Dissociable effects of monoamine reuptake inhibitors on distinct forms of impulsive behavior in rats

Abstract

Rationale: High levels of impulsivity are a core symptom of psychiatric disorders such as ADHD, mania, personality disorders and drug addiction. The effectiveness of drugs targeting dopamine (DA), noradrenaline (NA) and/or serotonin (5-HT) in the treatment of impulse control disorders emphasizes the role of monoaminergic neurotransmission in impulsivity. However, impulsive behavior is behaviorally and neurally heterogeneous, and several caveats remain in our understanding of the role of monoamines in impulse control.

Objectives: This study aims to investigate the role of DA, NA and 5-HT in two main behavioral dimensions of impulsivity.

Methods: The effects of selective DA (GBR12909; 2.5-10 mg/kg), NA (atomoxetine; 0.3-3.0 mg/kg) and 5-HT (citalopram; 0.3-3.0 mg/kg) reuptake inhibitors as well as amphetamine (0.25-1.0 mg/kg) were evaluated on impulsive action in the five-choice serial reaction time task (5-CSRTT) and impulsive choice in the delayed reward task (DRT). In the 5-CSRTT, neuropharmacological challenges were performed under baseline and long intertrial interval (ITI) conditions to enhance impulsive behavior in the task.

Results: Amphetamine and GBR12909 increased impulsive action and perseverative responding and decreased accuracy and response latency in the 5-CSRTT. Atomoxetine increased errors of omission and response latency under baseline conditions in the 5-CSRTT. Under a long ITI, atomoxetine also reduced premature and perseverative responding and increased accuracy. Citalopram improved impulse control in the 5-CSRTT. Amphetamine and GBR12909, but not citalopram or atomoxetine, reduced impulsive choice in the DRT.

Conclusions: Elevation of DA neurotransmission increases impulsive action and reduces impulsive choice. Increasing NA or 5-HT neurotransmission reduces impulsive action.

Fig. 1

Effects of amphetamine (a), the selective DA reuptake inhibitor GBR12909 (b), the selective NA reuptake inhibitor atomoxetine (c) and the selective 5-HT reuptake inhibitor citalopram (d) on premature responding, i.e., impulsive action under baseline conditions (visual stimulus presented 5 s after trial initiation) in the 5-CSRTT. In total, n = 16 animals were included in the analysis. Asterisk indicates p < 0.05 and two asterisks indicates p < 0.01 compared to vehicle treatment (paired samples t-test). All data are expressed as mean ± SEM

Fig. 2

Effects of amphetamine (a), the selective DA reuptake inhibitor GBR12909 (b), the selective NA reuptake inhibitor atomoxetine (c) and the selective 5-HT reuptake inhibitor citalopram (d) on 5-CSRTT performance under long ITI conditions (visual stimulus presented 7 s after trial initiation). In total, n = 15 animals were included in the analysis. Asterisk indicates p < 0.05 and two asterisks indicates p < 0.01 compared to vehicle treatment (paired samples t-test). All data are expressed as mean ± SEM

Fig. 3

Effects of amphetamine (a), the selective DA reuptake inhibitor GBR12909 (b), the selective NA reuptake inhibitor atomoxetine (c) and the selective 5-HT reuptake inhibitor citalopram (d) on the percentage choice for the large reinforcer in the delayed reward paradigm. In total, n = 13–15 animals were included in the analysis. Asterisk indicates p < 0.05 and two asterisks indicates p < 0.01 compared to vehicle treatment (paired samples t-test). All data are expressed as mean ± SEM