Neurochemical Research

, Volume 30, Issue 12, pp 1493–1500 | Cite as

Semax, An ACTH(4-10) Analogue with Nootropic Properties, Activates Dopaminergic and Serotoninergic Brain Systems in Rodents

  • Kirill O. EreminEmail author
  • Vladimir S. Kudrin
  • Pirjo Saransaari
  • Simo S. Oja
  • Igor A. Grivennikov
  • Nikolay F. Myasoedov
  • Kirill S. Rayevsky


Corticotrophin (ACTH) and its analogues, particularly Semax (Met-Glu-His-Phe-Pro-Gly-Pro), demonstrate nootropic activity. Close functional and anatomical links have been established between melanocortinergic and monoaminergic brain systems. The aim of present work was to investigate the effects of Semax on neurochemical parameters of dopaminergic- and serotonergic systems in rodents. The tissue content of 5-hydroxyindoleacetic acid (5-HIAA) in the striatum was significantly increased (+25%) 2 h after Semax administration. The extracellular striatal level of 5-HIAA gradually increased up to 180% within 1–4 h after Semax (0.15 mg/kg, ip) administration. This peptide alone failed to alter the tissue and extracellular concentrations of dopamine and its metabolites. Semax injected 20 min prior d-amphetamine dramatically enhanced the effects of the latter on the extracellular level of dopamine and on the locomotor activity of animals. Our results reveal the positive modulatory effect of Semax on the striatal serotonergic system and the ability of Semax to enhance both the striatal release of dopamine and locomotor behavior elicited by d-amphetamine.

Key words

3,4-Dihydroxyphenylacetic acid 5-hydroxyindoleacetic acid ACTH analogues cognitive enhancers d-amphetamine dopamine dopamine receptors locomotor activity melanocortin receptors neurotrophic factors Semax serotonin 


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  1. 1.
    Wied, D. 1966Inhibitory effects of ACTH and related peptides on extinction of conditioned avoidance behavior in ratsProc. Soc. Exp. Biol. Med.1222832PubMedGoogle Scholar
  2. 2.
    Kumar, K. B., Karanth, K. S. 1995Effects of ACTH and ACTH 4-10 on aversive memory retrieval in ratsJ. Neural Transm. Gen. Sect.101223229PubMedCrossRefGoogle Scholar
  3. 3.
    Wied, D. 1997Neuropeptides in learning and memory processesBehav. Brain Res.838390PubMedGoogle Scholar
  4. 4.
    Horvath, K. M., Meerlo, P., Felszeghy, K., Nyakas, C., Luiten, P. G. 1999Early postnatal treatment with ACTH4-9 analog ORG 2766 improves adult spatial learning but does not affect behavioural stress reactivityBehav. Brain Res.106181188PubMedGoogle Scholar
  5. 5.
    Witter, A., Greven, H. M., Wied, D. 1975Correlation between structure, behavioral activity and rate of biotransformation of some ACTH4-9 analogsJ. Pharmacol. Exp. Ther.193853860PubMedGoogle Scholar
  6. 6.
    Strand, F. L. 2000David and Goliath – the slingshot that started the neuropeptide revolutionEur. J. Pharmacol.405312PubMedCrossRefGoogle Scholar
  7. 7.
    Strand, F. L. 2003Neuropeptides: General characteristics and neuropharmaceutical potential in treating CNS disordersProg. Drug Res.61137PubMedGoogle Scholar
  8. 8.
    Asmarin, I. P., Nezavibat’ko, V. N., Miasoedov, N. F., Kamenskii, A. A., Grivennikov, I.A., Ponomareva-Stepnaia, M. A., Andreeva, L. A., Kaplan, , Ia, A., Koshelev, V. B., Riasina, T. V. 1997A nootropic adrenocorticotropin analog 4-10-semax (l5 years experience in its design and study)Zh. Vyssh. Nerv. Deiat. Im. I. P. Pavlova47420430in RussianPubMedGoogle Scholar
  9. 9.
    Potaman, V. N., Antonova, L. V., Dubynin, V. A., Zaitzev, D. A., Kamensky, A. A., Myasoedov, N. F., Nezavibatko, V. N. 1991Entry of the synthetic ACTH(4-10) analogue into the rat brain following intravenous injectionNeurosci. Lett.127133136PubMedCrossRefGoogle Scholar
  10. 10.
    Ashmarin, I. P., Nezavibatko, V. N., Levitskaya, N. G., Koshelev, V. B., Kamensky, A. A. 1995Design and investigation of an ACTH(4-10) analogue lacking d-amino acids and hydrophobic radicalsNeurosci. Res. Commun.16105112Google Scholar
  11. 11.
    Dolotov, O. V., Seredenina, T. S., Levitskaya, N. G., Kamensky, A. A., Andreeva, L. A., Alfeeva, L. Y., Nagaev, I. Y., Zolotarev, Y. A., Grivennikov, I. A., Engele, Y., Myasoedov, N. F. 2003The heptapeptide SEMAX stimulates BDNF expression in different areas of the rat brain in vivo Dokl. Biol. Sci.391292295PubMedCrossRefGoogle Scholar
  12. 12.
    Kaplan, , Ya, A., Kochetova, A. G., Nezavibathko, V. N., Rjasina, T. V., Ashmarin, I. P. 1996Synthetic ACTH analogue semax displays nootropic-like activity in humansNeurosci. Res. Commun.19115123CrossRefGoogle Scholar
  13. 13.
    Adan, R. A. H., Gispen, W. H. 1997Brain melanocortin receptors: From cloning to functionPeptides1812791287PubMedCrossRefGoogle Scholar
  14. 14.
    Adan, R. A. H., Gispen, W. H. 2000Melanocortins and the brain: From effects via receptors to drug targetsEur. J. Pharmacol.4051324PubMedCrossRefGoogle Scholar
  15. 15.
    Kishi, T., Aschkenasi, C. J., Lee, C. E., Mountjoy, K. G., Saper, C. B., Elmquist, J. K. 2003Expression of melanocortin 4 receptor mRNA in the central nervous system of the ratJ. Comp. Neurol.457213235PubMedCrossRefGoogle Scholar
  16. 16.
    Adan, R. A. H., Oosterom, J., Ludvigsdottir, G., Brakkee, J. H., Burbach, J. P. H., Gispen, W. H. 1994Identification of antagonists for MC3, MC4 and MC5 receptorsEur. J. Pharmacol.269331337PubMedGoogle Scholar
  17. 17.
    Versteeg, D. H., Crom, M. P., Mulder, A. H. 1986ACTH-(1-24) and alpha-MSH antagonize dopamine receptor-mediated inhibition of striatal dopamine and acetylcholine releaseLife Sci.38835840PubMedCrossRefGoogle Scholar
  18. 18.
    Florijn, W. J., Boer, T., Tonnaer, J. A., Versteeg, D. H. 1992Characterization of the inhibitory effect of adrenocorticotropin/melanocyte-stimulating hormone-like peptides on the binding of dopamine receptor ligands to the dopamine D2 receptor in vitro J. Pharmacol. Exp. Ther.263787792PubMedGoogle Scholar
  19. 19.
    Florijn, W. J., Holtmaat, A. J., Lang, H., Spierenburg, H., Gispen, W. H., Versteeg, D. H. 1993Peptide-induced grooming behavior and caudate nucleus dopamine releaseBrain Res.625169172PubMedCrossRefGoogle Scholar
  20. 20.
    Lindblom, J., Opmane, B., Mutulis, F., Mutule, I., Petrovska, R., Klusa, V., Bergstrom, L., Wikberg, J. E. S. 2001The MC4 receptor mediates α-MSH induced release of nucleus accumbens dopamineNeuroreport1221552158PubMedGoogle Scholar
  21. 21.
    Kawashima, N., Chaki, S., Okuyama, S. 2003Electrophysiological effects of melanocortin receptor ligands on neuronal activities of monoaminergic neurons in ratsNeurosci. Lett.353119122PubMedCrossRefGoogle Scholar
  22. 22.
    Barros, D. M., Izquierdo, L. A., Medina, J. H., Izquierdo, I. 2003Pharmacological findings contribute to the understanding of the main physiological mechanisms of memory retrievalCurr. Drug Target. CNS Neurol. Disord.28194Google Scholar
  23. 23.
    Hefco, V., Yamada, K., Hefco, A., Hritcu, L., Tiron, A., Nabeshima, T. 2003Role of the mesotelencephalic dopamine system in learning and memory processes in the ratEur. J. Pharmacol.4755560PubMedCrossRefGoogle Scholar
  24. 24.
    Jay, T. M. 2003Dopamine: A potential substrate for synaptic plasticity and memory mechanismsProg. Neurobiol.69375390PubMedCrossRefGoogle Scholar
  25. 25.
    Afanas’ev, I. I., Anderzhanova, E. A., Kudrin, V. S., Rayevsky, K. S. 2001Effects of amphetamine and sydnocarb on dopamine release and free radical generation in rat striatumPharmacol. Biochem. Behav.69653658PubMedGoogle Scholar
  26. 26.
    Paxinos, G., Watson, C. 1986The Rat Brain Stereotaxic Coordinates2Academic PressSydneyGoogle Scholar
  27. 27.
    Anderzhanova, E., Rayevsky, K. S., Saransaari, P., Oja, S. S. 2003Effect of sulpiride on the amphetamine-induced changes in extracellular dopamine, DOPAC, and hydroxyl radical generation in the rat striatumNeurochem. Res.2812411248PubMedCrossRefGoogle Scholar
  28. 28.
    Boer, J. A., Vliet, I. M., Westenberg, H. G. 1995Recent developments in the psychopharmacology of social phobiaEur. Arch. Psychiat. Clin. Neurosci.244309316CrossRefGoogle Scholar
  29. 29.
    Chaki, S., Hirota, S., Funakoshi, T., Suzuki, Y., Suetake, S., Okubo, T., Ishii, T., Nakazato, A., Okuyama, S. 2003Anxiolytic-like and antidepressant-like activities of MCL0129 {1-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine}, a novel and potent nonpeptide antagonist of the melanocortin-4 receptorJ. Pharmacol. Exp. Ther.304818826PubMedCrossRefGoogle Scholar
  30. 30.
    Shadrina, M. I., Dolotov, O. V., Grivennikov, I. A., Slominsky, P. A., Andreeva, L. A., Inozemtseva, L. S., Limborska, S. A., Myasoedov, N. F. 2001Rapid induction of neurotrophin mRNAs in rat glial cell cultures by Semax, an adrenocorticotropic hormone analogNeurosci. Lett.308115118PubMedCrossRefGoogle Scholar
  31. 31.
    Blochl, A., Sirrenberg, C. 1996Neurotrophins stimulate the release of dopamine from rat mesencephalic neurons via Trk and p75Lntr receptorsJ. Biol. Chem.2712110021107PubMedGoogle Scholar
  32. 32.
    Goggi, J., Pullar, I. A., Carney, S. L., Bradford, H. F. 2002Modulation of neurotransmitter release induced by brain-derived neurotrophic factor in rat brain striatal slices in␣vitro Brain Res.9413442PubMedCrossRefGoogle Scholar
  33. 33.
    Goggi, J., Pullar, I. A., Carney, S. L., Bradford, H. F. 2003Signalling pathways involved in the short-term potentiation of dopamine release by BDNFBrain Res.968156161PubMedCrossRefGoogle Scholar
  34. 34.
    Narita, M., Aoki, K., Takagi, M., Yajima, Y., Suzuki, T. 2003Implication of brain-derived neurotrophic factor in the release of dopamine and dopamine-related behaviors induced by methamphetamineNeuroscience119767775PubMedCrossRefGoogle Scholar
  35. 35.
    Hashimoto, K., Shimizu, E., Iyo, M. 2004Critical role of brain-derived neurotrophic factor in mood disordersBrain Res. Brain Res. Rev.45104114PubMedCrossRefGoogle Scholar
  36. 36.
    Duman, R. S. 2004Role of neurotrophic factors in the etiology and treatment of mood disordersNeuromol. Med.51125CrossRefGoogle Scholar
  37. 37.
    Garza, A. A., Ha, T. G., Garcia, C., Chen, M. J., Russo-Neustadt, A. A. 2004Exercise, antidepressant treatment, and BDNF mRNA expression in the aging brainPharmacol. Biochem. Behav.77209220PubMedCrossRefGoogle Scholar
  38. 38.
    Karege, F., Perret, G., Bondolfi, G., Schwald, M., Bertschy, G., Aubry, J. M. 2002Decreased serum brain-derived neurotrophic factor levels in major depressed patientsPsychiat. Res.109143148CrossRefGoogle Scholar
  39. 39.
    Tsai, S. J. 2004Down-regulation of the Trk-B signal pathway: The possible pathogenesis of major depressionMed. Hypotheses62215218PubMedGoogle Scholar
  40. 40.
    Shirayama, Y., Chen, A. C., Nakagawa, S., Russell, D. S., Duman, R. S. 2002Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depressionJ. Neurosci.2232513261PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Kirill O. Eremin
    • 1
    • 2
    Email author
  • Vladimir S. Kudrin
    • 1
  • Pirjo Saransaari
    • 2
  • Simo S. Oja
    • 2
    • 3
  • Igor A. Grivennikov
    • 4
  • Nikolay F. Myasoedov
    • 4
  • Kirill S. Rayevsky
    • 1
  1. 1.V.V. Zakusov’s Research Institute of Pharmacology RAMSMoscowRussia
  2. 2.Brain Research CenterUniversity of TampereFinland
  3. 3.Department of Clinical PhysiologyTampere University HospitalTampereFinland
  4. 4.Institute of Molecular Genetics RASMoscowRussia

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