Skip to main content
SpringerLink
Log in

Milnacipran enhances the control of impulsive action by activating D1-like receptors in the infralimbic cortex

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Elevated impulsivity is often observed in patients with depression. We recently found that milnacipran, an antidepressant and a serotonin/noradrenaline reuptake inhibitor, could enhance impulse control in rats. However, the neural mechanisms underlying the effects of milnacipran on impulsive action remain unclear. Milnacipran increases not only extracellular serotonin and noradrenaline but also dopamine specifically in the medial prefrontal cortex, which is one of the brain regions responsible for impulsive action.

Objectives

Our goal was to identify whether D1- and/or D2-like receptors in the infralimbic cortex (IL), the ventral portion of the medial prefrontal cortex, mediates the milnacipran-enhanced impulse control in a three-choice serial reaction time task.

Methods

The rats were bilaterally injected with SCH23390, a selective D1-like receptor antagonist (0.3 or 3 ng/side) or eticlopride, a selective D2-like receptor antagonist (0.3 or 1 μg/side) into the IL after acute intraperitoneal administration of milnacipran (10 mg/kg).

Results

Intra-IL SCH23390 injections reversed the milnacipran-enhanced impulse control, whereas injections of eticlopride into the IL failed to block the effects of milnacipran on impulsive action.

Conclusions

This is the first report that demonstrates a critical role for D1-like receptors of the IL in milnacipran-enhanced control of impulsive action.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Arsenault-Lapierre G, Kim C, Turecki G (2004) Psychiatric diagnoses in 3275 suicides: a meta-analysis. BMC Psychiatry 4:37

    Article  PubMed  Google Scholar 

  • Bourne JA (2001) SCH 23390: the first selective dopamine D1-like receptor antagonist. CNS Drug Rev 7(4):399–414

    Article  PubMed  CAS  Google Scholar 

  • Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin SM, Gehlert DR, Perry KW (2002) Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology 27(5):699–711

    Article  PubMed  CAS  Google Scholar 

  • Carboni E, Tanda GL, Frau R, Di Chiara G (1990) Blockade of the noradrenaline carrierincreases extracellular dopamine concentrations in the prefrontal cortex: evidence that dopamine is taken up in vivo by noradrenergic terminals. J Neurochem 55:1067–1070

    Article  PubMed  CAS  Google Scholar 

  • Carli M, Samanin R (2000) The 5-HT(1A) receptor agonist 8-OH-DPAT reduces rats’ accuracy of attentional performance and enhances impulsive responding in a five-choice serial reaction time task: role of presynaptic 5-HT(1A) receptors. Psychopharmacology 149(3):259–268

    Article  PubMed  CAS  Google Scholar 

  • Carr DB, Sesack SR (2000) Projections from the rat prefrontal cortex to the ventral tegmental area: target specificity in the synaptic associations with mesoaccumbens and mesocortical neurons. J Neurosci 20(10):3864–3873

    PubMed  CAS  Google Scholar 

  • Carr DB, O’Donnell P, Card JP, Sesack SR (1999) Dopamine terminals in the rat prefrontal cortex synapse on pyramidal cells that project to the nucleus accumbens. J Neurosci 19(24):11049–11060

    PubMed  CAS  Google Scholar 

  • Chudasama Y, Passetti F, Rhodes SE, Lopian D, Desai A, Robbins TW (2003) Dissociable aspects of performance on the 5-choice serial reaction time task following lesions of the dorsal anterior cingulate, infralimbic and orbitofrontal cortex in the rat: differential effects on selectivity, impulsivity and compulsivity. Behav Brain Res 146:105–119

    Article  PubMed  CAS  Google Scholar 

  • Cole BJ, Robbins TW (1987) Amphetamine impairs the discriminative performance of rats with dorsal noradrenergic bundle lesions on a 5-choice serial reaction time task: new evidence for central dopaminergic-noradrenergic interactions. Psychopharmacology 91:458–466

    Article  PubMed  CAS  Google Scholar 

  • Cooper JR, Bloom FE, Roth RH (2003) The biochemical basis of neuropharmacology. Oxford University Press, New York

    Google Scholar 

  • Corruble E, Benyamina A, Bayle F, Falissard B, Hardy P (2003) Understanding impulsivity in severe depression? A psychometrical contribution. Prog Neuropsychopharmacol Biol Psychiatry 27(5):829–833

    Article  PubMed  Google Scholar 

  • Dalley JW, Mar AC, Economidou D, Robbins TW (2007) Neurobehavioral mechanisms of impulsivity: fronto-striatal systems and functional neurochemistry. Pharmacol Biochem Behav 90:250–260

    Article  PubMed  Google Scholar 

  • Diergaarde L, Pattij T, Poortvliet I, Hogenboom F, de Vries W, Schoffelmeer AN, De Vries TJ (2008) Impulsive choice and impulsive action predict vulnerability to distinct stages of nicotine seeking in rats. Biol Psychiatry 63(3):301–308

    Article  PubMed  CAS  Google Scholar 

  • Fletcher PJ, Tampakeras M, Sinyard J, Higgins GA (2007) Opposing effects of 5-HT(2A) and 5-HT(2C) receptor antagonists in the rat and mouse on premature responding in the five-choice serial reaction time test. Psychopharmacology (Berl) 195(2):223–234

    Article  CAS  Google Scholar 

  • Gabbott PL, Warner TA, Jays PR, Salway P, Busby SJ (2005) Prefrontal cortex in the rat: projections to subcortical autonomic, motor, and limbic centers. J Comp Neurol 492:145–177

    Article  PubMed  Google Scholar 

  • Gaspar P, Bloch B, Le Moine C (1995) D1 and D2 receptor gene expression in the rat frontal cortex: cellular localization in different classes of efferent neurons. Eur J Neurosci 7(5):1050–1063

    Article  PubMed  CAS  Google Scholar 

  • Gill TM, Castaneda PJ, Janak PH (2010) Dissociable roles of the medial prefrontal cortex and nucleus accumbens core in goal-directed actions for differential reward magnitude. Cereb Cortex 20(12):2884–2899

    Article  PubMed  Google Scholar 

  • Hall H, Köhler C, Gawell L (1985) Some in vitro receptor binding properties of [3H]eticlopride, a novel substituted benzamide, selective for dopamine-D2 receptors in the rat brain. Eur J Pharmacol 111(2):191–199

    Article  PubMed  CAS  Google Scholar 

  • Harrison AA, Everitt BJ, Robbins TW (1997) Central 5-HT depletion enhances impulsive responding without affecting the accuracy of attentional performance: interactions with dopaminergic mechanisms. Psychopharmacology (Berl) 133(4):329–342

    Article  CAS  Google Scholar 

  • Holm S (1979) A simple sequentially rejective multiple test procedure. Scand J Stat 6:65–70

    Google Scholar 

  • Jackson ME, Frost AS, Moghaddam B (2001) Stimulation of prefrontal cortex at physiologically relevant frequencies inhibits dopamine release in the nucleus accumbens. J Neurochem 78(4):920–923

    Article  PubMed  CAS  Google Scholar 

  • Jose PA, Yu PY, Yamaguchi I, Eisner GM, Mouradian MM, Felder CC, Felder RA (2007) Dopamine D1 receptor regulation of phospholipase C. Hypertens Res 18(Suppl 1):S39–S42

    Google Scholar 

  • King D, Zigmond MJ, Finlay JM (1997) Effects of dopamine depletion in the medial prefrontal cortex on the stress-induced increase in extracellular dopamine in the nucleus accumbens core and shell. Neuroscience 77(1):141–153

    Article  PubMed  CAS  Google Scholar 

  • Kitaichi Y, Inoue T, Nakagawa S, Izumi T, Koyama T (2005) Effect of milnacipran on extracellular monoamine concentrations in the medial prefrontal cortex of rats pre-treated with lithium. Eur J Pharmacol 516:219–226

    Article  PubMed  CAS  Google Scholar 

  • Kitaichi Y, Inoue T, Izumi T, Nakagawa S, Tanaka T, Masui T, Koyama T (2008) Effect of co-administration of a serotonin–noradrenaline reuptake inhibitor and a dopamine agonist on extracellular monoamine concentrations in rats. Eur J Pharmacol 584(2–3):285–290

    Article  PubMed  CAS  Google Scholar 

  • Le Moine C, Gaspar P (1998) Subpopulations of cortical GABAergic interneurons differ by their expression of D1 and D2 dopamine receptor subtypes. Brain Res Mol Brain Res 58(1–2):231–236

    Article  PubMed  Google Scholar 

  • Leland DS, Arce E, Feinstein JS, Paulus MP (2006) Young adult stimulant users’ increased striatal activation during uncertainty is related to impulsivity. NeuroImage 33(2):725–731

    Article  PubMed  Google Scholar 

  • Liu YP, Lin YL, Chuang CH, Kao YC, Chang ST, Tung CS (2009) Alpha adrenergic modulation on effects of norepinephrine transporter inhibitor reboxetine in five-choice serial reaction time task. J Biomed Sci 16:72

    Article  PubMed  Google Scholar 

  • Loos M, Pattij T, Janssen MC, Counotte DS, Schoffelmeer AN, Smit AB, Spijker S, van Gaalen MM (2010) Dopamine receptor D1/D5 gene expression in the medial prefrontal cortex predicts impulsive choice in rats. Cereb Cortex 20(5):1064–1070

    Article  PubMed  Google Scholar 

  • Lu XY, Churchill L, Kalivas PW (1997) Expression of D1 receptor mRNA in projections from the forebrain to the ventral tegmental area. Synapse 25(2):205–214

    Article  PubMed  CAS  Google Scholar 

  • Maalouf FT, Brent D, Clark L, Tavitian L, McHugh RM, Sahakian BJ, Phillips ML (2011) Neurocognitive impairment in adolescent major depressive disorder: state vs. trait illness markers. J Affect Disord 133(3):625–632

    Article  PubMed  Google Scholar 

  • McGirr A, Renaud J, Bureau A, Seguin M, Lesage A, Turecki G (2008) Impulsive-aggressive behaviours and completed suicide across the life cycle: a predisposition for younger age of suicide. Psychol Med 38(3):407–417

    Article  PubMed  CAS  Google Scholar 

  • Millan MJ, Newman-Tancredi A, Quentric Y, Cussac D (2001) The “selective” dopamine D1 receptor antagonist, SCH23390, is a potent and high efficacy agonist at cloned human serotonin2C receptors. Psychopharmacology (Berl) 156(1):58–62

    Article  CAS  Google Scholar 

  • Milstein JA, Dalley JW, Robbins TW (2010) Methylphenidate-induced impulsivity: pharmacological antagonism by beta-adrenoreceptor blockade. J Psychopharmacol 24(3):309–321

    Article  PubMed  CAS  Google Scholar 

  • Murphy ER, Dalley JW, Robbins TW (2005) Local glutamate receptor antagonism in the rat prefrontal cortex disrupts response inhibition in a visuospatial attentional task. Psychopharmacology (Berl) 179(1):99–107

    Article  CAS  Google Scholar 

  • Myers JL, Well AD (2010) Research design and statistical analysis, 3rd edn. Routledge Academic, New York

    Google Scholar 

  • Navarra R, Comery TA, Graf R, Rosenzweig-Lipson S, Day M (2008) The 5-HT(2C) receptor agonist WAY-163909 decreases impulsivity in the 5-choice serial reaction time test. Behav Brain Res 188(2):412–415

    Article  PubMed  CAS  Google Scholar 

  • Neumeyer JL, Kula NS, Bergman J, Baldessarini RJ (2003) Receptor affinities of dopamine D1 receptor-selective novel phenylbenzazepines. Eur J Pharmacol 474(2–3):137–140

    Article  PubMed  CAS  Google Scholar 

  • Oda S, Funato H, Adachi-Akahane S, Ito M, Okada A, Igarashi H, Yokofujita J, Kuroda M (2010) Dopamine D5 receptor immunoreactivity is differentially distributed in GABAergic interneurons and pyramidal cells in the rat medial prefrontal cortex. Brain Res 1329:89–102

    Article  PubMed  CAS  Google Scholar 

  • Ohmura Y, Yamaguchi T, Futami Y, Togashi H, Izumi T, Matsumoto M, Yoshida T, Yoshioka M (2009) Corticotropin releasing factor enhances attentional function as assessed by the five-choice serial reaction time task in rats. Behav Brain Res 198(2):429–433

    Article  PubMed  CAS  Google Scholar 

  • Passetti F, Chudasama Y, Robbins TW (2002) The frontal cortex of the rat and visual attentional performance: dissociable functions of distinct medial prefrontal subregions. Cereb Cortex 12(12):1254–1268

    Article  PubMed  Google Scholar 

  • Pattij T, Janssen MC, Vanderschuren LJ, Schoffelmeer AN, van Gaalen MM (2006) Involvement of dopamine D1 and D2 receptors in the nucleus accumbens core and shell in inhibitory response control. Psychopharmacology 191:587–598

    Article  PubMed  Google Scholar 

  • Pattij T, Schetters D, Schoffelmeer AN, van Gaalen MM (2012) On the improvement of inhibitory response control and visuospatial attention by indirect and direct adrenoceptor agonists. Psychopharmacology (Berl) 219(2):327–340

    Article  CAS  Google Scholar 

  • Paxinos G, Watson C (1996) The rat brain in stereotaxic coordinates, 3rd edn. Academic, San Diego

    Google Scholar 

  • Perroud N, Baud P, Mouthon D, Courtet P, Malafosse A (2011) Impulsivity, aggression and suicidal behavior in unipolar and bipolar disorders. J Affect Disord 134(1–3):112–118

    Article  PubMed  Google Scholar 

  • Perry JL, Larson EB, German JP, Madden GJ, Carroll ME (2005) Impulsivity (delay discounting) as a predictor of acquisition of IV cocaine self-administration in female rats. Psychopharmacology 178:193–201

    Article  PubMed  CAS  Google Scholar 

  • Pozzi L, Invernizzi R, Cervo L, Vallebuona F, Samanin R (1994) Evidence that extracellular concentrations of dopamine are regulated by noradrenergic neurons in the frontal cortex of rats. J Neurochem 63:195–200

    Article  PubMed  CAS  Google Scholar 

  • Radcliffe RA, Erwin VG (1996) Alterations in locomotor activity after microinjections of GBR-12909, selective dopamine antagonists or neurotensin into the medial prefrontal cortex. J Pharmacol Exp Ther 277(3):1467–1476

    PubMed  CAS  Google Scholar 

  • Richfield EK, Penney JB, Young AB (1989) Anatomical and affinity state comparisons between dopamine D1 and D2 receptors in the rat central nervous system. Neuroscience 30(3):767–777

    Article  PubMed  CAS  Google Scholar 

  • Rivera A, Peñafiel A, Megías M, Agnati LF, López-Téllez JF, Gago B, Gutiérrez A, de la Calle A, Fuxe K (2008) Cellular localization and distribution of dopamine D(4) receptors in the rat cerebral cortex and their relationship with the cortical dopaminergic and noradrenergic nerve terminal networks. Neuroscience 155(3):997–1010

    Article  PubMed  CAS  Google Scholar 

  • Robbins TW (2002) The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry. Psychopharmacology 163:362–380

    Article  PubMed  CAS  Google Scholar 

  • Robinson ES, Eagle DM, Mar AC, Bari A, Banerjee G, Jiang X, Dalley JW, Robbins TW (2008) Similar effects of the selective noradrenaline reuptake inhibitor atomoxetine on three distinct forms of impulsivity in the rat. Neuropsychopharmacology 33(5):1028–1037

    Article  PubMed  CAS  Google Scholar 

  • Sasaki A, Mochizuki N, Sugihara T (1994) Metabolic fate of the new antidepressant, milnacipran, in rats. Clinical Report 28(12):3649–3670

    Google Scholar 

  • Sokolowski JD, Salamone JD (1994) Effects of dopamine depletions in the medial prefrontal cortex on DRL performance and motor activity in the rat. Brain Res 642:20–28

    Article  PubMed  CAS  Google Scholar 

  • Stahl SM, Grady MM, Moret C, Briley M (2005) SNRIs: their pharmacology, clinical efficacy, and tolerability in comparison with other classes of antidepressants. CNS Spectr 10(9):732–747

    PubMed  Google Scholar 

  • Sun H, Green TA, Theobald DE, Birnbaum SG, Graham DL, Zeeb FD, Nestler EJ, Winstanley CA (2010) Yohimbine increases impulsivity through activation of cAMP response element binding in the orbitofrontal cortex. Biol Psychiatry 67(7):649–656

    Article  PubMed  CAS  Google Scholar 

  • Swendsen JD, Merikangas KR, Canino GJ, Kessler RC, Rubio-Stipec M, Angst J (1998) The comorbidity of alcoholism with anxiety and depressive disorders in four geographic communities. Compr Psychiatry 39(4):176–184

    Article  PubMed  CAS  Google Scholar 

  • Tang L, Todd RD, Heller A, O’Malley KL (1994) Pharmacological and functional characterization of D2, D3 and D4 dopamine receptors in fibroblast and dopaminergic cell lines. J Pharmacol Exp Ther 268(1):495–502

    PubMed  CAS  Google Scholar 

  • Tsutsui-Kimura I, Ohmura Y, Izumi T, Yamaguchi T, Yoshida T, Yoshioka M (2009) The effects of serotonin and/or noradrenaline reuptake inhibitors on impulsive-like action assessed by the 3-choice serial reaction time task: a simple and valid model of impulsive action using rats. Behav Pharmacol 20(5–6):474–483

    Article  PubMed  CAS  Google Scholar 

  • Tsutsui-Kimura I, Ohmura Y, Izumi T, Yamaguchi T, Yoshida T, Yoshioka M (2010) Nicotine provokes impulsive-like action by stimulating alpha4beta2 nicotinic acetylcholine receptors in the infralimbic, but not in the prelimbic cortex. Psychopharmacology 209:351–359

    Article  PubMed  CAS  Google Scholar 

  • Van Eden CG, Hoorneman EM, Buijs RM, Matthijssen MA, Geffard M, Uylings HB (1987) Immunocytochemical localization of dopamine in the prefrontal cortex of the rat at the light and electron microscopical level. Neuroscience 22(3):849–862

    Article  PubMed  Google Scholar 

  • van Gaalen MM, Brueggeman RJ, Bronius PF, Schoffelmeer AN, Vanderschuren LJ (2006) Behavioral disinhibition requires dopamine receptor activation. Psychopharmacology (Berl) 187(1):73–85

    Article  CAS  Google Scholar 

  • Vertes RP (2004) Differential projections of the infralimbic and prelimbic cortex in the rat. Synapse 51(1):32–58

    Article  PubMed  CAS  Google Scholar 

  • Winstanley CA, Chudasama Y, Dalley JW, Theobald DE, Glennon JC, Robbins TW (2003) Intra-prefrontal 8-OH-DPAT and M100907 improve visuospatial attention and decrease impulsivity on the five-choice serial reaction time task in rats. Psychopharmacology (Berl) 167(3):304–314

    CAS  Google Scholar 

  • Yamamoto BK, Novotney S (1998) Regulation of extracellular dopamine by the norepinephrine transporter. J Neurochem 71:274–280

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This work was partially supported by Asahi-Kasei Co. Ltd.

Author information

Authors and Affiliations

  1. Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, N15 W7, Kita-ku, Sapporo, 060-8638, Japan

    Iku Tsutsui-Kimura, Yu Ohmura, Takeshi Izumi, Haruko Kumamoto, Takayuki Yoshida & Mitsuhiro Yoshioka

  2. Department of Pharmacology, Faculty of Pharmaceutical Sciences, Nagasaki International University, Sasebo, 859-3298, Japan

    Taku Yamaguchi

  3. Japan Society for the Promotion of Science, Tokyo, Japan

    Iku Tsutsui-Kimura

Authors
  1. Iku Tsutsui-Kimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu Ohmura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takeshi Izumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Haruko Kumamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Taku Yamaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takayuki Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mitsuhiro Yoshioka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yu Ohmura.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 231 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tsutsui-Kimura, I., Ohmura, Y., Izumi, T. et al. Milnacipran enhances the control of impulsive action by activating D1-like receptors in the infralimbic cortex. Psychopharmacology 225, 495–504 (2013). https://doi.org/10.1007/s00213-012-2835-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-012-2835-5

Keywords

Search

Navigation