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

Callahan, Patrick M.; Plagenhoef, Marc; Blake, David T.; Terry, Alvin V.

doi:10.1016/j.neuropharm.2019.05.016

Cited by 29 publications

(21 citation statements)

References 57 publications

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“…Positive effects of ATX on premature responses across various 5-CSRT task variants have been widely reported, occasionally with a concomitant slowing of response speed and increased omissions (e.g. Blondeau and Dellu-Hagedorn, 2007;Navarra et al, 2008;Robinson et al, 2008;Baarendse and Vanderschuren, 2012;Fernando et al, 2012;Paterson et al, 2012;Robinson, 2012;Tomlinson et al, 2014;Callahan et al, 2019). Similar to the present findings, the effects of ATX on premature responding may be most apparent in test subjects identified as high impulsive (Fernando et al, 2012;Tomlinson et al, 2014).…”

Section: Characterization Of Amp Mph Atx and Nic On Performancesupporting

confidence: 86%

“…Indeed, ATX failed to produce a significant improvement in accuracy (measured either as % correct or % hit) under any 5-CSRTT schedule or in any attentional subgroup. Positive effects of ATX on attentional measures have been reported in some 5-CSRTT studies typically under conditions of delayed ITI (see Navarra et al, 2008;Baarendse and Vanderschuren, 2012;Paterson et al, 2012;Callahan et al, 2019), and in low attentive subgroups (Robinson, 2012;Tomlinson et al, 2014). However, these findings are inconsistent (e.g.…”

Section: Characterization Of Amp Mph Atx and Nic On Performancementioning

confidence: 99%

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Characterization of Amphetamine, Methylphenidate, Nicotine, and Atomoxetine on Measures of Attention, Impulsive Action, and Motivation in the Rat: Implications for Translational Research

Higgins

Silenieks²,

MacMillan³

et al. 2020

Front. Pharmacol.

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Amphetamine (AMP), methylphenidate (MPH), and atomoxetine (ATX) are approved treatments for ADHD, and together with nicotine (NIC), represent pharmacological agents widely studied on cognitive domains including attention and impulsive action in humans. These agents thus represent opportunities for clinical observation to be reinvestigated in the preclinical setting, i.e., reverse translation. The present study investigated each drug in male, Long Evans rats trained to perform either (1) the fivechoice serial reaction time task (5-CSRTT), (2) Go/NoGo task, or (3) a progressive ratio (PR) task, for the purpose of studying each drug on attention, impulsive action and motivation. Specific challenges were adopted in the 5-CSRTT designed to tax attention and impulsivity, i.e., high frequency of stimulus presentation (sITI), variable reduction in stimulus duration (sSD), and extended delay to stimulus presentation (10-s ITI). Initially, performance of a large (> 80) cohort of rats in each task variant was conducted to examine performance stability over repeated challenge sessions, and to identify subgroups of "high" and "low" attentive rats (sITI and sSD schedules), and "high" and "low" impulsives (10-s ITI). Using an adaptive sequential study design, the effects of AMP, MPH, ATX, and NIC were examined and contrasting profiles noted across the tests. Both AMP (0.03-0.3 mg/kg) and MPH (1-6 mg/kg) improved attentional performance in the sITI but not sSD or 10-s ITI condition, NIC (0.05-0.2 mg/kg) improved accuracy across all conditions. ATX (0.1-1 mg/kg) detrimentally affected performance in the sITI and sSD condition, notably in "high" performers. In tests of impulsive action, ATX reduced premature responses notably in the 10-s ITI condition, and also reduced false alarms in Go/NoGo. Both AMP and NIC increased premature responses in all task variants, although AMP reduced false alarms highlighting differences between these two measures of impulsive action. The effect of MPH was mixed and appeared baseline dependent. ATX reduced break point for food reinforcement suggesting a detrimental effect on motivation for primary reward. Taken

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Section: Characterization Of Amp Mph Atx and Nic On Performancesupporting

confidence: 86%

Section: Characterization Of Amp Mph Atx and Nic On Performancementioning

confidence: 99%

Characterization of Amphetamine, Methylphenidate, Nicotine, and Atomoxetine on Measures of Attention, Impulsive Action, and Motivation in the Rat: Implications for Translational Research

Higgins

Silenieks²,

MacMillan³

et al. 2020

Front. Pharmacol.

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“…On the basis of evidence showing that AMPH and MPH impair 'waiting' impulsivity (Navarra et al 2008;Pattij et al 2007) and decrease response latency (Bizarro et al 2004), we predicted that administration of these drugs would lead to an improvement of performance in short ITI trials especially. On the contrary, since ATO reduces impulsivity (Blondeau and Dellu-Hagedorn 2007) and slows responding in some contexts (Callahan et al 2019), we predicted that ATO would mostly enhance performance on long ITI trials. To better dissect the role that noradrenaline (NA) plays in modulating performance of HI and LI rats, we also assessed the effects of systemic administration of atipamezole (ATI), an alpha-2a antagonist, and phenylephrine (PHEN), an alpha1 agonist.…”

Section: Introductionmentioning

confidence: 88%

“…In addition, the unpredictability in the presentation of each ITI increases attentional load, whilst controlling for the habituation or timing strategies that the animals may adopt as the session progresses (Bizarro et al 2004 ; Cope et al 2016 ). Whilst other studies have examined performance under vITI versions of the 5CSRTT (Bizarro et al 2004 ; Callahan et al 2019 ; Carli et al 1983 ; Navarra et al 2008 ; Paterson et al 2011 ; Robinson 2012 ; Sirviö et al 1993 ), none have yet investigated whether HI and LI rats perform differentially during this experimental manipulation and whether a specific impulsivity phenotype confers a selective advantage in performance. Blondeau and Dellu-Hagedorn ( 2007 ) tested whether rats segregated on the basis of impulsivity as well as attentional accuracy show a selective advantage in long (8 s) ITI as opposed to short (2 s) ITI trials.…”

Section: Introductionmentioning

confidence: 99%

Adaptive aspects of impulsivity and interactions with effects of catecholaminergic agents in the 5-choice serial reaction time task: implications for ADHD

et al. 2021

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Background Work in humans has shown that impulsivity can be advantageous in certain settings. However, evidence for so-called functional impulsivity is lacking in experimental animals. Aims This study investigated the contexts in which high impulsive (HI) rats show an advantage in performance compared with mid- (MI) and low impulsive (LI) rats. We also assessed the effects of dopaminergic and noradrenergic agents to investigate underlying neurotransmitter mechanisms. Methods We tested rats on a variable inter-trial interval (ITI) version of the 5-choice serial reaction time task (5CSRTT). Rats received systemic injections of methylphenidate (MPH, 1 mg/kg and 3 mg/kg), atomoxetine (ATO, 0.3 mg/kg and 1 mg/kg), amphetamine (AMPH, 0.2 mg/kg), the alpha-2a adrenoceptor antagonist atipamezole (ATI, 0.3 mg/kg) and the alpha-1 adrenoceptor agonist phenylephrine (PHEN, 1 mg/kg) prior to behavioural testing. Results Unlike LI rats, HI rats exhibited superior performance, earning more reinforcers, on short ITI trials, when the task required rapid responding. MPH, AMPH and ATI improved performance on short ITI trials and increased impulsivity in long ITI trials, recapitulating the behavioural profile of HI. In contrast, ATO and PHEN impaired performance on short ITI trials and decreased impulsivity, thus mimicking the behavioural profile of LI rats. The effects of ATO were greater on MI rats and LI rats. Conclusions These findings indicate that impulsivity can be advantageous when rapid focusing and actions are required, an effect that may depend on increased dopamine neurotransmission. Conversely, activation of the noradrenergic system, with ATO and PHEN, led to a general inhibition of responding.

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“…While most studies to date have focused on norepinephrine therapy as a treatment for neuropsychiatric symptoms in late dementia, there is recent increased interest in repurposing the many available drugs that target the LC-NE system for use in early-phase AD clinical trials (Chalermpalanupap et al, 2017). Atomoxetine, a norepinephrine reuptake inhibitor, has been shown to improve attention, memory, and executive functions in nonhuman primate studies (Callahan et al, 2019) and human studies of adults with ADHD (Ni et al, 2013), but did not improve cognition as an augment to cholinesterase-inhibitor therapy in patients with mild-to-moderate AD (Mohs et al, 2009). However, as in many AD clinical trials to date, it is possible that treatment was initiated too late and the effect of such medications at early disease stages is yet to be seen.…”

Section: Discussionmentioning

confidence: 99%

Differential Involvement of the Locus Coeruleus in Early- and Late-Onset Alzheimer’s Disease: A Potential Mechanism of Clinical Differences?

Bolton

Tam

2020

Preprint

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Early-onset Alzheimers disease (EOAD) has been associated with an increased likelihood of atypical clinical manifestations such as attentional impairment, yet the cause of this heterogeneity remains unclear. The locus coeruleus (LC) is implicated early in Alzheimers disease pathology and is associated with attentional functioning. This study investigated post-mortem atrophy of the LC in EOAD and late-onset Alzheimers disease (LOAD) in a large, well-characterized sample. Results show nearly four times greater likelihood of higher LC atrophy in EOAD as compared to LOAD after controlling for other measures of pathological progression (p < .005). Follow-up analyses within the EOAD group revealed that compared to those who displayed mild or no LC atrophy at autopsy, those with moderate-severe atrophy of the LC displayed significantly worse performance on various baseline measures of attentional functioning (p < .05), despite similar overall cognition (p = .25). These findings suggest the LC is an important potential driver of clinical and pathological heterogeneity in EOAD.

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

Cited by 29 publications

References 57 publications

Characterization of Amphetamine, Methylphenidate, Nicotine, and Atomoxetine on Measures of Attention, Impulsive Action, and Motivation in the Rat: Implications for Translational Research

Characterization of Amphetamine, Methylphenidate, Nicotine, and Atomoxetine on Measures of Attention, Impulsive Action, and Motivation in the Rat: Implications for Translational Research

Adaptive aspects of impulsivity and interactions with effects of catecholaminergic agents in the 5-choice serial reaction time task: implications for ADHD

Differential Involvement of the Locus Coeruleus in Early- and Late-Onset Alzheimer’s Disease: A Potential Mechanism of Clinical Differences?

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