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D1 and D2 specific dopamine antagonist modulate the caudate nucleus neuronal responses to chronic methylphenidate exposure

  • Translational Neurosciences - Original Article
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Abstract

The psychostimulant, methylphenidate (MPD), is the first line treatment as a pharmacotherapy to treat behavioral disorders such as attention deficit hyperactivity disorder (ADHD). MPD is commonly misused in non-ADHD (normal) youth and young adults both as a recreational drug and for cognitive enhancing effects to improve their grades. MPD is known to act on the reward circuit; including the caudate nucleus (CN). The CN is comprised of medium spiny neurons containing largely dopamine (DA) D1 and D2 receptors. It has been widely shown that the DA system plays an important role in the response to MPD exposure. We investigated the role of both D1 and D2 DA receptors in the CN response to chronic MPD administration using specific D1 and D2 DA antagonist. Four groups of young adult, male SD rats were used: a saline (control) and three MPD dose groups (0.6, 2.5, and 10.0 mg/kg). The experiment lasted 11 consecutive days. Each MPD dose group was randomly divided into two subgroups to receive either a 0.4 mg/kg SCH-23390 selective D1 DA antagonist or a 0.3 mg/kg raclopride selective D2 DA antagonist prior to their final (repetitive) MPD rechallenge administration. It was observed that selective D1 DA antagonist (SCH-23390) given 30 min prior to the last MPD exposure at ED11 partially reduced or prevented the effect induced by MPD exposure in CN neuronal firing rates across all MPD doses. Selective D2 DA antagonist (raclopride) resulted in less obvious trends; some CN neuronal firing rates exhibited a slight increase in all MPD doses.

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References

  • Arnsten AF, Dudley AG (2005) MPD improves prefrontal cortical cognitive function through alpha2 adrenoceptor and dopamine D1 receptor actions: relevance to therapeutic effects in attention deficit hyperactive disorder. Behav Brain Funct 1(1):2

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Calabresi P, Piccomi B, Tozzi A, Ghiglieri V, DiFillipo M (2014) Direct and indirect pathways of basal ganglia: a critical reappraisal. Nat Neurosci 17:1022–1030

    Article  CAS  PubMed  Google Scholar 

  • Carpenter MB (1976) Anatomy of the basal ganglia and related nuclei: a review. Adv Neurol 14:7–48

    CAS  PubMed  Google Scholar 

  • Chao J, Nestler EJ (2004) Molecular neurobiology of drug addiction. Annu Rev Med 55:113–132

    Article  CAS  PubMed  Google Scholar 

  • Chong SL, Claussen CM, Dafny N (2012) Nucleus accumbens neuronal activity in freely behaving rats is modulated following acute and chronic methylphenidate administration. Brain Res Bull 10:445–456

    Article  Google Scholar 

  • Claussen CM, Dafny N (2012) Acute and chronic methylphenidate modulates the neuronal activity of the caudate nucleus recorded from freely behaving rats. Brain Res Bull 87:387–396

    Article  CAS  PubMed  Google Scholar 

  • Claussen CM, Dafny N (2015) Caudate neuronal recording in freely behaving animals following acute and chronic dose response methylphenidate exposure. Pharmacol Biochem Behav 136:21–30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Claussen CM, Chong SL, Dafny N (2012) Selective bilateral lesion to caudate nucleus modulates the acute and chronic methylphenidate effects. Pharmacol Biochem Behav 101(2):208–216

    Article  CAS  PubMed  PubMed Central  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 129:85–94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Claussen CM, Witte LJ, Dafny N (2015) Single exposure of dopamine D1 antagonist prevents and D2 antagonist attenuates methylphenidate effect. J Exp Pharmacol 7:1–9

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dafny N (1980) Multiunit recording from medial basal hypothalamus following acute and chronic morphine treatment. Brain Res 190:584–592

    Article  CAS  PubMed  Google Scholar 

  • Dafny N (1982) The hypothalamus exhibits electrophysiologic evidence for morphine tolerance and dependence. Exp Neurol 77:66–77

    Article  CAS  PubMed  Google Scholar 

  • Dafny N (2014) Does methylphenidate (MPD) have the potential to become a drug of abuse? Biochem Pharmacol J 3:155–160

    Google Scholar 

  • Dafny N, Terkel J (1990) Hypothalamic neuronal activity associated with onset of pseudopregnancy in the rat. Neuroendocrinology 51:459–467

    Article  CAS  PubMed  Google Scholar 

  • Dafny N, Yang PB (2006) The role of age, genotype, sex, and route of acute and chronic administration of methylphenidate: a review of its locomotor effects. Brain Res Bull 68:393–405

    Article  CAS  PubMed  Google Scholar 

  • Fond G, Gavaret M, Vidal C, Brunel L, Riveline JP, Micoulaud-Franchi JA, Domenech P (2016) Misuse of prescribed stimulants in the medical student community: motives and behaviors: a population-based cross-sectional study. Medicine (Baltimore) 95(16):e3366

    Article  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, Ghelani D, Martin S, Swann A, Dafny N (1997) Methylphenidate: diurnal effects on locomotor and stereotypic behavior in the rat. Brain Res 777(1–2):1–12

    Article  CAS  PubMed  Google Scholar 

  • Gaytan O, Nason R, Alagugurusamy R, Swann A, Dafny N (2000) MK 801 blocks the development of sensitization to the locomotor effects of methylphenidate. Brain Res Bull 51:485–492

    Article  CAS  PubMed  Google Scholar 

  • Gerfen CR, Surmeier J (2011) Modulation of striatal projection systems by dopamine. Annu Rev Neurosci 34:331–466

    Article  Google Scholar 

  • Ginsberg Y, Quintero J, Anand E, Casillas M, Upadhyaya HP (2014) Underdiagnosis of attention-deficit/hyperactivity disorder in adult patients: a review of the literature. Prim Care Companion CNS Disord 16(3):13r01600

    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 456:702–705

    Article  CAS  PubMed  Google Scholar 

  • Gronier B (2011) In vivo electrophysiological effects of methylphenidate in the prefrontal cortex: involvement of dopamine D1 and alpha 2 adrenergic receptors. Eur Neuropsychopharmacol 21:192–204

    Article  CAS  PubMed  Google Scholar 

  • Hildt E, Lieb K, Bagusat C, Franke AG (2015) Reflections on addiction in students using stimulants for neuroenhancement: a preliminary interview study. Biomed Res Int 2015:621075

    Article  PubMed  PubMed Central  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 121(3):327–345

    Article  CAS  PubMed  Google Scholar 

  • Kalivas PW, Pierce RC (2007) Locomotor behavior. Curr Protoc Neurosci Chapter 8:Unit 8.1

    PubMed  Google Scholar 

  • Kalivas PW, Stewart J (1991) Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity. Brain Res Brain Res Rev 3:223–244

    Article  Google Scholar 

  • Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P (2009) Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens. Proc Natl Acad Sci USA 106(8):2915–2920

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kreitzer AC, Malenka RC (2008) Striatal plasticity and basal ganglia circuit function. Neuron 4:543–554

    Article  Google Scholar 

  • Kuczenki 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

    Google Scholar 

  • Kuribara H, Uchihashi Y (1993) SCH 23390 equivalently, but YM-09151-2 differentially reduces the stimulant effects of metamphetamine, MK-801 and ketamine: assessment by discrete shuttle avoidance in mice. Jpn J Pharmacol 62(1):111–114

    Article  CAS  PubMed  Google Scholar 

  • Lee M, Dafny N (2014) Cocaine alters the daily activity patterns of adult SD female rats. J Behav Brain Sci 4:523–524

    Article  Google Scholar 

  • Liu YP, Lin PJ, Tseng CJ, Wan FJ, Tung CS (2009) Role of dopaminergic DAD1 and DAD2 receptors in the sensitization of amphetamine-suppressed schedule-induced polydipsia in rats. Chin J Physiol 52(5):280–288

    Article  CAS  PubMed  Google Scholar 

  • Meng ZH, Feldpaush DL, Merchant KM (1998) Clozapine and haloperidol block the induction of behavioral sensitization to amphetamine and associated genomic responses in rats. Brain Res Mol Brain Res 61(3):9–50

    Google Scholar 

  • Meririnne E, Kankaanpää A, Seppälä T (2001) Rewarding properties of methylphenidate: sensitization by prior exposure to the drug and effects of dopamine D1- and D2-receptor antagonists. J Pharmacol Exp Ther 298:539–550

    CAS  PubMed  Google Scholar 

  • Nestler EJ (2001) Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci 2:119–128

    Article  CAS  PubMed  Google Scholar 

  • Nestler EJ (2004) Molecular mechanisms of drug addiction. Neuropharmacology 47(Suppl 1):24–32

    Article  CAS  PubMed  Google Scholar 

  • Nestler EJ (2008) Review. Transcriptional mechanisms of addiction: role of DeltaFosB. Philos Trans R Soc Lond B Biol Sci 363:3245–3255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd edn. Academic Press, Sydney, Australia

    Google Scholar 

  • Rebec GV (2006) Behavioral electrophysiology of psychostimulants. Neuropsychopharmacology 31(11):2341–2348

    Article  CAS  PubMed  Google Scholar 

  • Salek RL, Claussen CM, Perez A, Dafny N (2012) Acute and chronic methylphenidate alters prefrontal cortex neuronal activity recorded from freely behaving rats. Eur J Pharmacol 679:60–67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shippenberg TS, Heidbreder C (1995) Sensitization to the conditioned rewarding effects of cocaine: pharmacological and temporal characteristics. J Pharmacol Exp Ther 273(2):808–815

    CAS  PubMed  Google Scholar 

  • Stix G (2009) Turbocharging the brain. Sci Am 301(46–9):52–55

    Google Scholar 

  • Tang B, Dafny N (2013) Dorsal raphe neuronal activities are modulated by methylphenidate. J Neural Transm 120(5):721–731

    Article  CAS  PubMed  Google Scholar 

  • Teo SK, Stirling DI, Hoberman AM, Christian MS, Thomas SD, Khetani VD (2003) d-methylphenidate and d, l-methylphenidate are not developmental toxicants in rats and rabbits. Birth Defects Res B Dev Reprod Toxicol 68:162–171

    Article  CAS  PubMed  Google Scholar 

  • Ujike H, Akiyama K, Otsuki S (1990) D-2 but not D-1 dopamine agonists produce augmented behavioral response in rats after subchronic treatment with methamphetamine or cocaine. Psychopharmacology 102:459–464

    Article  CAS  PubMed  Google Scholar 

  • Volkow ND, DingYS 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 12:2162–2168

    Google Scholar 

  • Yang PB, Swann AC, Dafny N (2006a) Acute and chronic methylphenidate dose–response assessment on three adolescent male rat strains. Brain Res Bull 71:301–310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang PB, Swann AC, Dafny N (2006b) Chronic methylphenidate modulates locomotor activity and sensory evoked responses in the VTA and NAc of freely behaving rats. Neuropharmacology 51:546–556

    Article  CAS  PubMed  Google Scholar 

  • Yang PB, Swann AC, Dafny N (2006c) 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 2:3

    Article  PubMed  PubMed Central  Google Scholar 

  • Yang PB, Swann AC, Dafny N (2006d) 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 1073–1074:164–174

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Yang PB, Atkins KD, Dafny N (2011a) Behavioral sensitization and cross-sensitization between methylphenidate amphetamine, and 3,4-methylenedioxymethamphetamine (MDMA) in female SD rats. Eur J Pharmacol 66:72–85

    Article  Google Scholar 

  • Yang PB, Cuellar DO 3rd, Swann AC, Dafny N (2011b) Age and genetic strain differences in response to chronic methylphenidate administration. Behav Brain Res 218(1):206–217

    Article  CAS  PubMed  Google Scholar 

  • Zhang D, Lou H, Jiao D, Zhang X, Wang Y, Xia J, Zhang XuM (2004) Cocaine-induced intracellular signaling and gene expression are oppositely regulated by the dopamine D1 and D3 receptors. J Neurosci 24(13):3344–3354

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This research was supported by a National Institutes of Health (NIH) Grant, DA R01 027222.

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Authors and Affiliations

  1. Department of Neurobiology and Anatomy, University of Texas McGovern Medical School at Houston, 6431 Fannin Street Suite 7.208B, Houston, USA

    Sidish Venkataraman, Catherine Claussen & Nachum Dafny

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  1. Sidish Venkataraman
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  2. Catherine Claussen
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  3. Nachum Dafny
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Correspondence to Nachum Dafny.

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Venkataraman, S., Claussen, C. & Dafny, N. D1 and D2 specific dopamine antagonist modulate the caudate nucleus neuronal responses to chronic methylphenidate exposure. J Neural Transm 124, 159–170 (2017). https://doi.org/10.1007/s00702-016-1647-x

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