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Locus coeruleus neuronal activity correlates with behavioral response to acute and chronic doses of methylphenidate (Ritalin) in adolescent rats

  • Psychiatry and Preclinical Psychiatric Studies - Original Article
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Abstract

The objective of this study is to gain insight into the behavioral and neuronal changes induced by acute and chronic methylphenidate (MPD) administration. Specifically, there is limited knowledge of the effects of MPD on the locus coeruleus (LC), the main site of norepinephrine synthesis in the brain. In this study, LC neuronal firing rate was recorded simultaneously with locomotor activity in freely moving adolescent rats. Adolescent rats were chosen to mimic the age group in humans most affected by MPD exposure. Following acute dose of 0.6, 2.5 or 10 mg/kg MPD, all rats showed an increase in locomotor activity. However, in response to chronic MPD doses, individual rats showed either a further increase or decrease in their locomotor activity as compared to the effect initiated by the acute dose—expressing either behavioral sensitization or tolerance, respectively. The LC neuronal recordings from animals expressing behavioral sensitization showed that the majority of units responded to chronic MPD exposure by further increasing firing rates as compared to the initial response to the acute MPD exposure. For the LC neuronal units recorded from animals expressing behavioral tolerance, however, the majority of the units responded to chronic exposure by attenuating or no significant effect on their firing rate as compared to the acute MPD exposure. This observation indicates a correlation between the LC neuronal responses and behavioral activity to chronic MPD exposure. The study shows that LC participates in the effect of MPD and the behavioral expression of sensitization and tolerance to chronic exposure of MPD.

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References

  • Algahim MF, Yang PB, Wilcox VT, Burau KD, Swann AC, Dafny N (2009) Prolonged methylphenidate treatment alters the behavioral diurnal activity pattern of adult male Sprague-Dawley rats. Pharmacol Biochem Behav 92(1):93–99

    Article  CAS  PubMed  Google Scholar 

  • Amaral DG, Sinnamon HM (1977) The locus coeruleus: neurobiology of a central noradrenergic nucleus. Prog Neurobiol 9(3):147–196

    Article  CAS  PubMed  Google Scholar 

  • Askenasy EP, Taber KH, Yang PB, Dafny N (2007) Methylphenidate (Ritalin): behavioral studies in the rat. Int J Neurosci 117(6):757–794

    Article  CAS  PubMed  Google Scholar 

  • Barron E, Yang PB, Swann AC, Dafny N (2009) Adolescent and adult male spontaneous hyperactive rats (SHR) respond differently to acute and chronic methylphenidate (Ritalin). Int J Neurosci 119(1):40–58

    Article  CAS  PubMed  Google Scholar 

  • Biederman J, Spencer T (1999) Attention-deficit/hyperactivity disorder (ADHD) as a noradrenergic disorder. Biol Psychiatry 46(9):1234–1242

    Article  CAS  PubMed  Google Scholar 

  • Britton GB (2012) Cognitive and emotional behavioural changes associated with methylphenidate treatment: a review of preclinical studies. Int J Neuropsychopharmacol 15(1):41–53

    Article  CAS  PubMed  Google Scholar 

  • Claussen CM, Chong SL, Dafny N (2014) Nucleus accumbens neuronal activity correlates to the animal’s behavioral response to acute and chronic methylphenidate. Physiol Behav 22(129):85–94

    Article  Google Scholar 

  • Dafny N (1980) Neurophysiological evidence for tolerance and dependence on opiates: simultaneous multiunit recordings from septum, thalamus, and caudate nucleus. J Neurosci Res 5(4):339–349

    Article  CAS  PubMed  Google Scholar 

  • Deupree JD, Reed AL, Bylund DB (2007) Differential effects of the tricyclic antidepressant desipramine on the density of adrenergic receptors in juvenile and adult rats. J Pharmacol Exp Ther 321(2):770–776

    Article  CAS  PubMed  Google Scholar 

  • Drouin C, Page M, Waterhouse B (2006) Methylphenidate enhances noradrenergic transmission and suppresses mid- and long-latency sensory responses in the primary somatosensory cortex of awake rats. J Neurophysiol 96(2):622–632

    Article  CAS  PubMed  Google Scholar 

  • Dulcan M (1997) Practice parameters for the assessment and treatment of children, adolescents, and adults with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 36(10 Suppl):85S–121S

    Article  CAS  PubMed  Google Scholar 

  • Frolov A, Reyes-Vasquez C, Dafny N (2015) Behavioral and neuronal recording of the nucleus accumbens in adolescent rats following acute and repetitive exposure to methylphenidate. J Neurophysiol 113(1):369–379

    Article  CAS  PubMed  Google Scholar 

  • Gaytan O, Yang P, Swann A, Dafny N (2000) Diurnal differences in sensitization to methylphenidate. Brain Res 864(1):24–39

    Article  CAS  PubMed  Google Scholar 

  • Godfrey J (2009) Safety of therapeutic methylphenidate in adults: a systematic review of the evidence. J Psychopharmacol 23(2):194–205

    Article  CAS  PubMed  Google Scholar 

  • Greely H, Sahakian B, Harris J, Kessler RC, Gazzaniga M, Campbell P, Farah MJ (2008) Towards responsible use of cognitive-enhancing drugs by the healthy. Nature 456(7223):702–705

    Article  CAS  PubMed  Google Scholar 

  • Igata S, Hayashi T, Itoh M, Akasu T, Takano M, Ishimatsu M (2014) Persistent α1-adrenergic receptor function in the nucleus locus coeruleus causes hyperexcitability in AD/HD model rats. J Neurophysiol 111(4):777–786

    Article  CAS  PubMed  Google Scholar 

  • Jones Z, Dafny N (2014) Acute and chronic dose-response effect of methylphenidate on ventral tegmental area neurons correlated with animal behavior. J Neural Transm (Vienna) 121(3):327–345

    Article  CAS  Google Scholar 

  • Kalivas PW, Duffy P, DuMars LA, Skinner C (1988) Behavioral and neurochemical effects of acute and daily cocaine administration in rats. J Pharmacol Exp Ther 245(2):485–492

    CAS  PubMed  Google Scholar 

  • Kidani Y, Ishimatsu M, Akasu T (2010) Methylphenidate enhances inhibitory synaptic transmission by increasing the content of norepinephrine in the locus coeruleus of juvenile rats. Kurume Med J 57(1–2):29–38

    Article  CAS  PubMed  Google Scholar 

  • Kuczenski R, Segal DS (2001) Locomotor effects of acute and repeated threshold doses of amphetamine and methylphenidate: relative roles of dopamine and norepinephrine. J Pharmacol Exp Ther 296(3):876–883

    CAS  PubMed  Google Scholar 

  • Kuczenski R, Segal DS (2002) Exposure of adolescent rats to oral methylphenidate: preferential effects on extracellular norepinephrine and absence of sensitization and cross-sensitization to methamphetamine. J Neurosci 22(16):7264–7271

    CAS  PubMed  Google Scholar 

  • Kushikata T, Yoshida H, Kudo M, Kudo T, Kudo T, Hirota K (2011) Role of coerulean noradrenergic neurones in general anaesthesia in rats. Br J Anaesth 107(6):924–929

    Article  CAS  PubMed  Google Scholar 

  • Lacroix D, Ferron A (1988) Electrophysiological effects of methylphenidate on the coeruleo-cortical noradrenergic system in the rat. Eur J Pharmacol 149(3):277–285

    Article  CAS  PubMed  Google Scholar 

  • Leblanc-Duchin D, Taukulis HK (2004) Behavioral reactivity to a noradrenergic challenge after chronic oral methylphenidate (ritalin) in rats. Pharmacol Biochem Behav 79(4):641–649

    Article  CAS  PubMed  Google Scholar 

  • Ma CL, Arnsten AF, Li BM (2005) Locomotor hyperactivity induced by blockade of prefrontal cortical alpha2-adrenoceptors in monkeys. Biol Psychiatry 57(2):192–195

    Article  CAS  PubMed  Google Scholar 

  • Moore RY, Bloom FE (1979) Central catecholamine neuron systems: anatomy and physiology of the norepinephrine and epinephrine systems. Annu Rev Neurosci 2:113–168

    Article  CAS  PubMed  Google Scholar 

  • Morton WA, Stockton GG (2000) Methylphenidate Abuse and Psychiatric Side Effects. Prim Care Companion J Clin Psychiatry 2(5):159–164

    Article  PubMed  PubMed Central  Google Scholar 

  • Murrin LC, Sanders JD, Bylund DB (2007) Comparison of the maturation of the adrenergic and serotonergic neurotransmitter systems in the brain: implications for differential drug effects on juveniles and adults. Biochem Pharmacol 73(8):1225–1236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nemoda Z, Angyal N, Tarnok Z, Gadoros J, Sasvari-Szekely M (2009) Carboxylesterase 1 gene polymorphism and methylphenidate response in ADHD. Neuropharmacology 57(7–8):731–733

    Article  CAS  PubMed  Google Scholar 

  • Olpe HR, Berecek KH, Jones RS, Steinmann MW, Sonnenburg C, Hofbauer KG (1985) Reduced activity of locus coeruleus neurons in hypertensive rats. J Hypertens 3(4):S93–S95

    CAS  Google Scholar 

  • Pliszka SR, McCracken JT, Maas JW (1996) Catecholamines in attention-deficit hyperactivity disorder: current perspectives. J Am Acad Child Adolesc Psychiatry 35(3):264–272

    Article  CAS  PubMed  Google Scholar 

  • Podet A, Lee MJ, Swann AC, Dafny N (2010) Nucleus accumbens lesions modulate the effects of methylphenidate. Brain Res Bull 82(5–6):293–301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rebec GV, Segal DS (1978) Dose-dependent biphasic alterations in the spontaneous activity of neurons in the rat neostriatum produced by d-amphetamine and methylphenidate. Brain Res 150(2):353–366

    Article  CAS  PubMed  Google Scholar 

  • Robinson TE (1984) Behavioral sensitization: characterization of enduring changes in rotational behavior produced by intermittent injections of amphetamine in male and female rats. Psychopharmacology 84(4):466–475

    Article  CAS  PubMed  Google Scholar 

  • Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 18(3):247–291

    Article  CAS  PubMed  Google Scholar 

  • Sanchez-Mora C, Ribases M, Mulas F, Soutullo C, Sans A, Pamias M, Casas M, Ramos-Quiroga JA (2012) Genetic bases of attention deficit hyperactivity disorder. Rev Neurol. 55(10):609–618

    CAS  PubMed  Google Scholar 

  • Sherwood N, Timiras PS (1970) A stereotaxic atlas of the developing rat brain. University of California Press, Berkeley

  • Stix G (2009) Turbocharging the brain. Sci Am 301(4):46–49 (52–55)

    Article  PubMed  Google Scholar 

  • Tang B, Dafny N (2012) Methylphenidate modulates the locus coeruleus neuronal activity in freely behaving rat. Eur J Pharmacol 695(1–3):48–56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang B, Dafny N (2013) Behavioral and dorsal raphe neuronal activity following acute and chronic methylphenidate in freely behaving rats. Brain Res Bull 98:53–63

    Article  CAS  PubMed  Google Scholar 

  • Volkow ND, Swanson JM (2008) The action of enhancers can lead to addiction. Nature 451(7178):520

    Article  CAS  PubMed  Google Scholar 

  • Volkow ND, Ding YS, Fowler JS, Wang GJ, Logan J, Gatley SJ, Schlyer DJ, Pappas N (1995) A new PET ligand for the dopamine transporter: studies in the human brain. J Nucl Med 36(12):2162–2168

    CAS  PubMed  Google Scholar 

  • Volkow ND, Wang GJ, Fowler JS, Ding YS (2005) Imaging the effects of methylphenidate on brain dopamine: new model on its therapeutic actions for attention-deficit/hyperactivity disorder. Biol Psychiatry 57(11):1410–1415 (Epub 2005 Jan 12)

    Article  CAS  PubMed  Google Scholar 

  • Yang PB, Amini B, Swann AC, Dafny N (2003) Strain differences in the behavioral responses of male rats to chronically administered methylphenidate. Brain Res 971(2):139–152

    Article  CAS  PubMed  Google Scholar 

  • Yang PB, Swann AC, Dafny N (2006) Sensory-evoked potentials recordings from the ventral tegmental area, nucleus accumbens, prefrontal cortex, and caudate nucleus and locomotor activity are modulated in dose-response characteristics by methylphenidate. Brain Res 16(1073–1074):164–174

    Article  Google Scholar 

  • Yang PB, Swann AC, Dafny N (2007) Methylphenidate treated at the test cage–dose-dependent sensitization or tolerance depend on the behavioral assay used. Crit Rev Neurobiol 19(1):59–77

    Article  PubMed  Google Scholar 

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Acknowledgements

This study was funded by NIH DA ROI 027222 Grant.

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Authors and Affiliations

  1. Department of Neurobiology and Anatomy, University of Texas Health Science Center at Houston, McGovern Medical School, 6431 Fannin Street Suite 7.208B, P.O. Box 20708, Houston, TX, 77030, USA

    Natasha Kharas & Nachum Dafny

  2. Departmento de Fisiologia, Division de Investigacion, Univsersidad Nacional Autonoma de Mexico, Mexico City, Mexico

    Cruz Reyes-Vazquez

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  1. Natasha Kharas
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  2. Cruz Reyes-Vazquez
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  3. Nachum Dafny
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Correspondence to Nachum Dafny.

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Kharas, N., Reyes-Vazquez, C. & Dafny, N. Locus coeruleus neuronal activity correlates with behavioral response to acute and chronic doses of methylphenidate (Ritalin) in adolescent rats. J Neural Transm 124, 1239–1250 (2017). https://doi.org/10.1007/s00702-017-1760-5

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  • DOI: https://doi.org/10.1007/s00702-017-1760-5

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