Neurochemical Journal

, Volume 6, Issue 2, pp 144–152 | Cite as

Possible mechanisms for the effects of neuromodulators on the perception of time intervals

  • I. G. Sil’kis
Theoretical Articles


We propose possible mechanisms for the effects of neuromodulators on the perception of time on the basis of our hypothesis that estimation of intervals between sensory stimuli depends on the beat frequency of a “internal clock,” which is inversely proportional to the latency of reentering excitation of the neocortex. These effects are based on the modification of the efficacy of excitatory inputs to the cortical neurons, as well as inputs from the cortex to the striatum, which are necessary for the disinhibition of thalamic neurons by the basal ganglia and subsequent excitation of the cortex. The character of influence is determined by the concentration of neuromodulators, the types of receptors activated by them on neurons of the striatum and cortex, and the modulation rules. According to the proposed mechanism, an increase in the frequency of the “internal clock” and overestimation of the duration of intervals may result from treatment with dopaminergic drugs, agonists of dopamine D1 and D2 receptors, and opioids and cannabinoids, which promote an increase in the dopamine concentration, as well as antagonists of adenosine A1 and A2A and muscarinic M2 receptors, whose activation facilitates disinhibition of the thalamus by the basal ganglia. Antagonists of A1, M2, and D2 receptors, which prevent depression of excitatory inputs to neocortical pyramidal cells, also can increase the frequency of the “internal clock.” The activation of a large number of D2 receptors on the cortical pyramidal cells, which results from a considerable increase in dopamine concentration, like activation of cannabinoid CB1 receptors, should promote a decrease in the frequency of the “internal clock” and the underestimation of interval duration. The activation of D2 and M2 receptors on the GABAergic interneurons of the cortex under conditions of strong inhibition of pyramidal neurons may increase the beat frequency of the “internal clock.” The proposed mechanism helps to understand the causes of errors in time perception in neurological diseases and to explain the discrepancies in the results of studies on the effects of neuromodulators on the estimation of time. The hypothesis may be experimentally examined by treatment of the striatum or neocortex with agonists and antagonists of various types of receptors and measurement of the drug-induced changes in the interval between the first and second peaks in the distribution of latencies of responses of cortical neurons to sensory stimulus.


time perception neuromodulators striatum prefrontal cortex synaptic plasticity 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Rammsayer, T., Int. J. Neurosci., 1990, vol. 53, nos. 2–4, pp. 111–120.PubMedCrossRefGoogle Scholar
  2. 2.
    Carroll, C.A., O’Donnell, B.F., Shekhar, A., and Hetrick, W.P., Brain Cogn., 2009, vol. 71, no. 3, pp. 345–353.PubMedCrossRefGoogle Scholar
  3. 3.
    Malapani, C., Deweer, B., and Gibbon, J., J. Cogn. Neurosci., 2002, vol. 14, no. 2, pp. 311–322.PubMedCrossRefGoogle Scholar
  4. 4.
    Toplak, M.E., Rucklidge, J.J., Hetherington, R., John, S.C.F., and Tannock, R., J. Child. Psychol. Psychiatry, 2003, vol. 44, no. 6, pp. 888–903.PubMedCrossRefGoogle Scholar
  5. 5.
    Meck, W.H., Cogn. Brain Res., 1996, vol. 3, nos. 3–4, pp. 227–242.CrossRefGoogle Scholar
  6. 6.
    Petry, N.M., Bickel, W.K., and Arnett, M., Addiction, 1998, vol. 93, no. 5, pp. 729–738.PubMedCrossRefGoogle Scholar
  7. 7.
    Odum, A.L. and Ward, R.D., J. Exp. Anal. Behav., 2004, vol. 82, no. 2, pp. 197–212.PubMedCrossRefGoogle Scholar
  8. 8.
    Rammsayer, T., NeuroQuantology, 2009, vol. 7, no. 1, pp. 103–113.Google Scholar
  9. 9.
    Coull, J.T., Vidal, F., Nazarian, B., and Macar, F., Science, 2004, vol. 303, no. 5663, pp. 1506–1508.PubMedCrossRefGoogle Scholar
  10. 10.
    Coull, J.T., Nazarian, B., and Vidal, F., J. Cogn. Neurosci., 2008, vol. 20, no. 12, pp. 2185–2197.PubMedCrossRefGoogle Scholar
  11. 11.
    Hinton, S.C. and Meck, W.H., Cogn. Brain Res., 2004, vol. 21, no. 2, pp. 171–182.CrossRefGoogle Scholar
  12. 12.
    Jahanshahi, M., Jones, C.R., Dirnberger, G., and Frith, C.D., J. Neurosci., 2006, vol. 26, no. 47, pp. 12266–12273.PubMedCrossRefGoogle Scholar
  13. 13.
    Jin, D.Z., Fujii, N., and Graybiel, A.M., Proc. Natl. Acad. Sci. USA, 2009, vol. 106, no. 45, pp. 19156–19161.PubMedCrossRefGoogle Scholar
  14. 14.
    Jones, C.R., Malone, T.J., Dirnberger, G., Edwards, M., and Jahanshahi, M., Brain Cogn., 2008, vol. 68, no. 1, pp. 30–41.PubMedCrossRefGoogle Scholar
  15. 15.
    Matell, M.S. and Meck, W.H., Cog. Brain Res., 2004, vol. 21, no. 2, pp. 139–170.CrossRefGoogle Scholar
  16. 16.
    Meck, W.H., Penney, T.B., and Pouthas, V., Curr. Opin. Neurobiol., 2008, vol. 18.Google Scholar
  17. 17.
    Sil’kis, I.G., Usp. Fiziol. Nauk, 2011, vol. 42, no. 2, pp. 41–56.PubMedGoogle Scholar
  18. 18.
    Silkis, I.G., Biosystems, 1998, vol. 48, nos. 1–3, pp. 205–213.PubMedCrossRefGoogle Scholar
  19. 19.
    Silkis, I., Biosystems, 2000, vol. 57, no. 3, pp. 187–196.PubMedCrossRefGoogle Scholar
  20. 20.
    Silkis, I., Biosystems, 2001, vol. 59, no. 1, pp. 7–14.PubMedCrossRefGoogle Scholar
  21. 21.
    Sil’kis, I.G., Neurosci. Behav. Physiol., 2003a, vol. 33, no. 6, pp. 529–541.PubMedCrossRefGoogle Scholar
  22. 22.
    Hinton, S.C., Meck. W.H., and MacFall J.R, NeuroImage, 1996, vol. 3, no. Suppl. 1, p. 224.CrossRefGoogle Scholar
  23. 23.
    Sil’kis, I.G., Neurosci. Behav. Physiol., 2003b, vol. 33, pp. 379–386.PubMedCrossRefGoogle Scholar
  24. 24.
    Silkis, I., Biosystems, 2007, vol. 89, nos. 1–3, pp. 227–235.PubMedCrossRefGoogle Scholar
  25. 25.
    Matell, M.S., Bateson, M., and Meck, W.H., Psychopharmacology (Berl), 2006, vol. 188, no. 2, pp. 201–212.CrossRefGoogle Scholar
  26. 26.
    Zheng, P., Zhang, X.X., Bunney, B.S., and Shi, W.X., Neuroscience, 1999, vol. 91, no. 2, pp. 527–535.PubMedCrossRefGoogle Scholar
  27. 27.
    Rammsayer, T.H., Neuropsychobiology, 1997, vol. 35, no. 1, pp. 36–45.PubMedCrossRefGoogle Scholar
  28. 28.
    Lustig, C. and Meck, W.H., Brain Cogn, 2005, vol. 58, no. 1, pp. 9–16.PubMedCrossRefGoogle Scholar
  29. 29.
    Davis, K.L., Kahn, R.S., Ko, G., and Davidson, M., Am. J. Psychiatry, 1991, vol. 148, no. 11, pp. 1474–1486.PubMedGoogle Scholar
  30. 30.
    Waters, F. and Jablensky, A., Psychiatry Res., 2009, vol. 167, nos. 1–2, pp. 12–20.PubMedCrossRefGoogle Scholar
  31. 31.
    Lee, K.-H., Bhaker, R.S., Mysore, A., Parks, R.W., Birkett, P.B.L., and Woodruff, P.W.R., Psychiatry Res., 2009, vol. 166, nos. 2–3, pp. 174–183.PubMedCrossRefGoogle Scholar
  32. 32.
    Meck, W.H. and Benson, A.M., Brain Cogn., 2002, vol. 48, no. 1, pp. 195–211.PubMedCrossRefGoogle Scholar
  33. 33.
    Rutschmann, J. and Rubinstein, L., J. Psychiatr. Res, 1996, vol. 4, no. 2, pp. 107–114.CrossRefGoogle Scholar
  34. 34.
    Seamans, J.K., Gorelova, N., Durstewitz, D., and Yang, C.R., J. Neurosci., 2001, vol. 21, no. 10, pp. 3628–3638.PubMedGoogle Scholar
  35. 35.
    Xu, T.X. and Yao, W.D., Proc. Natl. Acad. Sci. USA, 2010, vol. 107, no. 37, pp. 16366–16371.PubMedCrossRefGoogle Scholar
  36. 36.
    Ji, Y., Yang, F., Papaleo, F., Wang, H.X., Gao, W.J., Weinberger, D.R., and Lu, B., Proc. Natl. Acad. Sci. USA, 2009, vol. 106, no. 46, pp. 19593–19598.PubMedCrossRefGoogle Scholar
  37. 37.
    Oda, S., Funato, H., Adachi-Akahane, S., Ito, M., Okada, A., Igarashi, H., Yokofujita, J., and Kuroda, M., Brain Res., 2010, vol. 1329, pp. 89–102.PubMedCrossRefGoogle Scholar
  38. 38.
    Glausier, J.R., Khan, Z.U., and Muly, E.C., Cereb. Cortex, 2009, vol. 19, no. 8, pp. 1820–1834.PubMedCrossRefGoogle Scholar
  39. 39.
    Kröner, S., Krimer, L.S., Lewis, D.A., and Barrionuevo, G., Cereb. Cortex, 2007, vol. 17, no. 5, pp. 1020–1032.PubMedCrossRefGoogle Scholar
  40. 40.
    Svenningsson, P., Le Moine C., Kull B., Sunahara R., Bloch B., Fredholm B.B, Neuroscience, 1997, vol. 80, no. 4, pp. 1171–1185.PubMedCrossRefGoogle Scholar
  41. 41.
    Yoshimura, H., Curr. Neuropharmacol., 2005, vol. 3, no. 4, pp. 309–316.PubMedCrossRefGoogle Scholar
  42. 42.
    Ochiishi, T., Chen, L., Yukawa, A., Saitoh, Y., Sekino, Y., Arai, T., Nakata, H., and Miyamoto, H., J. Comp. Neurol., 1999, vol. 411, no. 2, pp. 301–316.PubMedCrossRefGoogle Scholar
  43. 43.
    O’shaughnessy, C.T., Aram, J.A., and Lodge, D., Epilepsy Res., 1988, vol. 2, no. 5, pp. 294–301.PubMedCrossRefGoogle Scholar
  44. 44.
    Terry, P., Doumas, M., Desai, R.I., and Wing, A.M., Psychopharmacol., 2009, vol. 202, no. 4, pp. 719–729.CrossRefGoogle Scholar
  45. 45.
    Martin, F.H. and Garfield, J., Biol. Psychol., 2006, vol. 71, no. 1, pp. 63–73.PubMedCrossRefGoogle Scholar
  46. 46.
    Liu, T.T., Behzadi, Y., Restom, K., Uludag, K., Lu, K., Buracas, G.T., Dubowitz, D.J., and Buxton, R.B., Neuroimage, 2004, vol. 23, no. 4, pp. 1402–1413.PubMedCrossRefGoogle Scholar
  47. 47.
    Gruber, R.P. and Block, R.A., Hum. Psychopharmacol., 2005, vol. 20, no. 4, pp. 275–285.PubMedCrossRefGoogle Scholar
  48. 48.
    Ferre, S., Popoli, P., Tinner-Staines, B., and Fuxe, K., Neurosci. Let., 1996, vol. 208, no. 2, pp. 109–112.CrossRefGoogle Scholar
  49. 49.
    Botella, P., Bosch, F., Romero, F.J., and Parra, A., Hum. Psychopharmacol., 2001, vol. 16, no. 7, pp. 533–540.PubMedCrossRefGoogle Scholar
  50. 50.
    Gruber, R.P. and Block, R.A., Hum. Psychopharmacol., 2003, vol. 18, no. 5, pp. 351–359.PubMedCrossRefGoogle Scholar
  51. 51.
    Arushanyan, E.B., Baida, O.A., Mastyagin, S.S., Popova, A.P., and Shikina, I.B., Fiziol. Chel., 2003, vol. 29, no. 4, pp. 49–53.Google Scholar
  52. 52.
    Hicks, R.E., Prospective and Retrospective Judgments of Time: a Neurobehavioral Analysis. In Time, Action and Cognition: Towards Bridging the Gap, Macar F, Pouthas V, Friedman WJ (Eds). Kluwer Academic:, Dordrecht, Netherlands, 1992.Google Scholar
  53. 53.
    Stine, M.M., O’Connor, R.J., Yatko, B.R., Grunberg, N.E., and Klein, L.C., Hum. Psychopharmacol., 2002, vol. 17, no. 7, pp. 361–367.PubMedCrossRefGoogle Scholar
  54. 54.
    Mrzljak, L., Levey, A.I., Belcher, S., and Goldman-Rakic, P.S., J. Comp. Neurol., 1998, vol. 390, no. 1, pp. 112–132.PubMedCrossRefGoogle Scholar
  55. 55.
    Wang, L. and Yuan, L.L., J. Physiol., 2009, vol. 587.Google Scholar
  56. 56.
    Antal, A., Kovanecz, I., and Bodis-Wollner, I., Physiol. Behav., 1994, vol. 56, no. 1, pp. 161–166.PubMedCrossRefGoogle Scholar
  57. 57.
    Alcantara, A.A., Mrzljak, L., Jakab, R.L., Levey, A.I., Hersch, S.M., and Goldman-Rakic, P.S., J. Comp. Neurol., 2001, no. 4, pp. 445–460.Google Scholar
  58. 58.
    Berz, S., Bttig, K., and Welzl, H., Physiol. Behav., 1992, vol. 51, no. 3, pp. 493–499.PubMedCrossRefGoogle Scholar
  59. 59.
    Rouge-Pont, F., Usiello, A., Benoit-Marand, M., Gonon, F., Piazza, P.V., and Borrelli, E., J. Neurosci., 2002, vol. 22, no. 8, pp. 3293–3301.PubMedGoogle Scholar
  60. 60.
    Bossong, M.G., van Berckel, B.N., Boellaard, R., Zuurman, L., Schuit, R.C., Windhorst, A.D., van Gerven, J.M., Ramsey, N.F., Lammertsma, A.A., and Kahn, R.S., Neuropsychopharmacology, 2009, vol. 34, no. 3, pp. 759–766.PubMedCrossRefGoogle Scholar
  61. 61.
    Ward, R.D. and Odum, A.L., J. Exp. Anal. Behav., 2005, vol. 84, no. 3, pp. 401–415.PubMedCrossRefGoogle Scholar
  62. 62.
    Odum, A.L. and Schaal, D.W., J. Exp. Anal. Behav., 2000, vol. 74, no. 2, pp. 229–243.PubMedCrossRefGoogle Scholar
  63. 63.
    Glass, M., Dragunow, M., and Faull, R.L., Neuroscience, 1997, vol. 77, no. 2, pp. 299–318.PubMedCrossRefGoogle Scholar
  64. 64.
    Han, C.J. and Robinson, J.K., Behav. Neurosci., 2001, vol. 115, no. 1, pp. 243–246.PubMedCrossRefGoogle Scholar
  65. 65.
    Hicks, R.E., Gualtieri, C.T., Mayo, P.,Jr., and Perez-Reyes, M., Neuropsychobiology, 1984, vol. 12, no. 4, pp. 229–237.PubMedCrossRefGoogle Scholar
  66. 66.
    Mathew, R.J., Wilson, W.H., Turkington, T.G., and Coleman, R.E., Brain Res., 1998, vol. 797, no. 2, pp. 183–189.PubMedCrossRefGoogle Scholar
  67. 67.
    McClure, G.Y. and McMillan, D.E., J. Pharmacol. Exp. Ther., 1997, vol. 281, no. 3, pp. 1368–1380.PubMedGoogle Scholar
  68. 68.
    Hobson, J.A., Stickgold, R., and Pace-Schott, E.F., Neuroreport, 1998, vol. 9, no. 3, pp. R1–R14.PubMedCrossRefGoogle Scholar
  69. 69.
    Danilin, V.P and Latash, L.P., Zhurn. Vyssh. Nerv. Deyat., 1979, vol. 29, no. 3, pp. 502–509.Google Scholar
  70. 70.
    Huang, Z.L., Urade Y. and Hayaishi, O., Curr. Top. Med. Chem., 2011, vol. 11, no. 8, pp. 1047–1057.PubMedCrossRefGoogle Scholar
  71. 71.
    Gottesmann, C. and Joncas, S., Sleep Res. Online, 2000, vol. 3, no. 1, pp. 1–4.PubMedGoogle Scholar
  72. 72.
    Lena, I., Parrot, S., Deschaux, O., Muffat-Joly, S., Sauvinet, V., Renaud, B., Suaud-Chagny, M.F., and Gottesmann, C., J. Neurosci. Res., 2005, vol. 81, no. 6, pp. 891–899.PubMedCrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2012

Authors and Affiliations

  1. 1.Institute of Higher Nervous Activity and NeurophysiologyRussian Academy of SciencesMoscowRussia
  2. 2.MoscowRussia

Personalised recommendations