Cognitive Improvement by Activation of α7 Nicotinic Acetylcholine Receptors: From Animal Models to Human Pathophysiology
Morten S. Thomsen,
Henrik H. Hansen,
Mikkelsen B. Timmerman,
Jens D. Mikkelsen.
Agonists and positive allosteric modulators of the α7 nicotinic acetylcholine receptor (nAChR) are currently being developed for the treatment of cognitive disturbances in patients with schizophrenia or Alzheimers disease. This review describes the neurobiological properties of the α7 nAChR and the cognitive effects of α7 nAChR activation, focusing on the translational aspects in the development of these drugs. The functional properties and anatomical localization of the α7 nAChR makes it well suited to modulate cognitive function. Accordingly, systemic administration of α7 nAChR agonists improves learning, memory, and attentional function in variety of animal models, and procognitive effects of α7 nAChR agonists have recently been demonstrated in patients with schizophrenia or Alzheimers disease. The α7 nAChR desensitizes rapidly in vitro, and this has been a major concern in the development of α7 nAChR agonists as putative drugs. Our review of the existing literature shows that development of tolerance to the behavioral effects of α7 nAChR agonists does not occur in animal models or humans. However, the long-term memory-enhancing effects seen in animal models are not mimicked in healthy humans and schizophrenic patients, where attentional improvement predominates. This discrepancy may result from inherent differences in testing methods or from species differences in the level of expression of α7 nAChRs in limbic brain regions, and may hamper preclinical evaluation of α7 nAChR activation. It is therefore important to consider the translational power of the animal models used before entering into a clinical evaluation of the pro-cognitive effects of α7 nAChR activation.
Keywords: Nicotine, Alzheimer's disease, schizophrenia, attention, working memory, prefrontal cortex, hippocampus, acetylcholine
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