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

Abstract

The α7 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 α7 nAChR levels underlies the enhanced and sustained procognitive effect of repeated administration of α7 nAChR agonists. We further compare the effect of agonists to that of α7 nAChR positive allosteric modulators (PAMs), which do not induce upregulation of the α7 nAChR. Using the social discrimination test as a measure of short-term memory, we show that the α7 nAChR agonist A-582941 improves short-term memory immediately after repeated (7× daily), but not a single administration. The α7 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 [125I]-bungarotoxin autoradiography revealed no direct correlation between α7 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 α7 nAChR agonists and PAMs exhibit sustained pro-cognitive effects after repeated administration, and altered levels of the α7 nAChR per se, or that of endogenous regulators of nAChR function, are likely not the major cause of this effect.

Positive allosteric modulators of alpha 7 nicotinic acetylcholine receptors reverse ketamine-induced schizophrenia-like deficits in rats

“…Callahan et al (2013) demonstrated that the combination of PNU-120596 (1-10 mg/kg) with a subthreshold dose of donepezil improved recognition memory. Moreover, the effects of CCMI (described as AVL-3288) on recognition memory were assessed in the social discrimination test in rats (Thomsen et al, 2011). In this study, the memory-enhancing effects of CCMI (1 mg/kg) were demonstrated at 24 h after repeated, but not single, administration.…”

“…It cannot be excluded that repeated dosing protocols might reveal differences between these two types of α7-nAChR PAMs. For example, Thomsen et al (2011) demonstrated enhanced social cognition in rats after a 7-day administration of CCMI but not of PNU-120596.…”

Nicotinic α7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex

“…agonists can improve the performance of a variety of memory and attention tasks that depend on PFC circuits (30)(31)(32)(33). The study identifies the cellular basis for these behavioral actions, showing that stimulation of α7-nAChRs produces an inverted-U dose-response both for spatially tuned neuronal firing patterns and for behavioral performance, enhancing NMDAR-mediated neuronal representations of visual space.…”

Allosteric alpha-7 nicotinic receptor modulation and P50 sensory gating in schizophrenia: A proof-of-mechanism study

“…In this context, a recent study is of particular interest showing that the a7 nAChR agonist A-582941 and the a7 nAChR PAM AVL-3288 increase short-term memory in rats 24 h after repeated, but not a single, administration, suggesting that it is repeated administration of both agonists and PAMs, i.e., chronic rather than acute dosing, which may produce sustained (e.g. neuroplastic) effects on cognitive performance (Thomsen et al, 2011). Needless to say that if one decides to conduct a chronic dosing trial as part of a proof-of-mechanism study, one would ideally use additional functional biomarkers (and not just P50 sensory gating) that are more closely related to the concept of neuroplasticity like transcranial magnetic stimulation (TMS)-elicited motor-evoked potential (MEP) amplitudes (Thirugnanasambandam et al, 2011).…”