Treating schizophrenia symptoms with an α7 nicotinic agonist, from mice to men
Section snippets
α7 and P50 auditory gating
People with schizophrenia, in addition to the cardinal symptoms of hallucinations and delusions, suffer from the inability to focus attention. This may stem from being overwhelmed by extraneous sensory stimuli [2] which impairs the person's ability to think coherently. This “flooding” has been modeled in the laboratory physiologically by measuring the amplitude of the evoked responses to identical paired auditory stimuli separated by 500 ms [3]. The P50 auditory evoked response occurs 40–75 ms
α7 in learning and memory
Although nicotine seems to improve cognition, the involvement of high or low affinity nicotinic cholinergic receptors is unclear. Withdrawal from nicotine in normal smokers has been shown to cause attention impairments [59]. Nicotine administration may just be relieving withdrawal and correcting those deficits. However, if low-dose nicotine is administered to normal non-smokers, thereby avoiding the confound of withdrawal, there is enhanced performance on the continuous performance test with
DMXBA as a prototype drug
Nicotine has several limitations as a therapeutic agent for schizophrenia. Nicotine induces tachyphylaxis and thus does not maintain sustained benefit. Additionally, the long-term health risks of chronic nicotine use are unknown. Nicotine is also addictive and without sustained use, people can experience symptoms of withdrawal [79]. Thus, alternative nicotinic agonists that are less potentially toxic would be helpful in the treatment of schizophrenia.
One of the few agents that has reached
Other potential nicotinic targets
A series of other putative cholinergic receptor agonists have been developed as potential candidates for the treatment of schizophrenia and Alzheimer's disease. Drugs currently in development include a 1,4-diaza-bicyclo[3.2.2]nonane-4-carboxylic acid 4-pyridin-2yl-phenyl ester at Pfizer Inc., and a N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (14 PHA-543,613) also at Pfizer, Inc. The second compound demonstrates reversal of amphetamine-induced N40 gating deficit in
Discussion
The α7 nicotinic cholinergic receptor role in schizophrenia has been established through multiple independent pathways. An initial clinical observation of increased frequency of smoking in schizophrenia lead to the observation that these patients extract more nicotine from the cigarettes they smoke than do other smokers [15], [10]. Examination of the symptom of being overwhelmed by extraneous sensory stimuli lead to finding a physiological deficit, the P50 auditory evoked potential, which
Acknowledgements
This work was supported by an NIMH grant (MH065588) to AO, an NIMH grant (MH073725) to KES and the NARSAD Toulmin Independent Investigator Award to KES.
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