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) agon ists ABT-418 [(S)-3-methyl-2-pyrrolidinyl)isoxazole] and ABT-089 [2-me thyl-3-(2-(S)-pyrrolindinylmethoxy)pyridine dihydrochloride] on the de layed recall accuracy of adult monkeys exposed to distracting stimuli. Unpredictable exposure to a random visual array produced marked decre ments in recall accuracy on trials with the shortest delay intervals, reducing the accuracy on these trials by 23.4%. Intramuscular (IM) adm inistration of (-)-nicotine, in doses of 5.4-43.3 nmol/kg, attenuated the effect of the distracter, but did not completely prevent it. Both ABT-418 (2.0-16.2 nmol/kg, IM) and ABT-089 (16.4-32.8 nmol/kg, IM) pre vented distractibility, producing increases of 7.5-25.0% in accuracy o n trials disrupted by distracter exposure. Further, both compounds als o improved accuracy on trials during which distracters were not presen ted, an effect which was not observed after (-)-nicotine administratio n. Nicotinic-mediated side effects were not observed following adminis tration of any compound. Thus, nAChR stimulation reduces distractibili ty in adult monkeys and may, therefore, represent a target for the pha rmacologic treatment of disorders associated with susceptibility to di straction. ABT-418 and ABT-089 appear to be particularly useful in thi s regard, a likely result of their selective agonist activity at nAChR s expressed in the brain.