Behavioural pharmacologyEffects of serotonin–norepinephrine reuptake inhibitors on locomotion and prefrontal monoamine release in spontaneously hypertensive rats
Introduction
Attention-deficit/hyperactivity disorder (ADHD) is one of the most common developmental disorders in children, with a prevalence of 5–10% (Polanczyk et al., 2007, Scahill and Schwab-Stone, 2000). Moreover, 2.9–4.4% of the adult population have continuing ADHD (Faraone and Biederman, 2005, Kessler et al., 2006). Although the etiology of ADHD is not known, it is likely that dysfunction of catecholaminergic signaling plays a key role, particularly in prefrontal cortical regions (Arnsten, 2009). The pharmacotherapy of ADHD is based on evidence that norepinephrine and dopamine are highly involved in motor control and several domains of cognition, including working memory, attention, and executive function. Atomoxetine blocks selectively the norepinephrine transporter, whereas methylphenidate blocks the dopamine and norepinephrine transporters (Bymaster et al., 2002, Easton et al., 2007, Gehlert et al., 1995, Tatsumi et al., 1997). In vivo microdialysis studies have shown that these drugs increase extracellular levels of norepinephrine and dopamine in brain cortical regions (Berridge et al., 2006, Bymaster et al., 2002, Koda et al., 2010, Weikop et al., 2007). It should be noted that methylphenidate has opposite effects, depending on the dose. Low doses (0.25–1 mg/kg, i.p.) of methylphenidate improve cognitive function without locomotor-activating effects (Berridge et al., 2006), whereas high doses (10 mg/kg) induce hyperlocomotion (Koda et al., 2010). Methylphenidate at doses that induce hyperlocomotion increase extracellular dopamine levels in the striatum and nucleus accumbens, where has been associated with reinforcing and locomotor-activating effects (Bymaster et al., 2002, Koda et al., 2010). In addition, recent study using high-speed chronoamperometric recording techniques shows the sub-regional differences in dopamine release and uptake in the striatum and nucleus accumbens of rodent ADHD models (Miller et al., 2012). Serotonin–norepinephrine reuptake inhibitors are widely used for the treatment of major depressive disorder. Microdialysis studies show that duloxetine, venlafaxine, and milnacipran increase not only the extracellular levels of serotonin and norepinephrine but also those of dopamine in rat prefrontal cortex (Kihara and Ikeda, 1995, Kitaichi et al., 2005, Koch et al., 2003, Millan et al., 2001), but not affect dopamine levels in the striatum (Millan et al., 2001), when compared at similar doses. Several clinical trials have examined the effectiveness of venlafaxine (Findling et al., 2007, Zarinara et al., 2010) and duloxetine (Bilodeau et al., in press, Mahmoudi-Gharaei et al., 2011) for treating ADHD symptoms including inattention, oppositionality, and hyperactivity. These studies suggest that serotonin–norepinephrine reuptake inhibitors have potential in the treatment of ADHD. However, no study has examined the effects of serotonin–norepinephrine reuptake inhibitors on behavior in an animal model.
In this study, we examined the effects of duloxetine, venlafaxine, and milnacipran in comparison to atomoxetine and methylphenidate on locomotion and prefrontal monoamine systems in spontaneously hypertensive rats (SHR), an animal model of ADHD (Arime et al., 2011, Sagvolden et al., 2005). To elucidate the roles of both monoamine systems in the effects of serotonin–norepinephrine reuptake inhibitors, we also examined the effects of the selective serotonin reuptake inhibitor citalopram, the selective norepinephrine reuptake inhibitor reboxetine, and the tricyclic antidepressant desipramine which mainly inhibits the reuptake of norepinephrine and also inhibits the uptake to a lesser extent of serotonin.
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Animals and drug treatments
All animal studies were approved by the Animal Care and Use Committee of the Graduate School of Pharmaceutical Sciences, Osaka University. All studies followed the Guiding Principles for the Care of Laboratory Animals as described in the United States National Institutes of Health Guide for the Care and Use of Laboratory Animals. Every effort was made to minimize animal suffering, and to reduce the number of animals used. Three-week-old male SHR/NCrlCrlj and WKY/NCrlCrlj rats were obtained from
Effects of atomoxetine and methylphenidate on locomotion in SHR and WKY rats
We first examined the effects of acute treatment with atomoxetine and methylphenidate on locomotion in SHR and WKY rats (Fig. 1). Habituated SHR exhibited greater horizontal activity than habituated WKY control rats in the open-field, in agreement with the previous studies (Li and Huang, 2006). Atomoxetine (1 and 3 mg/kg) inhibited significantly horizontal locomotion in SHR, whereas it did not affect in WKY rats (Fig. 1A). Two-way ANOVA revealed significant main effects of strain (F1,53=99.808, P
Discussion
In this study, we investigated using SHR, an animal model of ADHD, whether serotonin–norepinephrine reuptake inhibitors, like the currently used ADHD drugs methylphenidate and atomoxetine, may have potential as pharmacotherapeutics for ADHD. First, we examined the effects of atomoxetine and methylphenidate on the enhanced horizontal activity in adolescent male SHR. Acute administration of atomoxetine (1 and 3 mg/kg) reduced the locomotion in SHR in the open-field test, in agreement with a recent
Acknowledgments
This study was supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (from the Ministry of Education, Culture, Sports, Science and Technology of Japan).
References (52)
- et al.
Lack of enhanced effect of antipsychotics combined with fluvoxamine on acetylcholine release in rat prefrontal cortex
J. Pharmacol. Sci.
(2006) - et al.
Catecholamine influences on prefrontal cortical function: relevance to treatment of attention deficit/hyperactivity disorder and related disorders
Pharmacol. Biochem. Behav.
(2011) - et al.
Treatment of ADHD with fluoxetine: a preliminary trial
J. Am. Acad. Child Adolesc. Psychiatry
(1991) - et al.
Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function
Biol. Psychiatry
(2006) - et al.
Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder
Neuropsychopharmacology
(2002) - et al.
Effects of amphetamine isomers, methylphenidate and atomoxetine on synaptosomal and synaptic vesicle accumulation and release of dopamine and noradrenaline in vitro in the rat brain
Neuropharmacology
(2007) - et al.
Methylphenidate and atomoxetine enhance prefrontal function through α2-adrenergic and dopamine D1 receptors
J. Am. Acad. Child Adolesc. Psychiatry
(2010) - et al.
Localization of rat brain binding sites for [3H]-tomoxetine, an enantiomerically pure ligand for norepinephrine reuptake sites
Neurosci. Lett.
(1993) - et al.
Novel halogenated analogs of tomoxetine that are potent and selective inhibitors of norepinephrine uptake in brain
Neurochem. Int.
(1995) - et al.
Subchronic milnacipran treatment increases basal extracellular noradrenaline concentrations in the medial prefrontal cortex of rats
Eur. J. Pharmacol.
(2005)
Comparison of effects of dual transporter inhibitors on monoamine transporters and extracellular levels in rats
Neuropharmacology
Early androgen treatment influences the pattern and amount of locomotion activity differently and sexually differentially in an animal model of ADHD
Behav. Brain Res.
The spontaneously hypertensive and Wistar Kyoto rat models of ADHD exhibit sub-regional differences in dopamine release and uptake in the striatum and nucleus accumbens
Neuropharmacology
Pharmacologic alternatives to psychostimulants for the treatment of attention-deficit/hyperactivity disorder
Child Adolesc. Psychiatr. Clin. N. Am.
Rodent models of attention-deficit/hyperactivity disorder
Biol. Psychiatry
Role of postsynaptic serotonin1A receptors in risperidone-induced increase in acetylcholine release in rat prefrontal cortex
Eur. J. Pharmacol.
Epidemiology of ADHD in schoolage children
Child Adolesc. Psychiatr. Clin. N. Am.
Desipramine treatment of children with attention-deficit hyperactivity disorder and tic disorder or Tourette's syndrome
J. Am. Acad. Child Adolesc. Psychiatry
The selective norepinephrine reuptake inhibitor atomoxetine counteracts behavioral impairments in trimethyltin-intoxicated rats
Eur. J. Pharmacol.
Pharmacological profile of antidepressants and related compounds at human monoamine transporters
Eur. J. Pharmacol.
Spontaneously hypertensive rats do not predict symptoms of attention-deficit hyperactivity disorder
Pharmacol. Biochem. Behav.
Differential effects of adjunctive methylphenidate and citalopram on extracellular levels of serotonin, noradrenaline and dopamine in the rat brain
Eur. Neuropsychopharmacol.
Strain differences in the behavioral responses of male rats to chronically administered methylphenidate
Brain Res.
Fluvoxamine enhances prefrontal dopaminergic neurotransmission in adrenalectomized/castrated mice via both 5-HT reuptake inhibition and σ1 receptor activation
Psychopharmacology
Differential locomotor responses in male rats from three strains to acute methylphenidate
Int. J. Neurosci.
Animal models of attention-deficit/hyperactivity disorder
Biol. Pharm. Bull.
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These authors equally contributed to this work.