Atomoxetine improves memory and other components of executive function in young-adult rats and aged rhesus monkeys

Abstract

Atomoxetine is a norepinephrine reuptake inhibitor and FDA-approved treatment for attention deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults. While there is some evidence that atomoxetine may improve additional domains of cognition beyond attention in both young adults and aged individuals, this subject has not been extensively investigated. Here, we evaluated atomoxetine (in low mg/kg doses) in a variable stimulus duration (vSD) and a variable intertrial interval (vITI) version of the five choice-serial reaction time task (5C-SRTT), and an eight-arm radial arm maze (RAM) procedure in young-adult rats. The compound was further evaluated (in μg/kg-low mg/kg doses) along with nicotine (as a reference compound) and the Alzheimer's disease treatment donepezil in a distractor version of a delayed match to sample task (DMTS-D) in aged monkeys (mean age = 21.8 years). Atomoxetine (depending on the dose) improved accuracy (sustained attention) as well as behaviors related to impulsivity, compulsivity and cognitive inflexibility in both the vSD and vITI tasks and it improved spatial reference memory in the RAM. In the DMTS-D task, both nicotine and atomoxetine, but not donepezil attenuated the effects of the distractor on accuracy at short delays (non-spatial working/short term memory). However, combining sub-effective doses of atomoxetine and donepezil did enhance DMTS-D accuracy indicating the potential of using atomoxetine as an adjunctive treatment with donepezil. Collectively, these animal studies support the further evaluation of atomoxetine as a repurposed drug for younger adults as well older individuals who suffer from deficits in attention, memory and other components of executive function.

Keywords: Attention; Cholinergic; Cognitive flexibility; Dementia; Distractibility; Noradrenergic.

Fig 1.

Effects of atomoxetine (0.3-3.0 mg/kg, i.p.) in a variable stimulus duration (vSD) version of the 5C-SRTT in adult Wistar rats. (A) Percent correct (accuracy); (B) total number of premature responses (impulsive behavior); (C) total number timeout responses (compulsive behavior/cognitive inflexibility); D. total number of magazine head entries (compulsive behavior/cognitive inflexibility). Each bar represents the mean ± SEM for each test group; (N=7 rats). * = significantly different (p<0.05) from vehicle (saline)-related response. ATX = atomoxetine.

Fig 2.

Effects of atomoxetine (0.3-3.0 mg/kg, i.p.) in a variable intertrial interval (vITI) version of the 5C-SRTT in adult Wistar rats. (A) Percent correct (accuracy); (B) total number of premature responses (impulsive behavior); (C) total number timeout responses (compulsive behavior/cognitive inflexibility); D. total number of magazine head entries (compulsive behavior/cognitive inflexibility). Each bar represents the mean ± SEM for each test group; (N=7 rats). * = significantly different (p<0.05) from vehicle (saline)-related response. ATX = atomoxetine.

Fig 3.

Effects of atomoxetine (1.0-5.6 mg/kg, s.c.) in a delayed non-match to position (DNMTP) version of a RAM task in young adult Long Evans rats. (A) Effects of atomoxetine on spatial working memory errors across the 10 days of treatment. (B) Effects of atomoxetine on spatial reference memory errors across the 10 days of treatment. The Inset to Fig 3B depicts the effects of atomoxetine on the Area Under the Curve (AUC) for spatial reference memory errors across the 10 days of testing, Data points represent mean (± S.E.M) for each treatment (N=13 rats/treatment) across the 10 days of testing. * = significantly different (p<0.05) from vehicle when compared to saline (vehicle) control. ATOM = atomoxetine.

Fig 4.

Effects of nicotine and atomoxetine in a distractor version of a delayed match to sample task (DMTS) in aged rhesus monkeys. (A). Baseline performance on standard DMTS trials and DMTS trials with distractor (DMTS-D). The DMTS-standard task consisted of 96 trials divided equally across the three delays (i.e., zero, short and long) whereas the DMTS-distractor task had 96 trials, 72 trials were non-distractor trials (presented equally across the three delays) and 24 trials were distractor trials for which an interfering visual stimulus was presented prior to the short and long delays. *= significantly different (p<0.05) from DMTS non-distractor-related accuracy (B). Effects of nicotine (0.0125-0.05 mg/kg, i.m.) on short delay DMTS-distractor performance in aged rhesus monkeys. (C). Effects of atomoxetine (0.03-1.0 mg/kg, i.m.) on short delay DMTS-distractor performance in aged rhesus monkeys. Histograms presented in Fig 4B and 4C represent the mean (± S.E.M.) values of the difference (delta) from DMTS distractor short delay accuracy and DMTS non-distractor short delay accuracy and are illustrated as the “change from non-distractor control”. The DMTS non-distractor control value represents the delta between the DMTS-standard short delay accuracy and the DMTS non-distractor response. * = significantly different (p<0.05) from DMTS non-distractor saline response. # = significantly different (p<0.05) from the DMTS distractor response. Nic = nicotine; ATX = atomoxetine. N=9

Fig. 5.

(A) Effects of donepezil on short delay performance in a distractor version of a delayed match to sample task (DMTS) in aged rhesus monkeys. (B). Effects of combing sub-effective test doses of atomoxetine (0.03 mg/kg, i.m.) and donepezil (0.05 mg/kg, i.m.) on short delay DMTS-distractor performance in aged rhesus monkeys. Data represent the mean (± S.E.M.) values of the delta change from non-distractor control performance (see Fig 4 legend for details). * = significantly different (p<0.05) from DMTS non-distractor saline response. # = significantly different (p<0.05) from the DMTS distractor response. Don = donepezil; ATX = atomoxetine. N=9