Sazetidine-A, a selective α4β2 nicotinic acetylcholine receptor ligand: effects on dizocilpine and scopolamine-induced attentional impairments in female Sprague–Dawley rats

• Published in: Psychopharmacologia Vol. 215; no. 4; pp. 621 - 630
• Main Authors: Rezvani, Amir H., Cauley, Marty, Sexton, Hannah, Xiao, Yingxian, Brown, Milton L., Paige, Mikell A., McDowell, Brian E., Kellar, Kenneth J., Levin, Edward D.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.06.2011; Springer
• Subjects: Animal experimentation; Animals; Attention - drug effects; Azetidines - chemistry; Azetidines - pharmacology; Behavior, Animal - drug effects; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cognition - drug effects; Dizocilpine Maleate - pharmacology; Dose-Response Relationship, Drug; Drug Interactions; Female; Ligands; Medical sciences; Mental illness; Methyl aspartate; Molecular Structure; Neurosciences; Nicotine; Original Investigation; Pharmacology/Toxicology; Photic Stimulation; Psychiatry; Psychomotor Performance - drug effects; Pyridines - chemistry; Pyridines - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic - metabolism; Scopolamine Hydrobromide - pharmacology; Sazetidine-A; MK-801; Sustained attention; Muscarinic cholinergic; Nicotinic receptors; NMDA glutaminergic; Rat; Ligand; Glutamate receptor; Alkaloid; Cholinergic receptor; Attentional disorder; NMDA; Female; Antagonist; Nicotinic receptor; Hyoscine; Dizocilpine; Rodentia; Neuroprotective agent; Anticholinergic agent; Vertebrata; Mammalia; Animal; Muscarinic receptor; NMDA receptor
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-010-2161-8

Background Neuronal nicotinic receptor systems have been shown to play key roles in cognition. Nicotine and nicotinic analogs improve attention and nicotinic antagonists impair it. This study was conducted to investigate the role of α4β2 nicotinic receptors in sustained attention using a novel selective α4β2 nicotinic receptor ligand, sazetidine-A. Methods Female rats were trained to perform the signal detection task to a stable baseline of accuracy. The rats were injected with saline, sazetidine-A (0.01, 0.03, and 0.1 mg/kg), dizocilpine (0.05 mg/kg), or their combination; or, in another experiment, the rats were injected with the same doses of sazetidine-A, scopolamine (0.02 mg/kg), or their combination. Results Percent hit and percent correct rejection showed that dizocilpine caused significant ( p  < 0.025) impairments in performance, which were significantly reversed by each of the sazetidine-A doses. Response omissions were significantly ( p  < 0.05) increased by dizocilpine, and this was also significantly reversed by each of the sazetidine-A doses. None of the sazetidine-A doses had significant effects on hit, correct rejection, or response omissions when given alone. Scopolamine also caused significant ( p  < 0.0005) impairments in percent hit and percent correct rejection and increased response omissions, which were significantly attenuated by all the sazetidine-A doses for percent hit and response omissions and by the highest dose of sazetidine-A for percent correct rejection. Both scopolamine and dizocilpine significantly ( p  < 0.0005) increased response latency, an effect which was significantly attenuated by sazetidine-A coadministration. Conclusions These studies imply an important role for α4β2 nicotinic receptors in improving sustained attention under conditions that disrupt it. Very low doses of sazetidine-A or drugs with a similar profile may provide therapeutic benefit for reversing attentional impairment in patients suffering from mental disorders and/or cognitive impairment.