Inhibition of G-Protein-Activated Inwardly Rectifying K+ Channels by the Selective Norepinephrine Reuptake Inhibitors Atomoxetine and Reboxetine

Kobayashi, Toru; Washiyama, Kazuo; Ikeda, Kazutaka

doi:10.1038/npp.2010.27

Cited by 24 publications

(16 citation statements)

References 61 publications

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“…One possibility is that norepinephrine influences the concentration and metabolism of dopamine in some indirect manner; therefore, such modulation may have caused the dystonic reaction (Kobayashi et al 2010). Therefore, our case illustrates a very rare adverse effect, and to the best of our knowledge, it is the first ever case of dystonia presenting as camptocormia in a child as a result of taking atomoxetine, although the persistence of the symptom, and the lack of rechallenge, makes the association at best probable.…”

Section: Discussionmentioning

confidence: 92%

Persistent Camptocormia Associated with Atomoxetine in a Child with Attention-Deficit/Hyperactivity Disorder

Bhattacharya

Praharaj

Sinha

2014

Journal of Child and Adolescent Psychopharmacology

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A tomoxetine, a selective norepinephrine reuptake inhibitor, was shown to be effective for the treatment of attentiondeficit/hyperactivity disorder (ADHD) in children and adolescents in meta-analysis of nine studies (Cheng et al. 2007). The commonest adverse events reported were gastrointestinal (appetite decrease, abdominal pain, vomiting, dyspepsia) and somnolence. We report the case of a child with ADHD who developed persistent camptocormia while being treated with atomoxetine. Case ReportA 7-year-old boy presented with a history of excess activity, poor attention at school, and falling academic grades over the past 2 years. His parents were informed by the schoolteacher that he would not stand quietly in the prayer line at the morning assembly, and would climb up the window grills of the classroom and frequently disturb his classmates when a lesson was being taught, causing disruption in the class functioning. His sleep and appetite were normal. There was no history of developmental delay, seizures, autistic features, or major medical illness nor was there any family history of neuropsychiatric problems. On behavioral observation, there was hyperactivity with marked distractibility to external stimuli along with frequent impulsive behavior. He had a score of 19 on the Conner's rating scale. A clinical impression of ADHD was noted, and the boy was prescribed atomoxetine 10 mg/day, in consideration of his weight of 20 kg, in addition to behavioral management.He came for follow-up 1 month later with his parents, who reported significant improvement (50% as per their observation) in both his hyperactivity and inattention, which they corroborated with the class teacher. His Conner's rating score was now 9. However, they observed that after 3 weeks of initiation of medications, the boy had a peculiar change in his posture characterized by a forward bending of his trunk, as a result of which he was not able to sit properly in his chair or look at the blackboard in the class. On examination, his trunk had a forward bend of 60 degrees from the vertical plane, but the rest of his neurological and general medical examination was normal. Investigations, including hematological and biochemical parameters and electrocardiogram (ECG) were unremarkable, and the CT scan of the brain was normal. He was admitted in the child psychiatry unit and because he was believed to have drug-induced camptocormia, atomoxetine was discontinued, and he was put on diazepam 5 mg orally. One week after admission, his posture began to improve, and his back straightened to 45 degrees after 1 month. He was not rechallenged with atomoxetine, as his parents did not wish to risk an exacerbation of the condition again. On the Naranjo adverse drug reaction scale, a score of 7 was noted, indicating a probable association (Naranjo et al. 1981). Methylphenidate (MPH) 10 mg was added to the regime, to which he gradually showed partial response. He has been on regular follow-up for 2 years, during which his ADHD symptoms remained under control with MPH 20 m...

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Section: Discussionmentioning

confidence: 92%

Persistent Camptocormia Associated with Atomoxetine in a Child with Attention-Deficit/Hyperactivity Disorder

Bhattacharya

Praharaj

Sinha

2014

Journal of Child and Adolescent Psychopharmacology

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“…In oocytes injected with mRNA for GIRK1/GIRK2, GIRK2, or GIRK1/GIRK4 subunits, an extracellular application of ATX or reboxetine reversibly reduced GIRK currents. The inhibitory effects were concentration dependent, but voltage-independent, and time-independent during each voltage pulse (Kobayashi et al 2010). Such findings were suggested to point to the therapeutic effects of NET inhibitors and their adverse side effects related to the nervous system and heart function.…”

Section: Drug Binding and Transport Inhibitionmentioning

confidence: 84%

“…Kobayashi and colleagues investigated the effects of ATX and reboxetine on G-proteinactivated inwardly rectifying K + (GIRK) channels using the Xenopus oocyte expression assay (Kobayashi et al 2010). In oocytes injected with mRNA for GIRK1/GIRK2, GIRK2, or GIRK1/GIRK4 subunits, an extracellular application of ATX or reboxetine reversibly reduced GIRK currents.…”

Section: Drug Binding and Transport Inhibitionmentioning

confidence: 99%

In vitro study methodologies to investigate genetic aspects and effects of drugs used in attention-deficit hyperactivity disorder

Grünblatt

Bartl²,

Marinova

et al. 2012

J Neural Transm

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Attention-deficit/hyperactivity disorder (ADHD) is one of the most common psychiatric disorders in children and adolescents, with up to 5 % affected worldwide. Twin and family studies on ADHD show its high familiality with heritability estimated around 70 %, but, to date, no specific polymorphism or gene was found to be specifically affected. Psychostimulants (amphetamine, methylphenidate) and non-psychostimulants (atomoxetine) are used successfully in ADHD therapy, but many of their mechanisms of action and their adverse effects are not yet fully understood. Therefore, both genetic findings and therapeutic interventions should be further investigated. One easy platform for such studies is in vitro analyses, which encompass neuronal cell culture studies, transfections of genetic constructs, binding and electrophysiology analyses. In this review, different methods will be referred in particular to ADHD findings, and new techniques will be mentioned for future studies of drug or genetic effects in vitro. DOI: https://doi.org/10.1007/s00702-012-0869-9Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-74484 Accepted Version Originally published at: Grünblatt, Edna; Bartl, Jasmin; Marinova, Zoya; Walitza, Susanne (2013). In vitro study methodologies to investigate genetic aspects and effects of drugs used in attention-deficit hyperactivity disorder. Journal of Neural Transmission, 120 (1)

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“…Because the volume of the Xenopus oocytes used was approximately 1 µl, the intracellular concentration of sertraline was presumed to be approximately 225 µM. For the analysis of concentration-response relationships, the data were fitted to a standard logistic equation [51] using KaleidaGraph (Synergy Software, Reading, PA, USA). The concentration of a drug that produces 50% of the maximal current response for that drug (EC 50 ), the concentrations required to reduce control currents by 25% and 50% (IC 25 and IC 50 , respectively), and the Hill coefficient ( n H ) were obtained from the concentration-response relationships.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Different Classes of Antidepressants

2011

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Various antidepressants are commonly used for the treatment of depression and several other neuropsychiatric disorders. In addition to their primary effects on serotonergic or noradrenergic neurotransmitter systems, antidepressants have been shown to interact with several receptors and ion channels. However, the molecular mechanisms that underlie the effects of antidepressants have not yet been sufficiently clarified. G protein-activated inwardly rectifying K+ (GIRK, Kir3) channels play an important role in regulating neuronal excitability and heart rate, and GIRK channel modulation has been suggested to have therapeutic potential for several neuropsychiatric disorders and cardiac arrhythmias. In the present study, we investigated the effects of various classes of antidepressants on GIRK channels using the Xenopus oocyte expression assay. In oocytes injected with mRNA for GIRK1/GIRK2 or GIRK1/GIRK4 subunits, extracellular application of sertraline, duloxetine, and amoxapine effectively reduced GIRK currents, whereas nefazodone, venlafaxine, mianserin, and mirtazapine weakly inhibited GIRK currents even at toxic levels. The inhibitory effects were concentration-dependent, with various degrees of potency and effectiveness. Furthermore, the effects of sertraline were voltage-independent and time-independent during each voltage pulse, whereas the effects of duloxetine were voltage-dependent with weaker inhibition with negative membrane potentials and time-dependent with a gradual decrease in each voltage pulse. However, Kir2.1 channels were insensitive to all of the drugs. Moreover, the GIRK currents induced by ethanol were inhibited by sertraline but not by intracellularly applied sertraline. The present results suggest that GIRK channel inhibition may reveal a novel characteristic of the commonly used antidepressants, particularly sertraline, and contributes to some of the therapeutic effects and adverse effects.

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Inhibition of G-Protein-Activated Inwardly Rectifying K+ Channels by the Selective Norepinephrine Reuptake Inhibitors Atomoxetine and Reboxetine

Cited by 24 publications

References 61 publications

Persistent Camptocormia Associated with Atomoxetine in a Child with Attention-Deficit/Hyperactivity Disorder

Persistent Camptocormia Associated with Atomoxetine in a Child with Attention-Deficit/Hyperactivity Disorder

In vitro study methodologies to investigate genetic aspects and effects of drugs used in attention-deficit hyperactivity disorder

Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Different Classes of Antidepressants

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