Central nicotinic receptor agonists ABT-418, ABT-089, and (-)-nicotine reduce distractibility in adult monkeys.
Increased distractibility is associated with both Alzheimer's disease and attention deficit disorder. The present study examined the effects of (-)-nicotine and the novel central nicotinic receptor (nAChR) agonists ABT-418 [(S)-3-methyl-2-pyrrolidinyl)isoxazole] and ABT-089 [2-methyl-3-(2-(S)-pyrrolindinylmethoxy)pyridine dihydrochloride] on the delayed recall accuracy of adult monkeys exposed to distracting stimuli. Unpredictable exposure to a random visual array produced marked decrements in recall accuracy on trials with the shortest delay intervals, reducing the accuracy on these trials by 23.4%. Intramuscular (i.m.) administration of (-)-nicotine, in doses of 5.4-43.3 nmol/kg, attenuated the effect of the distractor, but did not completely prevent it. Both ABT-418 (2.0-16.2 nmol/kg, i.m.) and ABT-089 (16.4-32.8 nmol/kg, i.m.) prevented distractibility, producing increases of 7.5-25.0% in accuracy on trials disrupted by distractor exposure. Further, both compounds also improved accuracy on trials during which distractors were not presented, an effect which was not observed after (-)-nicotine administration. Nicotinic-mediated side effects were not observed following administration of any compound. Thus, nAChR stimulation reduces distractibility in adult monkeys and may, therefore, represent a target for the pharmacologic treatment of disorders associated with susceptibility to distraction. ABT-418 and ABT-089 appear to be particularly useful in this regard, a likely result of their selective agonist activity at nAChRs expressed in the brain.
Prendergast
M A
MA
Department of Pharmacology and Toxicology, Alzheimer's Research Center, Medical College of Georgia, Augusta 30912-2300, USA.
Jackson
W J
WJ
Terry
A V
AV
Decker
M W
MW
Arneric
S P
SP
Buccafusco
J J
JJ
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001288:Attention / Q000187:drug effects*; D018678:Cholinergic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007555:Isoxazoles / Q000494:pharmacology*; D008253:Macaca mulatta; D008254:Macaca nemestrina; D008297:Male; D011939:Mental Recall / Q000187:drug effects; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D010775:Photic Stimulation; D011725:Pyridines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects*
D014151:Anti-Anxiety Agents; D018678:Cholinergic Agents; D007555:Isoxazoles; D018722:Nicotinic Agonists; D011725:Pyridines; D011759:Pyrrolidines; D011978:Receptors, Nicotinic; C088383:3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole; D009538:Nicotine; C108326:pozanicline