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Journal of Brain Sciences

March 2015, Volume 1, 1, pp 24-42

Locus Coeruleus Neuronal and Behavioral Activity Following Acute and Chronic Methylphenidate

Bin Tang


Nachum Dafny

Bin Tang 1 Nachum Dafny 1 

  1. Dept. of Neurobiology and Anatomy University of Texas Medical School at Houston, USA 1

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on PubMed

Pages: 24-42

DOI: 10.18488/journal.83/2015.1.1/

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Methylphenidate (MPD) is one of the choices to treat attention-deficit / hyperactivity disorder (ADHD), and its mechanism of action is not clear. Concomitant behavioral and locus coeruleus (LC) neuronal activity were recorded following acute and chronic (0.6, 2.5 and 10 mg/kg) MPD in freely moving rats. The experiment last for 10 days. (1) The behavioral recording showed that acute MPD increases in locomotor activity in a dose dependent manner.  (2) The same dose of chronic MPD administration elicits in some animals behavioral sensitization and in others behavioral tolerance. (3) The majority of the LC unit responded to acute MPD exposure by increase their firing rate. (4) The baseline activity on experimental day 10 (ED 10) after six daily repetitive MPD exposure was modulated in most of the LC units. (5) More than 90% of the LC unit respond to chronic MPD exposure and the majority of them by decrease their firing rate compared to the initial MPD effect. (6) The neuronal response to acute and chronic MPD recorded from animals expressing behavioral sensitization was significant difference from the LC units recorded from animals that expressed behavioral tolerance. Results indicated that the LC neuronal activities may contribute to the expression of behavioral sensitization and tolerance induced by chronic MPD administration and suggested that it is essential to record the animal’s behavioral responses concomitantly with the LC neuronal activity events.
Contribution/ Originality
This paper is the first study which reported the acute and chronic dose response property of MPD on LC neuronal activity recorded concomitant with animal behavior. The study show neuronal activity recorded from behavioral sensitized animal response to MPD differently compare to those LC units recorded from behavioral tolerance animals. 




  1. F. Arnsten, "Stimulants: Therapeutic actions in ADHD," Neuropsychopharmacology, vol. 31, pp. 2376-2383, 2006.
  2. T. E. Wilens, "Effects of methylphenidate on the catecholaminergic system in attention-deficit/hyperactivity disorder," J. Clin. Psychopharmacol, vol. 28, pp. S46-S53, 2008.
  3. J. Swanson and R. D. Baler, "Volkow, N.D. Understanding the effects of stimulant medications on cognition in individuals with attention-deficit hyperactivity disorder: A decade of progress," Neuropsychopharmacology, vol. 36, pp. 207-226, 2011.
  4. A. F. Arnsten, J. C. Steere, and R. D. Hunt, "The contribution of alpha 2-noradrenergic mechanisms of prefrontal cortical cognitive function. Potential significance for attention-deficit hyperactivity disorder," Arch. Gen. Psychiatry, vol. 53, pp. 448-455, 1996.
  5. S. R. Pliszka, J. T. McCracken, and J. W. Maas, "Catecholamines in attention-deficit hyperactivity disorder: Current perspectives," J. Am. Acad. Child Adolesc. Psychiatry, vol. 35, pp. 264-272, 1996.
  6. A. J. Zametkin and J. L. Rapoport, "Neurobiology of attention deficit disorder with hyperactivity: Where have we come in 50 years?," J. Am. Acad. Child Adolesc. Psychiatry, vol. 26, pp. 676-686, 1987.
  7. R. Kuczenski and D. S. Segal, "Exposure of adolescent rats to oral methylphenidate: Preferential effects on extracellular norepinephrine and absence of sensitization and cross-sensitization to methamphetamine," J. Neurosci., vol. 22, pp. 7264-7271, 2002.
  8. P. Brun, M. F. Suaud-Chagny, F. Gonon, and M. Buda, "In vivo noradrenaline release evoked in the anteroventral thalamic nucleus by locus coeruleus activation: An electrochemical study," Neuroscience, vol. 52, pp. 961-972, 1993.
  9. S. M. Florin-Lechner, J. P. Druhan, G. Aston-Jones, and R. J. Valentino, "Enhanced norepinephrine release in prefrontal cortex with burst stimulation of the locus coeruleus," Brain Res., vol. 742, pp. 89-97, 1996.
  10. D. G. Amaral and H. M. Sinnamon, "The locus coeruleus: Neurobiology of a central noradrenergic nucleus," Prog. Neurobiol., vol. 9, pp. 147-196, 1977.
  11. R. Y. Moore and F. E. Bloom, "Central catecholamine neuron systems: Anatomy and physiology of the norepinephrine and epinephrine systems," Annu. Rev. Neurosci., vol. 2, pp. 113-168, 1979.
  12. W. Berridge and B. D. Waterhouse, "The locus coeruleus-noradrenergic system: Modulation of behavioral state and state-dependent cognitive processes," Brain Res. Brain Res. Rev., vol. 42, pp. 33-84, 2003.
  13. G. Aston-Jones and F. E. Bloom, "Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle," J. Neurosci., vol. 1, pp. 876-886, 1981.
  14. J. A. Hobson, R. W. McCarley, and P. W. Wyzinski, "Sleep cycle oscillation: Reciprocal discharge by two brainstem neuronal groups," Science, vol. 189, pp. 55-58, 1975.
  15. L. Jacobs, "Single unit activity of locus coeruleus neurons in behaving animals," Prog. Neurobiol., vol. 27, pp. 183-194, 1986.
  16. S. L. Foote, G. Aston-Jones, and F. E. Bloom, "Impulse activity of locus coeruleus neurons in awake rats and monkeys is a function of sensory stimulation and arousal," Proc. Natl. Acad. Sci. U.S.A., vol. 77, pp. 3033-3037, 1980.
  17. O. Gaytan, R. Nason, R. Alagugurusamy, A. Swann, and N. Dafny, "MK-801 blocks the development of sensitization to the locomotor effects of methylphenidate," Brain Res. Bull., vol. 51, pp. 485-492, 2000.
  18. O. Gaytan, P. Yang, A. C. Swann, and N. Dafny, "Diurnal differences in sensitization to methylphenidate," Brain Res., vol. 864, pp. 24-39, 2000.
  19. O. Gaytan, A. C. Swann, and N. Dafny, "Disruption of sensitization to methylphenidate by a single administration of MK-801," Life Sci., vol. 70, pp. 2271-2285, 2002.
  20. P. B. Yang, B. Amini, A. C. Swann, and N. Dafny, "Strain differences in the behavioral responses of male rats to chronically administered methylphenidate," Brain Res., vol. 971, pp. 139-152, 2003.
  21. P. B. Yang, A. C. Swann, and N. Dafny, "Dose-response characteristics of methylphenidate on locomotor behavior and on sensory evoked potentials recorded from the VTA, NAc, and PFC in freely behaving rats," Behav. Brain Funct., vol. 3, 2006.
  22. P. B. Yang, A. C. Swann, and N. Dafny, "Chronic methylphenidate modulates locomotor activity and sensory evoked responses in the VTA and NAc of freely behaving rats," Neuropharmacology, vol. 51, pp. 546-556, 2006.
  23. P. B. Yang, A. C. Swann, and N. Dafny, "Acute and chronic methylphenidate dose-response assessment on three adolescent male rat strains," Brain Res. Bull., vol. 71, pp. 301-310, 2006.
  24. P. B. Yang, A. C. Swann, and N. Dafny, "Methylphenidate treated at the test cage--dose-dependent sensitization or tolerance depend on the behavioral assay used," Crit. Rev. Neurobiol., vol. 19, pp. 59-77, 2007.
  25. P. B. Yang, A. C. Swann, and N. Dafny, "Chronic administration of methylphenidate produces neurophysiological and behavioral sensitization," Brain Res., vol. 1145, pp. 66-80, 2007.
  26. P. B. Yang, A. C. Swann, and N. Dafny, "Psychostimulants given in adolescence modulate their effects in adulthood using the open field and the wheel-running assays," Brain Res. Bull., vol. 82, pp. 208-217, 2010.
  27. B. Amini, P. B. Yang, A. C. Swann, and N. Dafny, "Differential locomotor responses in male rats from three strains to acute methylphenidate," Int. J. Neurosci., vol. 114, pp. 1063-1084, 2004.
  28. B. Tang and N. Dafny, "Methylphenidate modulates the locus ceruleus neuronal activity in freely behaving rat," Eur. J. Pharmacol., vol. 695, pp. 48-56, 2012.
  29. O. Gaytan, D. Ghelani, S. Martin, A. C. Swann, and N. Dafny, "Methylphenidate: Diurnal effects on locomotor and stereotypic behavior in the rat," Brain Res., vol. 777, pp. 1-12, 1997.
  30. P. B. Yang, A. C. Swann, and N. Dafny, "Chronic pretreatment with methylphenidate induces cross-sensitization with amphetamine," Life Sci., vol. 73, pp. 2899-2911, 2003.
  31. N. Dafny and P. B. Yang, "The role of age, genotype, sex, and route of acute and chronic administration of methylphenidate: A review of its locomotor effects," Brain Res. Bull., vol. 68, pp. 393-405, 2006.
  32. M. E. Wolf, "The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants," Prog. Neurobiol., vol. 54, pp. 679-720, 1998.
  33. O. Gaytan, S. Al-rahim, A. C. Swann, and N. Dafny, "Sensitization to locomotor effects of methylphenidate in the rat," Life Sci., vol. 61, pp. L101-L107, 1997.
  34. R. C. Pierce and P. W. Kalivas, "A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants," Brain Res. Brain Res. Rev., vol. 25, pp. 192-216, 1997.
  35. G. Paxinos and C. Watson, "The rat brain in stereotaxic coordinates," Physiol Behav. Ref Type: Serial (Book,Monograph), 1986.
  36. N. Dafny, "The hypothalamus exhibits electrophysiologic evidence for morphine tolerance and dependence," Exp. Neurol., vol. 77, pp. 66-77, 1982.
  37. N. Dafny, "Multiunit recording from medial basal hypothalamus following acute and chronic morphine treatment," Brain Res., vol. 190, pp. 584-592, 1980.
  38. . Dafny and J. Terkel, "Hypothalamic neuronal activity associated with onset of pseudopregnancy in the rat," Neuroendocrinology, vol. 51, pp. 459-467, 1990.
  39. N. Dafny, J. R. Lee, and P. M. Dougherty, "Immune response products alter CNS activity: Interferon modulates central opioid functions," J. Neurosci. Res., vol. 19, pp. 130-139, 1988.
  40. M. Claussen and N. Dafny, "Acute and chronic methylphenidate modulates the neuronal activity of the caudate nucleus recorded from freely behaving rats," Brain Res. Bull., vol. 87, pp. 387-396, 2012.
  41. S. L. Chong, C. M. Claussen, and N. Dafny, "Nucleus accumbens neuronal activity in freely behaving rats is modulated following acute and chronic methylphenidate administration," Brain Res. Bull., vol. 87, pp. 445-456, 2012.
  42. R. L. Salek, C. M. Claussen, A. Perez, and N. Dafny, "Acute and chronic methylphenidate alters prefrontal cortex neuronal activity recorded from freely behaving rats," Eur. J. Pharmacol., vol. 679, pp. 60-67, 2012.
  43. B. Tang and N. Dafny, "Behavioral and dorsal raphe neuronal activity following acute and chronic methylphenidate in freely behaving rats," Brain Res. Bull., vol. 98, pp. 53-63, 2013.
  44. P. Yang, A. C. Swann, and N. Dafny, "NMDA receptor antagonist disrupts acute and chronic effects of methylphenidate," Physiol Behav., vol. 71, pp. 133-145, 2000.
  45. P. Yang, N. Singhal, G. Modi, A. C. Swann, and N. Dafny, "Effects of lithium chloride on induction and expression of methylphenidate sensitization," Eur. J. Pharmacol., vol. 426, pp. 65-72, 2001.
  46. P. Yang, A. Beasley, K. Eckermann, A. Swann, and N. Dafny, "Valproate prevents the induction of sensitization to methylphenidate (Ritalin) in rats," Brain Res., vol. 887, pp. 276-284, 2000.
  47. R. Kuczenski and D. S. Segal, "Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: Comparison with amphetamine," J. Neurochem., vol. 68, pp. 2032-2037, 1997.
  48. J. Biederman and T. Spencer, "Attention-deficit/hyperactivity disorder (ADHD) as a noradrenergic disorder," Biol. Psychiatry, vol. 46, pp. 1234-1242, 1999.
  49. C. Drouin, M. Page, and B. Waterhouse, "Methylphenidate enhances noradrenergic transmission and suppresses mid- and long-latency sensory responses in the primary somatosensory cortex of awake rats," J. Neurophysiol., vol. 96, pp. 622-632, 2006.
  50. P. Askenasy, K. H. Taber, P. B. Yang, and N. Dafny, "Methylphenidate (Ritalin): Behavioral studies in the rat," Int. J. Neurosci., vol. 117, pp. 757-794, 2007.
  51. M. F. Wu, S. A. Gulyani, E. Yau, E. Mignot, B. Phan, and J. M. Siegel, "Locus coeruleus neurons: Cessation of activity during cataplexy," Neuroscience, vol. 91, pp. 1389-1399, 1999.
  52. Aston-Jones, C. Chiang, and T. Alexinsky, "Discharge of noradrenergic locus coeruleus neurons in behaving rats and monkeys suggests a role in vigilance," Prog. Brain Res., vol. 88, pp. 501-520, 1991.
  53. Aston-Jones, M. T. Shipley, G. Chouvet, M. Ennis, B. E. Van, V. Pieribone, R. Shiekhattar, H. Akaoka, G. Drolet, and B. Astier, "Afferent regulation of locus coeruleus neurons: Anatomy, physiology and pharmacology," Prog. Brain Res., vol. 88, pp. 47-75, 1991.
  54. E. J. Nestler, "Molecular mechanisms of drug addiction," Neuropharmacology, vol. 47, pp. 24-32, 2004.
  55. Aston-Jones, J. Rajkowski, and J. Cohen, "Role of locus coeruleus in attention and behavioral flexibility," Biol. Psychiatry, vol. 46, pp. 1309-1320, 1999.
  56. S. Bouret and S. J. Sara, "Network reset: A simplified overarching theory of locus coeruleus noradrenaline function," Trends Neurosci., vol. 28, pp. 574-582, 2005.
  57. M. Weiss and P. E. Simson, "Neurochemical and electrophysiological events underlying stress-induced depression in an animal model," Adv. Exp. Med. Biol., vol. 245, pp. 425-440, 1988.
  58. E. M. Nikulina, J. E. Marchand, R. M. Kream, and K. A. Miczek, "Behavioral sensitization to cocaine after a brief social stress is accompanied by changes in fos expression in the murine brainstem," Brain Res., vol. 810, pp. 200-210, 1998.
  59. N. Carrey and M. Wilkinson, "A review of psychostimulant-induced neuroadaptation in developing animals," Neurosci. Bull., vol. 27, pp. 197-214, 2011.
  60. Y. Kim, M. A. Teylan, M. Baron, A. Sands, A. C. Nairn, and P. Greengard, "Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens," Proc. Natl. Acad. Sci. U. S. A, vol. 106, pp. 2915-2920, 2009.
  61. E. Fernandez-Espejo and N. Rodriguez-Espinosa, "Psychostimulant drugs and neuroplasticity," Pharmaceuticals, vol. 4, pp. 976-979, 2011.


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