title: Effects of AZD3480, a neuronal nicotinic acetylcholine receptor agonist, and donepezil on dizocilpine-induced attentional impairment in rats.
abstract: OBJECTIVE
  Nicotinic acetylcholine systems play major roles in cognitive function. Nicotine and a variety of nicotinic agonists improve attention, and nicotinic antagonist exposure impairs it. This study was conducted to investigate the effect of a novel nicotinic receptor agonist at α4β2 nicotinic receptors (AZD3480) on attention and reversal of pharmacologically induced attentional impairment produced by the NMDA glutamate antagonist dizocilpine (MK-801).
  
  
  METHODS
  Adult female Sprague-Dawley rats were trained to perform an operant visual signal detection task to a stable baseline of accuracy. The rats were then injected subcutaneously following a repeated measures, counter-balanced design with saline, AZD3480 (0.01, 0.1, and 1 mg/kg), dizocilpine (0.05 mg/kg), or their combinations 30 min before the test. The effect of donepezil on the same pharmacologically induced attentional impairment was also tested. A separate group of rats was injected with donepezil (0.01, 0.1, and 1 mg/kg), dizocilpine (0.05 mg/kg), or their combinations, and their attention were assessed. Saline was the vehicle control.
  
  
  RESULTS
  Dizocilpine caused a significant (p < 0.0005) impairment in percent correct performance. This attentional impairment was significantly (p < 0.0005) reversed by 0.01 and 0.1 mg/kg of AZD3480. AZD3480 by itself did not alter the already high baseline control performance. Donepezil (0.01-1.0 mg/kg) also significantly (p < 0.005) attenuated the dizocilpine-induced attentional impairment.
  
  
  CONCLUSIONS
  AZD3480, similar to donepezil, showed significant efficacy for counteracting the attentional impairment caused by the NMDA glutamate antagonist dizocilpine. Low doses of AZD3480 may provide therapeutic benefit for reversing attentional impairment in patients suffering from cognitive impairment due to glutamatergic dysregulation and likely other attentional disorders.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box 104790, Durham, NC 27710, USA. azadi@duke.edu
authors.forename: Amir H
authors.initials: AH
authors.lastname: Rezvani
authors.forename: Marty C
authors.initials: MC
authors.lastname: Cauley
authors.forename: Edwin C
authors.initials: EC
authors.lastname: Johnson
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gatto
authors.forename: Edward D
authors.initials: ED
authors.lastname: Levin
mesh_terms: D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control* / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D005260:Female; D007189:Indans / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018722:Nicotinic Agonists / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D011978:Receptors, Nicotinic / Q000378:metabolism; D017603:Signal Detection, Psychological
chemical_list: D007189:Indans; D018722:Nicotinic Agonists; D010880:Piperidines; D011725:Pyridines; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; C490152:ispronicline; D016291:Dizocilpine Maleate; D000077265:Donepezil