Effect of the attention deficit/hyperactivity disorder drug atomoxetine on extracellular concentrations of norepinephrine and dopamine in several brain regions of the rat

Swanson, Chad J.; Perry, Kenneth W.; Koch-Krueger, Susanne; Katner, Jason; Svensson, Kjell; Bymaster, Frank P.

doi:10.1016/j.neuropharm.2005.11.022

Cited by 183 publications

(142 citation statements)

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“…Atomoxetine may also reverse nicotine withdrawalrelated deficits in contextual fear conditioning by altering noradrenergic function. Both nicotine administration (see, eg, Azam and McIntosh, 2006;Barik and Wonnacott, 2006;Singer et al, 2004) and atomoxetine administration (Swanson et al, 2006) can increase norepinephrine levels in brain regions that are involved in contextual fear conditioning, including the hippocampus. Alterations in noradrenergic function that may result from chronic nicotine treatment, and withdrawal from chronic nicotine treatment could lead to disrupted contextual fear conditioning during nicotine withdrawal.…”

Section: Discussionmentioning

confidence: 99%

“…In experiment 3, mice withdrawn from chronic nicotine received saline or 2.0 mg/kg of atomoxetine before training or before testing for freezing in response to the context. For all experiments, atomoxetine was not administered before testing for freezing in response to the CS, because previous research (Swanson et al, 2006) indicates that rat brain concentrations of norepinephrine remain elevated 4 h after administration of a dose of atomoxetine that is similar to our effective dose of the drug. The doses of atomoxetine used for the present studies were selected based on a previous study from our lab .…”

Section: Drugs and Administrationmentioning

confidence: 99%

“…Atomoxetine, a norepinephrine-reuptake inhibitor approved by the FDA to treat attention deficit hyperactivity disorder (ADHD) (Kratochvil et al, 2003), increases the amount of synaptic norepinephrine and, to a lesser extent, dopamine and serotonin, by inhibiting the reuptake of these neurotransmitters (Swanson et al, 2006). In addition, a recent study (Tzavara et al, 2006) suggests that atomoxetine indirectly increases acetylcholine levels via activation of a-1 norepinephrine receptors and/or activation of D1 dopamine receptors.…”

Section: Introductionmentioning

confidence: 99%

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Atomoxetine Reverses Nicotine Withdrawal-Associated Deficits in Contextual Fear Conditioning

Davis

Gould

2007

Neuropsychopharmacol

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Recent evidence suggests that the cognitive symptoms of nicotine withdrawal and the cognitive symptoms of attention deficit hyperactivity disorder (ADHD) may share neural correlates. Thus, therapeutics that ameliorate ADHD symptoms may also ameliorate nicotine-withdrawal symptoms. The present research tested this hypothesis in an animal model of nicotine withdrawal-associated cognitive deficits using atomoxetine, a norepinephrine reuptake inhibitor that is approved by the FDA to treat the symptoms of ADHD. C57BL/6 mice were prepared with osmotic minipumps that administered 6.3 mg/kg/day of nicotine or saline, and the minipumps were removed after 12 days of continuous treatment. Twenty-four hours later, mice were trained in delay fear conditioning using two paired presentations of an auditory conditioned stimulus (CS) with a footshock unconditioned stimulus. Testing for freezing in response to the training context and for freezing in response to the CS occurred the next day. Nicotine-withdrawn mice and their saline-treated counterparts received either saline or atomoxetine before training and the context test. Consistent with previous research, the results indicate that mice withdrawn from chronic nicotine demonstrated lower levels of contextual fear conditioning than mice that were not withdrawn from chronic nicotine. Atomoxetine dose-dependently reversed the deficit, suggesting that nicotine withdrawal may be associated with changes in noradrenergic function, acetycholinergic function, and/or with changes in cell signaling cascades that are activated by both nicotine and norepinephrine. These data suggest that atomoxetine may be efficacious for treating nicotine withdrawalassociated cognitive deficits that promote relapse in abstinent smokers.

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Section: Discussionmentioning

confidence: 99%

Section: Drugs and Administrationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Atomoxetine Reverses Nicotine Withdrawal-Associated Deficits in Contextual Fear Conditioning

Davis

Gould

2007

Neuropsychopharmacol

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“…These results indicate that enhanced noradrenaline signaling reduces the motivation for, as well as the expression of social play behavior. Importantly, atomoxetine has been shown to increase extracellular prefrontal noradrenaline, prefrontal dopamine, and subcortical noradrenaline concentrations, but not to alter nucleus accumbens dopamine activity (Bymaster et al, 2002;Swanson et al, 2006). This likely explains why methylphenidate increases responding for social play, but atomoxetine does not.…”

Section: Dissociable Roles Of Dopamine and Noradrenaline In Social Plmentioning

confidence: 99%

Contrasting Roles of Dopamine and Noradrenaline in the Motivational Properties of Social Play Behavior in Rats

Achterberg

Kerkhof

Servadio

et al. 2015

Neuropsychopharmacol

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Social play behavior, abundant in the young of most mammalian species, is thought to be important for social and cognitive development. Social play is highly rewarding, and as such, the expression of social play depends on its pleasurable and motivational properties. Since the motivational properties of social play have only sporadically been investigated, we developed a setup in which rats responded for social play under a progressive ratio schedule of reinforcement. Dopaminergic neurotransmission plays a key role in incentive motivational processes, and both dopamine and noradrenaline have been implicated in the modulation of social play behavior. Therefore, we investigated the role of dopamine and noradrenaline in the motivation for social play. Treatment with the psychostimulant drugs methylphenidate and cocaine increased responding for social play, but suppressed its expression during reinforced play periods. The dopamine reuptake inhibitor GBR-12909 increased responding for social play, but did not affect its expression, whereas the noradrenaline reuptake inhibitor atomoxetine decreased responding for social play as well as its expression. The effects of methylphenidate and cocaine on responding for social play, but not their play-suppressant effects, were blocked by pretreatment with the dopamine receptor antagonist α-flupenthixol. In contrast, pretreatment with the α2-adrenoceptor antagonist RX821002 prevented the play-suppressant effect of methylphenidate, but left its effect on responding for social play unaltered. In sum, the present study introduces a novel method to study the incentive motivational properties of social play behavior in rats. Using this paradigm, we demonstrate dissociable roles for dopamine and noradrenaline in social play behavior: dopamine stimulates the motivation for social play, whereas noradrenaline negatively modulates the motivation for social play behavior and its expression.

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“…Swanson et al 38) noted that administration of the a2-adrenergic antagonist idazoxan after atomoxetine resulted in an increase in prefrontal cortical NA efflux that was greater than that seen with either compound alone, indicating an attenuating effect of adrenergic autoreceptors on NA efflux. Further, a dual-probe microdialysis study demonstrated that in rats, the NA-reuptake blocker desipramine inhibits NA reuptake at the somatodendritic and nerve terminal levels in noradrenergic cells.…”

Section: Discussionmentioning

confidence: 99%

Effects of Atomoxetine on Levels of Monoamines and Related Substances in Discrete Brain Regions in Mice Intermittently Deprived of Rapid Eye Movement Sleep

Niijima

Saito

Murai

et al. 2010

Biological & Pharmaceutical Bulletin

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Sleep deprivation represents a common type of stress that can, when extreme, lead to psychological and physiological damage, and even death, in experimental animals. 1) After a period of intermittent rapid eye movement sleep deprivation (REMSD) (72-96 h), rats stay awake for approximately 30 min, and during this period display hyperactivity, irritability, aggressiveness, and hypersexuality. 2) Recently, we showed in mice that 5 days' intermittent REMSD (20 h/d) results in explosive jumping behavior. This behavior was antagonized dose-dependently and significantly by treatment with atomoxetine (0.41-0.55 mg/kg, subcutaneously (s.c.)), which is used clinically to treat the symptoms of attention deficit/hyperactivity disorder (ADHD), 3) raising the possibility such jumping behavior may serve as a useful animal model of ADHD. Moreover, there may be a positive association between this animal model and a hyperfunctional status of noradrenergic systems since the firing of noradrenergic neurons in locus ceruleus (LC) continuous during rapid eye movement (REM) sleep deprivation. [4][5][6] ADHD is a childhood psychiatric disorder characterized by the presence of symptoms in three domains: inattention, impulsivity, and motor overactivity. 7) It has been suggested that these symptoms may be due to a combination of alerting deficits and executive-control deficits involving the prefrontal cortex. 8,9) Although existing studies contain several inconsistencies, on balance the evidence supports dysfunctions of the fronto-striatal neuronal circuits regulated by dopaminergic and noradrenergic afferents, with resultant executive deficits in cognitive functioning. [7][8][9][10] The stimulants amphetamine and methylphenidate, which are indirect agonist that increase extracellular monoamine concentration by inhibiting reuptake and/or promoting release, are the primary treatment for ADHD. 11) The efficacy of stimulants suggests that dopaminergic and/or noradrenergic dysregulation contribute to the expression of ADHD, while diversity in psychostimulant response suggests that the ADHD is not attributable to any single pathophysiologic mechanism. In the absence of specific therapeutic targets, the treatment strategy progresses from stimulant to non-stimulant drugs. 12) Atomoxetine is a non-stimulant drug and a selective inhibitor of the presynaptic noradrenaline (NA)-reuptake transporter (NAT). Indeed, it has an approximately 300-fold selectivity for NAT over the dopamine (DA)-uptake transporter (DAT), a finding that has increased interest in the role of NAT and noradrenergic systems in ADHD. 13) In the frontal cortex, NAT density is higher than DAT density, [14][15][16] and NAT blockade by atomoxetine is thought to block sequestration of DA into NA neurons. 13) Moreover, NAT is poorly expressed in the striatum, in contrast to its robust expression within the frontal cortex. 13) The above findings suggest that the therapeutic effects of drugs that block NAT are mediated by increasing both NA and DA in noradrenergic terminal areas such as ...

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Effect of the attention deficit/hyperactivity disorder drug atomoxetine on extracellular concentrations of norepinephrine and dopamine in several brain regions of the rat

Cited by 183 publications

References 34 publications

Atomoxetine Reverses Nicotine Withdrawal-Associated Deficits in Contextual Fear Conditioning

Atomoxetine Reverses Nicotine Withdrawal-Associated Deficits in Contextual Fear Conditioning

Contrasting Roles of Dopamine and Noradrenaline in the Motivational Properties of Social Play Behavior in Rats

Effects of Atomoxetine on Levels of Monoamines and Related Substances in Discrete Brain Regions in Mice Intermittently Deprived of Rapid Eye Movement Sleep

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