Faculty mentor/PI email address
navarra@rowan.edu
Keywords
Atomoxetine, Prefrontal Cortex, Cognitive Flexibility, Rodent
IRB or IACUC Protocol Number
SOM IACUC Protocol 2020-1194
Date of Presentation
5-6-2026 12:00 AM
Poster Abstract
Title: Atomoxetine enhances specific dimensions of cognitive performance in a rodent strategy shifting assay
Authors: Jessica Ivanov, Christopher P. Knapp, Barry D. Waterhouse, Rachel L. Navarra
Objective: Cognitive flexibility, a domain of executive function, supports adaptive shifts in behavior in response to changing environmental demands and task contingencies. Deficits in this capacity are common to neuropsychiatric disorders such as Attention Deficit Hyperactivity Disorder (ADHD), where improper regulation of the catecholamine transmitters dopamine (DA) and norepinephrine (NE) within the prefrontal cortex (PFC) has been implicated. Atomoxetine (ATX), a selective NE transporter (NET) inhibitor, elevates levels of NE and DA in the PFC and is an established non-stimulant treatment for ADHD. However, the precise aspects of executive function that benefit most from ATX treatment have not been fully characterized.
Methods: The effects of ATX (0.3 or 1 mg/kg, i.p.) were assessed in healthy male and female Long Evans rats utilizing an automated operant strategy shifting task (SST) of goal-directed behavior and cognitive flexibility. Rats were trained to press left and right levers to obtain sucrose rewards, then assessed for side preference. Initial discrimination required responding on the non-preferred lever (i.e., directional cue). Twenty-four hours later, animals received either dose of ATX or saline and performed the SST in sequential stages of different stimulus-response contingencies, which included 1) retrieval of the previous directional rule, 2) an intradimensional reversal requiring a switch to the opposite lever, and 3) an extradimensional shift requiring lever press responses cued by a visual stimulus rather than position. Performance measures included the number of trials to reach criterion (10 consecutive correct responses), response latency, magazine latency, and a throughput score integrating accuracy and speed of performance. Data were analyzed using two-way ANOVAs with Dunnett’s post-hoc tests.
Results: The 0.3 mg/kg dose of ATX reduced the number of trials required to reach criterion and increased throughput scores, particularly during the extradimensional shifts. In contrast, the 1 mg/kg dose ATX tended to impair trials to criterion. Neither dose affected response or magazine latencies, indicating these drug effects were specific to higher-order cognitive processing rather than influences on processing speed, motor output, or reward motivation.
Conclusion: Low-dose ATX (0.3 mg/kg) improves performance during the SST by decreasing the number of trials required to reach criterion and improving throughput scores across stages of the SST. Conversely, the 1 mg/kg dose of ATX shows potential to worsen performance. These findings indicate ATX (0.3 mg/kg) promotes cognitive flexibility without off-target effects on processing speed, locomotion, or motivation. This dose-dependent profile demonstrates that an optimal range of catecholamine modulation is required to enhance PFC-dependent functions, whereas excessive signaling can be disruptive. While observed in normal animals, the current work provides mechanistic insight that highlights the importance of careful dose selection for clinical translation, ensuring maximal therapeutic efficacy while avoiding further impairment in treating neuropsychiatric disorders.
Disciplines
Chemicals and Drugs | Laboratory and Basic Science Research | Medicine and Health Sciences
Atomoxetine Enhances Specific Dimensions of Cognitive Performance In A Rodent Strategy Shifting Assay
Title: Atomoxetine enhances specific dimensions of cognitive performance in a rodent strategy shifting assay
Authors: Jessica Ivanov, Christopher P. Knapp, Barry D. Waterhouse, Rachel L. Navarra
Objective: Cognitive flexibility, a domain of executive function, supports adaptive shifts in behavior in response to changing environmental demands and task contingencies. Deficits in this capacity are common to neuropsychiatric disorders such as Attention Deficit Hyperactivity Disorder (ADHD), where improper regulation of the catecholamine transmitters dopamine (DA) and norepinephrine (NE) within the prefrontal cortex (PFC) has been implicated. Atomoxetine (ATX), a selective NE transporter (NET) inhibitor, elevates levels of NE and DA in the PFC and is an established non-stimulant treatment for ADHD. However, the precise aspects of executive function that benefit most from ATX treatment have not been fully characterized.
Methods: The effects of ATX (0.3 or 1 mg/kg, i.p.) were assessed in healthy male and female Long Evans rats utilizing an automated operant strategy shifting task (SST) of goal-directed behavior and cognitive flexibility. Rats were trained to press left and right levers to obtain sucrose rewards, then assessed for side preference. Initial discrimination required responding on the non-preferred lever (i.e., directional cue). Twenty-four hours later, animals received either dose of ATX or saline and performed the SST in sequential stages of different stimulus-response contingencies, which included 1) retrieval of the previous directional rule, 2) an intradimensional reversal requiring a switch to the opposite lever, and 3) an extradimensional shift requiring lever press responses cued by a visual stimulus rather than position. Performance measures included the number of trials to reach criterion (10 consecutive correct responses), response latency, magazine latency, and a throughput score integrating accuracy and speed of performance. Data were analyzed using two-way ANOVAs with Dunnett’s post-hoc tests.
Results: The 0.3 mg/kg dose of ATX reduced the number of trials required to reach criterion and increased throughput scores, particularly during the extradimensional shifts. In contrast, the 1 mg/kg dose ATX tended to impair trials to criterion. Neither dose affected response or magazine latencies, indicating these drug effects were specific to higher-order cognitive processing rather than influences on processing speed, motor output, or reward motivation.
Conclusion: Low-dose ATX (0.3 mg/kg) improves performance during the SST by decreasing the number of trials required to reach criterion and improving throughput scores across stages of the SST. Conversely, the 1 mg/kg dose of ATX shows potential to worsen performance. These findings indicate ATX (0.3 mg/kg) promotes cognitive flexibility without off-target effects on processing speed, locomotion, or motivation. This dose-dependent profile demonstrates that an optimal range of catecholamine modulation is required to enhance PFC-dependent functions, whereas excessive signaling can be disruptive. While observed in normal animals, the current work provides mechanistic insight that highlights the importance of careful dose selection for clinical translation, ensuring maximal therapeutic efficacy while avoiding further impairment in treating neuropsychiatric disorders.