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Cabergoline, a dopamine receptor agonist, has an antidepressant-like property and enhances brain-derived neurotrophic factor signaling

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Abstract

Rationale

Dopamine agonists have been implicated in the treatment of depression. Cabergoline is an ergot derivative with a high affinity to dopamine D2-like receptors; however, there have been few preclinical studies on its antidepressant-like effects.

Materials and methods

Behavioral effects of cabergoline were examined in rats using forced swimming (FST), novelty-suppressed feeding (NST), open field (OFT), and elevated-plus maze (EPT) tests. In a single treatment paradigm, behaviors of rats were analyzed 4 h after single injection of cabergoline (s.c., 0–4 µmol/kg). In a repeated-treatment paradigm, OFT, EPT, and FST were conducted on days 11, 12, and13–14, respectively, during daily cabergoline injections (s.c., 0.5 µmol/kg), and then hippocampus was removed 24 h after the last injection. NST was conducted in a separate experiment at day 14. Western blotting was used for the analysis of the protein levels of brain-derived neurotrophic factor (BDNF) and the activation of intracellular signaling molecules.

Results

Single injection of cabergoline demonstrated decreased immobility in FST and distance traveled during 0–10 min in OFT, while time spent and entry into open arms were increased at 4 µmol/kg. When cabergoline was repeatedly administered, immobility in FST and the latency of feeding in NSF were significantly reduced, while vertical movement was increased in OFT. The time in closed arms was tended to be decreased in EPT. Expression of BDNF and activation of extracellular signal-regulated kinase 1 were up-regulated after the chronic administration of cabergoline.

Conclusions

Cabergoline exerts antidepressant- and anxiolytic-like effects, which may be mediated by potentiation of intracellular signaling of BDNF.

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References

  • Adachi N, Kunugi H (2008) Impaired secretion of brain-derived neurotrophic factor and neuropsychiatric diseases. Open Neurosci J 2:59–64

    CAS  Google Scholar 

  • Angelucci F, Mathé AA, Aloe L (2000) Brain-derived neurotrophic factor and tyrosine kinase receptor TrkB in rat brain are significantly altered after haloperidol and risperidone administration. J Neurosci Res 60:783–794

    Article  CAS  PubMed  Google Scholar 

  • Basso AM, Gallagher KB, Bratcher NA, Brioni JD, Moreland RB, Hsieh GC, Drescher K, Fox GB, Decker MW, Rueter LE (2005) Antidepressant-like effect of D(2/3) receptor-, but not D(4) receptor-activation in the rat forced swim test. Neuropsychopharmacology 30:1257–1268

    CAS  PubMed  Google Scholar 

  • Bodnoff SR, Suranyi-Cadotte B, Quirion R, Meaney MJ (1989) A comparison of the effects of diazepam versus several typical and atypical anti-depressant drugs in an animal model of anxiety. Psychopharmacology (Berl) 97:277–279

    Article  CAS  Google Scholar 

  • Castrén E, Võikar V, Rantamäki T (2007) Role of neurotrophic factors in depression. Curr Opin Pharmacol 7:18–21

    Article  PubMed  Google Scholar 

  • Chen B, Dowlatshahi D, MacQueen GM, Wang JF, Young LT (2001) Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry 50:260–265

    Article  CAS  PubMed  Google Scholar 

  • Dawson NM, Hamid EH, Egan MF, Meredith GE (2001) Changes in the pattern of brain-derived neurotrophic factor immunoreactivity in the rat brain after acute and subchronic haloperidol treatment. Synapse 39:70–81

    Article  CAS  PubMed  Google Scholar 

  • De La Garza RII, Mahoney JJ III (2004) A distinct neurochemical profile in WKY rats at baseline and in response to acute stress: implications for animal models of anxiety and depression. Brain Res 1021:209–218

    Article  Google Scholar 

  • Detke MJ, Rickels M, Lucki I (1995) Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants. Psychopharmacology (Berl) 121:66–72

    Article  CAS  Google Scholar 

  • Du F, Li R, Huang Y, Li X, Le W (2005) Dopamine D3 receptor-preferring agonists induce neurotrophic effects on mesencephalic dopamine neurons. Eur J Neurosci 22:2422–2430

    Article  PubMed  Google Scholar 

  • Duman RS, Monteggia LM (2006) A neurotrophic model for stress-related mood disorders. Biol Psychiatry 59:1116–1127

    Article  CAS  PubMed  Google Scholar 

  • Dunham JS, Deakin JF, Miyajima F, Payton A, Toro CT (2009) Expression of hippocampal brain-derived neurotrophic factor and its receptors in Stanley consortium brains. J Psychiatr Res 43:1175–1184

    Google Scholar 

  • Dunlop BW, Nemeroff CB (2007) The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry 64:327–337

    Article  CAS  PubMed  Google Scholar 

  • Dwivedi Y, Rizavi HS, Roberts RC, Conley RC, Tamminga CA, Pandey GN (2001) Reduced activation and expression of ERK1/2 MAP kinase in the post-mortem brain of depressed suicide subjects. J Neurochem 77:916–928

    Article  CAS  PubMed  Google Scholar 

  • Eilam D, Szechtman H (1989) Biphasic effect of D-2 agonist quinpirole on locomotion and movements. Eur J Pharmacol 161:151–157

    Article  CAS  PubMed  Google Scholar 

  • Einat H, Yuan P, Gould TD, Li J, Du J, Zhang L, Manji HK, Chen G (2003) The role of the extracellular signal-regulated kinase signaling pathway in mood modulation. J Neurosci 23:7311–7316

    CAS  PubMed  Google Scholar 

  • Feng P, Guan Z, Yang X, Fang J (2003) Impairments of ERK signal transduction in the brain in a rat model of depression induced by neonatal exposure of clomipramine. Brain Res 991:195–205

    Article  CAS  PubMed  Google Scholar 

  • Fumagalli F, Molteni R, Bedogni F, Gennarelli M, Perez J, Racagni G, Riva MA (2004) Quetiapine regulates FGF-2 and BDNF expression in the hippocampus of animals treated with MK-801. NeuroReport 15:2109–2112

    Article  CAS  PubMed  Google Scholar 

  • Fumagalli F, Molteni R, Calabrese F, Frasca A, Racagni G, Riva MA (2005) Chronic fluoxetine administration inhibits extracellular signal-regulated kinase 1/2 phosphorylation in rat brain. J Neurochem 93:1551–1560

    Article  CAS  PubMed  Google Scholar 

  • Gambarana C, Scheggi S, Tagliamonte A, Tolu P, De Montis MG (2001) Animal models for the study of antidepressant activity. Brain Res Brain Res Protoc 7:11–20

    Article  CAS  PubMed  Google Scholar 

  • Grønli J, Bramham C, Murison R, Kanhema T, Fiske E, Bjorvatn B, Ursin R, Portas CM (2006) Chronic mild stress inhibits BDNF protein expression and CREB activation in the dentate gyrus but not in the hippocampus proper. Pharmacol Biochem Behav 85:842–849

    Article  PubMed  Google Scholar 

  • Hetman M, Kanning K, Cavanaugh JE, Xia Z (1999) Neuroprotection by brain-derived neurotrophic factor is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase. J Biol Chem 274:22569–22580

    Article  CAS  PubMed  Google Scholar 

  • Huang EJ, Reichardt LF (2001) Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 24:677–736

    Article  CAS  PubMed  Google Scholar 

  • Inoue T, Tsuchiya K, Miura J, Sakakibara S, Denda K, Kasahara T, Koyama T (1996) Bromocriptine treatment of tricyclic and heterocyclic antidepressant-resistant depression. Biol Psychiatry 40:151–153

    Article  CAS  PubMed  Google Scholar 

  • Izumi T, Inoue T, Kitagawa N, Nishi N, Shimanaka S, Takahashi Y, Kusumi I, Odagaki Y, Denda K, Ohmori T, Koyama T (2000) Open pergolide treatment of tricyclic and heterocyclic antidepressant-resistant depression. J Affect Disord 61:127–132

    Article  CAS  PubMed  Google Scholar 

  • Kaplan DR, Miller FD (1997) Signal transduction by the neurotrophin receptors. Curr Opin Cell Biol 9:213–221

    Article  CAS  PubMed  Google Scholar 

  • Keller MB (2005) Issues in treatment-resistant depression. J Clin Psychiatry 66(Suppl 8):5–12

    CAS  PubMed  Google Scholar 

  • Koeltzow TE, Austin JD, Vezina P (2003) Behavioral sensitization to quinpirole is not associated with increased nucleus accumbens dopamine overflow. Neuropharmacology 44:102–110

    Article  CAS  PubMed  Google Scholar 

  • Kumamaru E, Numakawa T, Adachi N, Yagasaki Y, Izumi A, Niyaz M, Kudo M, Kunugi H (2008) Glucocorticoid prevents brain-derived neurotrophic factor-mediated maturation of synaptic function in developing hippocampal neurons through reduction in the activity of mitogen-activated protein kinase. Mol Endocrinol 22:546–558

    Article  CAS  PubMed  Google Scholar 

  • Küppers E, Beyer C (2001) Dopamine regulates brain-derived neurotrophic factor (BDNF) expression in cultured embryonic mouse striatal cells. NeuroReport 12:1175–1179

    Article  PubMed  Google Scholar 

  • Lattanzi L, Dell’Osso L, Cassano P, Pini S, Rucci P, Houck PR, Gemignani A, Battistini G, Bassi A, Abelli M, Cassano GB (2002) Pramipexole in treatment-resistant depression: a 16-week naturalistic study. Bipolar Disord 4:307–314

    Article  CAS  PubMed  Google Scholar 

  • Leentjens AF, Koester J, Fruh B, Shephard DT, Barone P, Houben JJ (2009) The effect of pramipexole on mood and motivational symptoms in Parkinson’s disease: a meta-analysis of placebo-controlled studies. Clin Ther 31:89–98

    Article  CAS  PubMed  Google Scholar 

  • Lemke MR (2008) Depressive symptoms in Parkinson’s disease. Eur J Neurol 15(Suppl 1):21–25

    Article  PubMed  Google Scholar 

  • Lemke MR, Brecht HM, Koester J, Kraus PH, Reichmann H (2005) Anhedonia, depression, and motor functioning in Parkinson’s disease during treatment with pramipexole. J Neuropsychiatry Clin Neurosci 17:214–220

    CAS  PubMed  Google Scholar 

  • Lemke MR, Brecht HM, Koester J, Reichmann H (2006) Effects of the dopamine agonist pramipexole on depression, anhedonia and motor functioning in Parkinson’s disease. J Neurol Sci 248:266–270

    Article  CAS  PubMed  Google Scholar 

  • López-Rubalcava C, Lucki I (2000) Strain differences in the behavioral effects of antidepressant drugs in the rat forced swimming test. Neuropsychopharmacology 22:191–199

    Article  PubMed  Google Scholar 

  • Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A (2002) Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes. J Pharmacol Exp Ther 303:791–804

    Article  CAS  PubMed  Google Scholar 

  • Millan MJ, Brocco M, Papp M, Serres F, La Rochelle CD, Sharp T, Peglion JL, Dekeyne A (2004a) S32504, a novel naphtoxazine agonist at dopamine D3/D2 receptors: III. Actions in models of potential antidepressive and anxiolytic activity in comparison with ropinirole. J Pharmacol Exp Ther 309:936–950

    Article  CAS  PubMed  Google Scholar 

  • Millan MJ, Seguin L, Gobert A, Cussac D, Brocco M (2004b) The role of dopamine D3 compared with D2 receptors in the control of locomotor activity: a combined behavioural and neurochemical analysis with novel, selective antagonists in rats. Psychopharmacology (Berl) 174:341–357

    Article  CAS  Google Scholar 

  • Miyagi M, Arai N, Taya F, Itoh F, Komatsu Y, Kojima M, Isaji M (1996) Effect of cabergoline, a long-acting dopamine D2 agonist, on reserpine-treated rodents. Biol Pharm Bull 19:1499–1502

    CAS  PubMed  Google Scholar 

  • Nibuya M, Morinobu S, Duman RS (1995) Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 15:7539–7547

    CAS  PubMed  Google Scholar 

  • Numakawa T, Nakayama H, Suzuki S, Kubo T, Nara F, Numakawa Y, Yokomaku D, Araki T, Ishimoto T, Ogura A, Taguchi T (2003) Nerve growth factor-induced glutamate release is via p75 receptor, ceramide, and Ca(2+) from ryanodine receptor in developing cerebellar neurons. J Biol Chem 278:41259–41269

    Article  CAS  PubMed  Google Scholar 

  • Numakawa T, Ishimoto T, Suzuki S, Numakawa Y, Adachi N, Matsumoto T, Yokomaku D, Koshimizu H, Fujimori KE, Hashimoto R, Taguchi T, Kunugi H (2004) Neuronal roles of the integrin-associated protein (IAP/CD47) in developing cortical neurons. J Biol Chem 279:43245–43253

    Article  CAS  PubMed  Google Scholar 

  • Numakawa T, Kumamaru E, Adachi N, Yagasaki Y, Izumi A, Kunugi H (2009) Glucocorticoid receptor interaction with TrkB promotes BDNF-triggered PLC-gamma signaling for glutamate release via a glutamate transporter. Proc Natl Acad Sci U S A 106:647–652

    Article  CAS  PubMed  Google Scholar 

  • Ohta K, Kuno S, Mizuta I, Fujinami A, Matsui H, Ohta M (2003) Effects of dopamine agonists bromocriptine, pergolide, cabergoline, and SKF-38393 on GDNF, NGF, and BDNF synthesis in cultured mouse astrocytes. Life Sci 73:617–626

    Article  CAS  PubMed  Google Scholar 

  • Ohta K, Fujinami A, Kuno S, Sakakimoto A, Matsui H, Kawahara Y, Ohta M (2004) Cabergoline stimulates synthesis and secretion of nerve growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor by mouse astrocytes in primary culture. Pharmacology 71:162–168

    Article  CAS  PubMed  Google Scholar 

  • Paré WP (1989) Stress ulcer susceptibility and depression in Wistar Kyoto (WKY) rats. Physiol Behav 46:993–998

    Article  PubMed  Google Scholar 

  • Parikh V, Khan MM, Mahadik SP (2004) Olanzapine counteracts reduction of brain-derived neurotrophic factor and TrkB receptors in rat hippocampus produced by haloperidol. Neurosci Lett 356:135–139

    Article  CAS  PubMed  Google Scholar 

  • Poo MM (2001) Neurotrophins as synaptic modulators. Nat Rev Neurosci 2:24–32

    Article  CAS  PubMed  Google Scholar 

  • Porsolt RD, Le Pichon M, Jalfre M (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266:730–732

    Article  CAS  PubMed  Google Scholar 

  • Qi X, Lin W, Li J, Pan Y, Wang W (2006) The depressive-like behaviors are correlated with decreased phosphorylation of mitogen-activated protein kinases in rat brain following chronic forced swim stress. Behav Brain Res 175:233–240

    Article  CAS  PubMed  Google Scholar 

  • Qi X, Lin W, Li J, Li H, Wang W, Wang D, Sun M (2008) Fluoxetine increases the activity of the ERK-CREB signal system and alleviates the depressive-like behavior in rats exposed to chronic forced swim stress. Neurobiol Dis 31:278–285

    Article  CAS  PubMed  Google Scholar 

  • Rektorová I, Rektor I, Bares M, Dostál V, Ehler E, Fanfrdlová Z, Fiedler J, Klajblová H, Kulist’ák P, Ressner P, Svátová J, Urbánek K, Velísková J (2003) Pramipexole and pergolide in the treatment of depression in Parkinson’s disease: a national multicentre prospective randomized study. Eur J Neurol 10:399–406

    Article  PubMed  Google Scholar 

  • Rogers DC, Costall B, Domeney AM, Gerrard PA, Greener M, Kelly ME, Hagan JJ, Hunter AJ (2000) Anxiolytic profile of ropinirole in the rat, mouse and common marmoset. Psychopharmacology (Berl) 151:91–97

    Article  CAS  Google Scholar 

  • Rogóz Z, Skuza G, Kłodzińska A (2004) Anxiolytic- and antidepressant-like effects of 7-OH-DPAT, preferential dopamine D3 receptor agonist, in rats. Pol J Pharmacol 56:519–526

    PubMed  Google Scholar 

  • Rowlett JK, Mattingly BA, Bardo MT (1995) Repeated quinpirole treatment: locomotor activity, dopamine synthesis, and effects of selective dopamine antagonists. Synapse 20:209–216

    Article  CAS  PubMed  Google Scholar 

  • Szechtman H, Talangbayan H, Canaran G, Dai H, Eilam D (1994) Dynamics of behavioral sensitization induced by the dopamine agonist quinpirole and a proposed central energy control mechanism. Psychopharmacology (Berl) 115:95–104

    Article  CAS  Google Scholar 

  • Takahashi H, Yoshida K, Higuchi H, Shimizu T, Inoue T, Koyama T (2003) Addition of a dopamine agonist, cabergoline, to a serotonin-noradrenalin reuptake inhibitor, milnacipran as a therapeutic option in the treatment of refractory depression: two case reports. Clin Neuropharmacol 26:230–232

    Article  CAS  PubMed  Google Scholar 

  • Tejani-Butt S, Kluczynski J, Paré WP (2003) Strain-dependent modification of behavior following antidepressant treatment. Prog Neuropsychopharmacol Biol Psychiatry 27:7–14

    Article  CAS  PubMed  Google Scholar 

  • Yagasaki Y, Numakawa T, Kumamaru E, Hayashi T, Su TP, Kunugi H (2006) Chronic antidepressants potentiate via sigma-1 receptors the brain-derived neurotrophic factor-induced signaling for glutamate release. J Biol Chem 281:12941–12949

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto M (2001) Depression in Parkinson’s disease: its prevalence, diagnosis, and neurochemical background. J Neurol 248(Suppl 3):III5–III11

    PubMed  Google Scholar 

  • Yaroslavsky I, Colletti M, Jiao X, Tejani-Butt S (2006) Strain differences in the distribution of dopamine (DA-2 and DA-3) receptor sites in rat brain. Life Sci 79:772–776

    Article  CAS  PubMed  Google Scholar 

  • Ying SW, Futter M, Rosenblum K, Webber MJ, Hunt SP, Bliss TV, Bramham CR (2002) Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: requirement for ERK activation coupled to CREB and upregulation of Arc synthesis. J Neurosci 22:1532–1540

    CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by the Health and Labor Sciences Research Grants (Research on Psychiatric and Neurological Diseases and Mental Health; Clinical Research for Development of Preventive Medicine and New Therapeutics) (H.K.), the JST, CREST (T.N., H.K), the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO) (H.K.), and Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS) (H.K.). The authors declare no conflict of interest. The experiments comply with the current laws of Japan.

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Authors and Affiliations

  1. Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, Tokyo, 187-8502, Japan

    Shuichi Chiba, Tadahiro Numakawa, Midori Ninomiya & Hiroshi Kunugi

  2. CREST of Japan Science and Technology Corporation, Saitama, Japan

    Tadahiro Numakawa & Hiroshi Kunugi

  3. Department of Pharmacology, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan

    Midori Ninomiya

  4. Department of Physiology, Brain Korea 21 Project for Medical Science, Brain Research Institute, Yonsei University College of Medicine, Seoul, South Korea

    Hyung Shin Yoon

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  1. Shuichi Chiba
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  2. Tadahiro Numakawa
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  3. Midori Ninomiya
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  4. Hyung Shin Yoon
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  5. Hiroshi Kunugi
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Correspondence to Hiroshi Kunugi.

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Chiba, S., Numakawa, T., Ninomiya, M. et al. Cabergoline, a dopamine receptor agonist, has an antidepressant-like property and enhances brain-derived neurotrophic factor signaling. Psychopharmacology 211, 291–301 (2010). https://doi.org/10.1007/s00213-010-1894-8

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  • DOI: https://doi.org/10.1007/s00213-010-1894-8

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