Trends in Pharmacological Sciences
ReviewNicotinic ACh receptors as therapeutic targets in CNS disorders
Section snippets
Functional role of nAChRs in the brain
The nAChRs belong to the superfamily of cys-loop receptors (Figure 1), which also includes the serotonin 5-HT3, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (GABA)A, GABAC, and glycine receptors, and participate in a variety of physiological functions, including the regulation of neuronal excitability and neurotransmitter release 1, 2, 3, 4. The nAChRs are widely distributed throughout the peripheral nervous system (PMS) and the CNS, as well as the immune system and various peripheral
AD
Neuronal nAChR dysfunction is involved in the pathophysiology of various neurodegenerative diseases, including AD and Parkinson's disease (PD). Here we will focus solely on AD since there are excellent recent reviews discussing the complexity between nAChR distribution within the nigro-striatal pathway, how nAChR function contribute to this network, and PD pathophysiology [53].
Neurodevelopmental disorders
The nAChRs are widely expressed on both differentiated and undifferentiated CNS cells, and are known to influence development and modulate multiple pathways of neurogenesis during brain development 114, 115. Here we discuss the role of nAChRs in two of the most common neurodevelopmental disorders, autism and schizophrenia.
Pain
Pain is an unpleasant sensory feeling that includes neuropathic, nociceptive, and psychogenic pain [148]. If the pain persists for longer than a few months, the condition is said to be chronic (as opposed to acute) pain [149]. The most common reason for neuropathic pain is a disruption in the normal functioning of the somatosensory system [150]. The nAChRs have been known for some time to be involved in the process of mediating pain, and as such the analgesic effects of nAChR agonists as well
Concluding remarks
The distribution of nAChRs in the nervous system is extensive yet discrete, and historically this has made them an active target of drug development for treating neurodegenerative diseases such as AD. However, the nAChRs are increasingly appreciated for their roles in neurodevelopment and sensory processing, and thus have been identified as therapeutic targets in autism, schizophrenia, and neuropathic pain. Unfortunately, no nAChR compounds have demonstrated disease-modifying properties for any
Acknowledgments
This work was supported by the Intramural Research Program, NIEHS/NIH to J.L.Y. and A.A.P., a kind gift to K.T.D. from J&W Mohn, and an Independent Investigator Research Grant from the Alzheimer's Association to K.T.D.
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