive effect of repeated administration of alpha 7 nAChR agonists. We further compare the effect of agonists to that of alpha 7 nAChR positive allosteric modulators (PAMs), which do not induce upregulation of the alpha 7 nAChR. Using the social discrimination test as a measure of short-term memory, we show that the alpha 7 nAChR agonist A582941 improves short-term memory immediately after repeated (76daily), but not a single administration. The alpha 7 nAChR PAMs PNU-120596 and AVL-3288 do not affect short-term memory immediately after a single or repeated administration. This demonstrates a fundamental difference in the behavioral effects of agonists and PAMs that may be relevant for clinical development. Importantly, A-582941 and AVL-3288 increase short-term memory 24 hrs after repeated, but not a single, administration, suggesting that repeated administration of both agonists and PAMs may produce sustained effects on cognitive performance. Subsequent [I-125]-bungarotoxin autoradiography revealed no direct correlation between alpha 7 nAChR levels in frontal cortical or hippocampal brain regions and short-term memory with either compound. Additionally, repeated treatment with A-582941 did not affect mRNA expression of RIC-3 or the lynx-like gene products lynx1, lynx2, PSCA, or Ly6H, which are known to affect nAChR function. In conclusion, both alpha 7 nAChR agonists and PAMs exhibit sustained pro-cognitive effects after repeated administration, and altered levels of the alpha 7 nAChR per se, or that of endogenous regulators of nAChR function, are likely not the major cause of this effect.