Chronic atomoxetine treatment during adolescence does not influence decision-making on a rodent gambling task, but does modulate amphetamine’s effect on impulsive action in adulthood

Abstract

In addition to the symptoms of inattention, hyperactivity, and impulsivity, individuals with attention deficit hyperactivity disorder exhibit impaired performance on tests of real-world cost/benefit decision-making. Atomoxetine, a nonstimulant drug approved for the treatment of attention deficit hyperactivity disorder, is a selective norepinephrine reuptake inhibitor administered chronically during adolescence, a time during which the frontal brain regions necessary for executive function undergo extensive maturation. This treatment protocol can affect behavior well into adulthood, but whether it produces long-term changes in complex decision-making has not been investigated. Twenty-four Long-Evans rats were administered saline or 1.0 mg/kg atomoxetine daily from postnatal day 40 to 54. Two weeks after treatment, the adult rats were trained and assessed on the rodent gambling task, in which the animals chose from four options varying in reward, punishment, and uncertainty. Impulsive action was also measured by recording the number of premature responses made. Regardless of the treatment administered during adolescence, rats learned to favor the advantageous options characterized by small, low-penalty rewards in lieu of the larger, higher-penalty reward options. Rodent gambling task performance was then assessed following acute treatment with atomoxetine (0.1-1.0 mg/kg) and amphetamine (0.3-1.5 mg/kg). Across groups, the highest dose of atomoxetine impaired decision-making and decreased premature responding at all doses tested. Amphetamine also impaired choice performance, but selectively increased impulsive action in rats that had previously received atomoxetine treatment during adolescence. These findings contribute to our understanding of the long-term effects associated with chronic adolescent atomoxetine exposure and suggest that this treatment does not alter decision-making under conditions of risk and uncertainty in adulthood.

MAM-E17 rat model impairments on a novel continuous performance task: effects of potential cognitive enhancing drugs

“…We observed detrimental effects of higher-dose (1.0 mg/kg) atomoxetine on d ′. Such impairments may be predicted by inverted-U theories of catecholamine function (Aston-Jones and Cohen 2005 ; Robbins and Arnsten 2009 ) and have also been observed in primates in a working memory task (Gamo et al 2010 ) and a decision-making task in rodents (Silveira et al 2016 ). The novel features of the rCPT relative to other rodent attentional paradigms may render it more demanding and more sensitive to detrimental effects of higher doses of pro-catecholaminergic agents.…”

Gambling disorder: an integrative review of animal and human studies

“…Interestingly, blockade of norepinephrine (NE) or 5‐HT signaling alone did not have an effect on performance in the rGT, but the combined increase in DA and NE or DA and 5‐HT did impair performance . This suggests that the interaction of transmitter systems is important for this complex paradigm modeling gambling‐like behavior.…”

“…74 Interestingly, blockade of norepinephrine (NE) or 5-HT signaling alone did not have an effect on performance in the rGT, but the combined increase in DA and NE or DA and 5-HT did impair performance. 75,76 This suggests that the interaction of transmitter systems is important for this complex paradigm modeling gambling-like behavior. Although increase in serotonin signaling with selective serotonin reuptake inhibitors (SSRIs) alone does not have large effects on gambling-like behavior in the rat, activation of 5-HT 1A receptor signaling specifically with 8-OH-DPAT impairs performance on the rGT, causing rats to increase their choice of the suboptimal option.…”

Elucidating the role of D4 receptors in mediating attributions of salience to incentive stimuli on Pavlovian conditioned approach and conditioned reinforcement paradigms

“…During complex behavioural tasks, such as the rSMT, animals have to integrate reward-related information from multiple sources to guide behaviour. Additionally, animals retain a representation of the outcome of the previous trial that exerts considerable influence over subsequent choices [21,74] and behaviour on such tasks, remains goal-directed, even after extensive training [84]. D 4 receptor activity has been suggested to contribute to maintaining homeostatic PFC activity levels [87,47], theoretically stabilizing representations of reward [22].…”