Cited by 123Neurotransmitter Receptor Influence on BehaviorTreatment of Major DepressionNeuroscience and Neuropharmacology Research

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Effects of duloxetine, a new serotonin and norepinephrine uptake inhibitor, on extracellular monoamine levels in rat frontal cortex.

Kihara, T, Ikeda, M·1995·The Journal of Pharmacology and Experimental Therapeutics

DOI 10.1016/s0022-3565(25)24303-8

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Abstract

The effects of duloxetine (LY248686), a new inhibitor of serotonin (5-hydroxytryptamine; 5-HT) and norepinephrine (NE) uptake on extracellular levels of NE, 5-HT and dopamine (DA), were studied in the rat frontal cortex and nucleus accumbens, using in vivo microdialysis. The oral administration of duloxetine (3.125-12.5 mg/kg) produced a dose-dependent increase in the output of both NE and 5-HT from the frontal cortex, this increase being maintained throughout the 4-hr observation period. Chronic administration of duloxetine (6.25 mg/kg, p.o.) for 14 days failed to alter basal NE and 5-HT levels in the frontal cortex, but augmented the duloxetine-induced increase in output of NE and 5-HT. Amitriptyline and maprotiline, administered p.o. at doses of 6.25 to 25 mg/kg, increased NE output, but the effect was weaker than that of duloxetine, and neither amitriptyline nor maprotiline changed 5-HT output from the frontal cortex. Duloxetine, amitriptyline, and maprotiline brought about increases in DA levels in the rat frontal cortex, the increase in DA levels induced by duloxetine being approximately two or three times more potent than that induced by amitriptyline and maprotiline. In the nucleus accumbens, duloxetine also produced a dose-dependent increase in DA output more potent than that produced by amitriptyline and maprotiline. These results show that duloxetine causes a potent and sustained increase in the output of both NE and 5-HT in the rat frontal cortex, related to its inhibition of NE and 5-HT uptake; these results also show that duloxetine increases DA output in the frontal cortex.

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Comparison of the thermogenic and hypophagic effects of sibutramine's metabolite 2 and other monoamine reuptake inhibitors
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Duloxetine's modest short-term influences in subcortical structures of first episode drug-naïve patients with major depressive disorder and panic disorder
Lai, C., & Wu, Y. (2011) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2011.03.011 · Cited by 20
“Duloxetine can increase dopamine output in a dose-dependent, potent and sustained style over rat NAc (Kihara and Ikeda, 1995).”
Effects of Duloxetine on Norepinephrine and Serotonin Transporter Activity in Healthy Subjects
Chappell, J. C., Eisenhofer, G., Owens, M. J., Haber, H. E., Lachno, D. R., Dean, R. A., Knadler, M. P., Nemeroff, C. B., Mitchell, M. I., Detke, M. J., et al. (2013) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0000000000000061 · Cited by 19
Antidepressant drugs specifically inhibiting noradrenaline reuptake enhance recognition memory in rats.
Feltmann, K., Konradsson‐Geuken, Å., Bundel, D. D., Lindskog, M., & Schilström, B. (2015) · Behavioral Neuroscience · doi:10.1037/bne0000100 · Cited by 17
“…2006), reboxetine (3 mg/kg; Borgkvist et al., 2012; Linnér et al., 2001), atomoxetine (3 mg/kg; Borgkvist et al., 2012), duloxetine (7 mg/kg; Kihara & Ikeda, 1995), mianserin (5 mg/kg; Wiker, Linner, Wadenberg, & Svensson, 2005) and desipramine (10 mg/kg; Bongiovanni, Kirkbride, Walmire, &…”
Background
Duloxetine ameliorates the impairment of diffuse noxious inhibitory control in rat models of peripheral neuropathic pain and knee osteoarthritis pain
Yoneda, S., Kasai, E., Matsuo, M., et al. (2020) · Neuroscience Letters · doi:10.1016/j.neulet.2020.134990 · Cited by 16
Chronic effects of antidepressants on serotonin release in rat raphe slice cultures: high potency of milnacipran in the augmentation of serotonin release
Nagayasu, K., Kitaichi, M., Nishitani, N., Asaoka, N., Shirakawa, H., Nakagawa, T., & Kaneko, S. (2013) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145713000771 · Cited by 16
“…chronic treatment of antidepressants causes an increase in basal extracellular 5-HT levels, in 5-HT release after antidepressant challenge in vivo, or in electrically evoked 5-HT release from slices (Bel and Artigas, 1993; Blier and Bouchard, 1994; Kihara and Ikeda, 1994; Kreiss and Lucki, 1995).”
Background
Effect of acute treatment with YM992 on extracellular serotonin levels in the rat frontal cortex
Hatanaka, K.-I., Yatsugi, S., & Yamaguchi, T. (2000) · European Journal of Pharmacology · doi:10.1016/s0014-2999(00)00174-6 · Cited by 15
Role of central serotonin and noradrenaline interactions in the antidepressants’ action: Electrophysiological and neurochemical evidence
Delcourte, S., Etiévant, A., & Haddjeri, N. (2021) · Progress in brain research · doi:10.1016/bs.pbr.2021.01.002 · Cited by 17
Noradrenaline reuptake inhibition increases control of impulsive action by activating D1-like receptors in the infralimbic cortex
Sasamori, H., Ohmura, Y., Yoshida, T., & Yoshioka, M. (2018) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2018.11.041 · Cited by 14
Subchronic milnacipran treatment increases basal extracellular noradrenaline concentrations in the medial prefrontal cortex of rats
Kitaichi, Y., Inoue, T., Izumi, T., et al. (2005) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2005.08.004 · Cited by 12
Duloxetine versus ‘active’ placebo, placebo or no intervention for major depressive disorder; a protocol for a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis
Siddiqui, F., Barbateskovic, M., Juul, S., Katakam, K. K., Munkholm, K., Gluud, C. N., & Jakobsen, J. C. (2021) · Systematic Reviews · doi:10.1186/s13643-021-01722-5 · Cited by 12
“In vivo and in vitro studies indicate that duloxetine inhibits the presynaptic neuronal reuptake of the neurotransmitters serotonin and norepinephrine, leading to their greater availability at the neuronal junctions and potentiating their action in the central nervous system [15, 16].”
Background
Preclinical discovery of duloxetine for the treatment of depression
Torres-Sánchez, S., Pérez-Caballero, L., Micó, J. A., Elorza, J., & Berrocoso, E. (2012) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2012.693912 · Cited by 12
“1 Acute duloxetine treatment In rat microdialysis studies, acute duloxetine increases 5-HT, NA and DA levels in the cerebral cortex [13-17], 5-HT and NA levels in the hippocampus [11,18] and DA levels in nucleus accumbens [15] in a dose-dependent manner.”
Background
Simultaneous Increases of Extracellular Monoamines in Microdialysates from Hypothalamus of Conscious Rats by Duloxetine, a Dual Serotonin and Norepinephrine Uptake Inhibitor
Engleman, E. A., Perry, K. W., Mayle, D. A., et al. (1995) · Neuropsychopharmacology · doi:10.1038/sj.npp.1380263 · Cited by 12
Role of Axonal and Somatodendritic Monoamine Transporters in Action of Uptake Blockers
Chen, N., & Reith, M. E. A. (1997) · Humana Press eBooks · doi:10.1007/978-1-59259-470-2_12 · Cited by 12
Past and current drug repurposing clinical trials to treat cognition in methamphetamine use: a scoping review of pharmacotherapy candidates
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Dual serotonin and noradrenaline reuptake inhibitors: Focus on their differences
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Treatments for neuropathic pain differentially affect delayed matching accuracy by macaques: Effects of amitriptyline and gabapentin
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“Although amitriptyline can also facilitate ascending a2-adrenergic transmission to forebrain structures involved in cognitive processing [35], the strong anti-muscarinic (i.”
Background
Selective Decrease in Serotonin Synthesis Rate in Rat Brainstem Raphe Nuclei Following Chronic Administration of Low Doses of Amitriptyline: an Effect Compatible with an Anti-Migraine Effect
Pringsheim, T. M., Dikšić, M., Dobson, C., et al. (2003) · Cephalalgia · doi:10.1046/j.1468-2982.2003.00526.x · Cited by 10
[18F]fluoroethoxy-benzovesamicol, a PET radiotracer for the vesicular acetylcholine transporter and cholinergic synapses
Mulholland, G. K., Wieland, D. M., Kilbourn, M. R., Frey, K. A., Sherman, P. S., Carey, J. E., & Kuhl, D. E. (1998) · Synapse · doi:10.1002/(sici)1098-2396(199811)30:3 · Cited by 100
Neurochemical and behavioral characterization of potential antidepressant properties of indeloxazine hydrochloride
Yamaguchi, T., Ohyama, M., Suzuki, M., et al. (1998) · Neuropharmacology · doi:10.1016/s0028-3908(98)00009-4 · Cited by 8
New N-(benzhydryloxyalkyl)-4-(carboxy/carbamoylmethyl) piperidine derivatives with antidepressant activity
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The role of peripheral serotonin and norepinephrine in the gastroprotective effect against stress of duloxetine
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Decreased Brain Ventricular Volume in Psychiatric Inpatients with Serotonin Reuptake Inhibitor Treatment
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Effect of a combination of duloxetine with hydroxyzine on experimental models of anxiety in mice
Addepalli, V., Patel, S., Kale, P. P., Sarkar, A., & Savai, J. (2015) · Indian Journal of Pharmacology · doi:10.4103/0253-7613.153424 · Cited by 8
“Similarly, the duloxetine treatment-induced increase in brain monoamine profile [Table 3] is in agreement with previous reports.[19,20] The 5-HT and NE reuptake action of the duloxetine help in treating anxiety associated neurobiological dysfunctions of the serotonergic and noradrenergic system.”
Result
Duloxetine protected indomethacin-induced gastric mucosal injury by increasing serotonin-dependent RANTES expression and activating PI3K-AKT-VEGF pathway
Ding, H., Wang, Y., Gao, Y., Ye, F., Yao, K., Cao, L., Liu, Z., Wang, G., & Zhang, J. (2024) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2024.116950 · Cited by 6
A Review of the Serotonin-Norepinephrine Reuptake Inhibitors: Pharmacologic Aspects and Clinical Implications for Treatment of Major Depressive Disorder and Associated Painful Physical Symptoms
Alev, L., Lenox‐Smith, A., Altın, M., & Dueñas, H. (2013) · Open Journal of Depression · doi:10.4236/ojd.2013.24011 · Cited by 6
“Kihara and Ikeda (Kihara & Ikeda, 1995) also showed using microdialysis that duloxetine administration in rats results in balanced increases in 5-HT and NE even at the lowest doses (without having to “push” the dose).”
Background
Presynaptic adaptive responses to constitutive versus adult pharmacologic inhibition of serotonin uptake
Luellen, B. A., Gilman, T. L., & Andrews, A. M. (2010) · Cambridge University Press eBooks · doi:10.1017/cbo9780511729935.002 · Cited by 6
The Combination of Antidepressant Duloxetine with Piracetam in Mice does not Produce Enhancement of Nootropic Activity
Kale, P. P., Addepalli, V., Sarkar, A., Patel, S., & Savai, J. (2014) · Experimental Neurobiology · doi:10.5607/en.2014.23.3.224 · Cited by 4
Future Strategies for the Treatment of Depression
Grosso, C. (2016) · Springer eBooks · doi:10.1007/978-3-319-14021-6_12 · Cited by 4

Authors: Kihara, T., & Ikeda, M.
Affiliations: Shionogi (Japan) (JP)
Venue: The Journal of Pharmacology and Experimental Therapeutics
Publisher: Elsevier BV
Published: 1995-01
Volume: 272
Issue: 1
Pages: 177-183
ISSN: 0022-3565 (ISSN-L)
DOI: 10.1016/s0022-3565(25)24303-8
OpenAlex: W1846318813
Cited by: 123
References: 0
Citations by year: 2025: 1 · 2024: 1 · 2023: 4 · 2022: 3 · 2021: 4 · 2020: 2 · 2019: 3 · 2018: 6 · 2017: 3 · 2016: 2 · 2015: 4 · 2014: 5 · 2013: 7 · 2012: 3
FWCI: 2.13
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
PubMed (publishedVersion)
PubMed
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: duloxetine, serotonin-norepinephrine reuptake inhibitors, serotonin, norepinephrine, dopamine, frontal cortex, nucleus accumbens, amitriptyline, maprotiline, chronic drug administration, antidepressant effects
MeSH terms: Duloxetine Hydrochloride, Amitriptyline, Animals, Biological Transport, Cerebral Cortex, Dopamine, Male, Maprotiline, Norepinephrine, Nucleus Accumbens, Serotonin, Thiophenes, Rats, Wistar, Rats

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Effects of duloxetine, a new serotonin and norepinephrine uptake inhibitor, on extracellular monoamine levels in rat frontal cortex.

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