| 1 | PLoS ONE 2011 -1 6: e27014 |
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| PMID | 22096516 |
| Title | Differential immediate and sustained memory enhancing effects of alpha7 nicotinic receptor agonists and allosteric modulators in rats. |
| Abstract | The ?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 ?7 nAChR levels underlies the enhanced and sustained procognitive effect of repeated administration of ?7 nAChR agonists. We further compare the effect of agonists to that of ?7 nAChR positive allosteric modulators (PAMs), which do not induce upregulation of the ?7 nAChR. Using the social discrimination test as a measure of short-term memory, we show that the ?7 nAChR agonist A-582941 improves short-term memory immediately after repeated (7× daily), but not a single administration. The ?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 [(125)I]-bungarotoxin autoradiography revealed no direct correlation between ?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 ?7 nAChR agonists and PAMs exhibit sustained pro-cognitive effects after repeated administration, and altered levels of the ?7 nAChR per se, or that of endogenous regulators of nAChR function, are likely not the major cause of this effect. |
| SCZ Keywords | schizophrenia |
| 2 | Curr Drug Targets 2012 May 13: 707-20 |
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| PMID | 22300038 |
| Title | The ?7 nicotinic acetylcholine receptor complex: one, two or multiple drug targets? |
| Abstract | The ?7 nicotinic acetylcholine receptor (nAChR) is a promising drug target for a number of diseases ranging from schizophrenia and Alzheimer's disease to chronic pain and inflammatory diseases. Focusing on the central nervous system, we describe how endogenous and experimental compounds and proteins regulate expression and function of the ?7 nAChR. Drug development efforts have hitherto focused on direct manipulation of the ?7 nAChR, but it is still not clear, whether agonism/antagonism or allosteric modulation is preferable as a potential drug therapy. In addition, the action of such compounds in vivo is highly dependent on ?7 nAChR-interacting proteins, such as RIC-3 and LYNX1, which modulate expression and function of the receptor. These regulatory proteins are often not expressed in in vitro models used to study ?7 nAChR function, and it is not known to what extent they are involved in diseases such as schizophrenia and Alzheimer's disease. Furthermore, ?7 nAChR agonists and allosteric modulators differentially alter expression and functionality of the ?7 nAChR with repeated administration, which suggests that there may be fundamentally different outcomes of long-term administration with these different types of compounds. Finally, we describe the special case of A?1-42 binding to the ?7 nAChR, which may pose a unique challenge to drug development of ?7 nAChR-specific ligands for Alzheimer's disease. Hopefully, a greater knowledge of the many factors influencing ?7 nAChR function as well as an increasing pipeline of specific drug candidates, enabling a more subtle manipulation of ?7 nAChR function, may facilitate ?7 nAChR drug development efforts. |
| SCZ Keywords | schizophrenia |