Abstract
Methylphenidate (MPD) is a psychostimulant used to treat attention deficit hyperactivity disorder. MPD exerts its neurocognitive effects through increasing concentrations of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in the neuronal synapse. This study recorded from adult freely behaving rats a total of 1170 neurons, 403 from the ventral tegmental area (VTA), 409 from locus coeruleus (LC), and 356 from dorsal raphe (DR) nucleus, which are the main sources of DA, NE, and 5-HT to the mesocorticolimbic circuitry, respectively. Electrophysiological and behavioral activities were recorded simultaneously following acute and repetitive (chronic) saline or 0.6, 2.5, or 10.0 mg/kg MPD. The uniqueness of this study is the evaluation of neuronal activity based on the behavioral response to chronic MPD. Animals received daily saline or MPD administration on experimental days 1–6 (ED1–6), followed by a 3-day wash-out period, and then MPD rechallenge on ED10. Each chronic MPD dose elicits behavioral sensitization in some animals, while in others, behavioral tolerance. Neuronal excitation following chronic MPD was observed in brains areas of animals exhibiting behavioral sensitization, while neuronal attenuation following chronic MPD was observed in those animals expressing behavioral tolerance. DR neuronal activity was most affected in response to acute and chronic MPD administration and responded differently compared to the neurons recorded from VTA and LC neurons at all doses. This suggests that although not directly related, DR and 5-HT are involved in the acute and chronic effects of MPD in adult rats, but exhibit a different role in response to MPD.
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References
Berridge CW, Waterhouse BD (2003) The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Brain Res Rev 42(1):33–84. https://doi.org/10.1016/s0165-0173(03)00143-7. (PMID: 12668290)
Chandler DJ (2016) Evidence for a specialized role of the locus coeruleus noradrenergic system in cortical circuitries and behavioral operations. Brain Res 1641(Pt B):197–206. https://doi.org/10.1016/j.brainres.2015.11.022. (Epub 2015 Nov 25. PMID: 26607255; PMCID: PMC4879003)
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. https://doi.org/10.1016/j.physbeh.2014.02.024. (Epub 2014 Feb 15. PMID: 24534179; PMCID: PMC4116108)
Cools R, Roberts AC, Robbins TW (2008) Serotoninergic regulation of emotional and behavioural control processes. Trends Cogn Sci 12(1):31–40. https://doi.org/10.1016/j.tics.2007.10.011. (Epub 2007 Dec 19. PMID: 18069045)
Devilbiss DM, Waterhouse BD (2004) The effects of tonic locus ceruleus output on sensory-evoked responses of ventral posterior medial thalamic and barrel field cortical neurons in the awake rat. J Neurosci 24(48):10773–10785. https://doi.org/10.1523/JNEUROSCI.1573-04.2004. (PMID: 15574728; PMCID: PMC6730210)
Ding YS, Fowler JS, Volkow ND, Dewey SL, Wang GJ, Logan J, Gatley SJ, Pappas N (1997) Chiral drugs: comparison of the pharmacokinetics of [11C]d-threo and L-threo-methylphenidate in the human and baboon brain. Psychopharmacology 131(1):71–78. https://doi.org/10.1007/s002130050267. (PMID: 9181638)
Fleckenstein AE, Volz TJ, Riddle EL, Gibb JW, Hanson GR (2007) New insights into the mechanism of action of amphetamines. Annu Rev Pharmacol Toxicol 47:681–698. https://doi.org/10.1146/annurev.pharmtox.47.120505.105140. (PMID: 17209801)
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. https://doi.org/10.1152/jn.00633.2013. (Epub 2014 Oct 15. PMID: 25318764; PMCID: PMC4294568)
Garland EJ (1998) Intranasal abuse of prescribed methylphenidate. J Am Acad Child Adolesc Psychiatry 37(6):573–574. https://doi.org/10.1097/00004583-199806000-00006. (PMID: 9628076)
Gatley SJ, Volkow ND, Gifford AN, Fowler JS, Dewey SL, Ding YS, Logan J (1999) Dopamine-transporter occupancy after intravenous doses of cocaine and methylphenidate in mice and humans. Psychopharmacology 146(1):93–100. https://doi.org/10.1007/s002130051093. (PMID: 10485970)
Gaytan O, al-Rahim S, Swann A, Dafny N (1997) Sensitization to locomotor effects of methylphenidate in the rat. Life Sci 61(8):PL101–PL107. https://doi.org/10.1016/s0024-3205(97)00598-5. (PMID: 9275016)
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(6):485–492. https://doi.org/10.1016/s0361-9230(99)00268-3. (PMID: 10758338)
González MM, Aston-Jones G (2006) Circadian regulation of arousal: role of the noradrenergic locus coeruleus system and light exposure. Sleep 29(10):1327–1336. https://doi.org/10.1093/sleep/29.10.1327. (PMID: 17068987)
Hnasko TS, Hjelmstad GO, Fields HL, Edwards RH (2012) Ventral tegmental area glutamate neurons: electrophysiological properties and projections. J Neurosci 32(43):15076–15085. https://doi.org/10.1523/JNEUROSCI.3128-12.2012. (PMID: 23100428; PMCID: PMC3685320)
Hodgkins P, Shaw M, Coghill D, Hechtman L (2012) Amfetamine and methylphenidate medications for attention-deficit/hyperactivity disorder: complementary treatment options. Eur Child Adolesc Psychiatry 21(9):477–492. https://doi.org/10.1007/s00787-012-0286-5. (Epub 2012 Jul 5. PMID: 22763750; PMCID: PMC3432777)
Jaeschke RR, Sujkowska E, Sowa-Kućma M (2021) Methylphenidate for attention-deficit/hyperactivity disorder in adults: a narrative review. Psychopharmacology 238(10):2667–2691. https://doi.org/10.1007/s00213-021-05946-0. (Epub 2021 Aug 26. PMID: 34436651; PMCID: PMC8455398)
Jones Z, Reyes-Vazquez C, Dafny N (2014) Ventral tegmental area neuronal activity correlates to animals’ behavioral response to chronic methylphenidate recorded from adolescent SD male rats. J Behav Brain Sci 4:168–189
Kapur A (2020) Is methylphenidate beneficial and safe in pharmacological cognitive enhancement? CNS Drugs 34(10):1045–1062. https://doi.org/10.1007/s40263-020-00758-w. (PMID: 32794136)
Kharas N, Whitt H, Reyes-Vasquez C, Dafny N (2017) Methylphenidate modulates dorsal raphe neuronal activity: behavioral and neuronal recordings from adolescent rats. Brain Res Bull 128:48–57. https://doi.org/10.1016/j.brainresbull.2016.10.011. (Epub 2016 Nov 23. PMID: 27889580; PMCID: PMC5224521)
Kim M, Kim J, Kim S, Jeong J (2020) Twitter analysis of the nonmedical use and side effects of methylphenidate: machine learning study. J Med Internet Res 22(2):e16466
Kuczenski R, Segal DS (1997) Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: comparison with amphetamine. J Neurochem 68(5):2032–2037. https://doi.org/10.1046/j.1471-4159.1997.68052032.x. (Erratum in: J Neurochem 1997 Sep;69(3):1332. PMID: 9109529)
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. https://doi.org/10.1523/JNEUROSCI.22-16-07264.2002. (PMID: 12177221; PMCID: PMC6757883)
Lee M, Dafny NDS (2014) Cocaine alters the daily activity patterns of adult rats. J Behav Brain Sci 4(11):523
Lee MJ, Yang PB, Wilcox VT, Burau KD, Swann AC, Dafny N (2009) Does repetitive Ritalin injection produce long-term effects on SD female adolescent rats? Neuropharmacology 57(3):201–207. https://doi.org/10.1016/j.neuropharm.2009.06.008. (Epub 2009 Jun 21. PMID: 19540860)
Llana ME, Crismon ML (1999) Methylphenidate: increased abuse or appropriate use? J Am Pharm Assoc (wash) 39(4):526–530. https://doi.org/10.1016/s1086-5802(16)30473-9. (PMID: 10467818)
Medina AC, Reyes-Vasquez C, Kharas N, Dafny N (2022) Adolescent rats respond differently to methylphenidate as compared to adult rats- concomitant VTA neuronal and behavioral Recordings. Brain Res Bull 183:1–12. https://doi.org/10.1016/j.brainresbull.2022.02.013. (Epub 2022 Feb 22. PMID: 35202752; PMCID: PMC8992835)
Miyazaki KW, Miyazaki K, Doya K (2012) Activation of dorsal raphe serotonin neurons is necessary for waiting for delayed rewards. J Neurosci 32(31):10451–10457. https://doi.org/10.1523/JNEUROSCI.0915-12.2012. (PMID: 22855794; PMCID: PMC6621383)
Paxinos G, Watson C (1986) The Rat Brain in Stereotaxic Coordinates. Academic Press
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. https://doi.org/10.1016/j.brainresbull.2010.05.006. (Epub 2010 May 12. PMID: 20470871; PMCID: PMC3935495)
Poe GR, Foote S, Eschenko O, Johansen JP, Bouret S, Aston-Jones G, Harley CW, Manahan-Vaughan D, Weinshenker D, Valentino R, Berridge C, Chandler DJ, Waterhouse B, Sara SJ (2020) Locus coeruleus: a new look at the blue spot. Nat Rev Neurosci 21(11):644–659. https://doi.org/10.1038/s41583-020-0360-9. (Epub 2020 Sep 17. PMID: 32943779; PMCID: PMC8991985)
Riddle EL, Hanson GR, Fleckenstein AE (2007) Therapeutic doses of amphetamine and methylphenidate selectively redistribute the vesicular monoamine transporter-2. Eur J Pharmacol 571(1):25–28. https://doi.org/10.1016/j.ejphar.2007.05.044. (Epub 2007 Jun 5. PMID: 17618619; PMCID: PMC2581712)
Root DH, Zhang S, Barker DJ, Miranda-Barrientos J, Liu B, Wang HL, Morales M (2018) Selective brain distribution and distinctive synaptic architecture of dual glutamatergic-GABAergic neurons. Cell Rep 23(12):3465–3479. https://doi.org/10.1016/j.celrep.2018.05.063. (PMID: 29924991; PMCID: PMC7534802)
Sara SJ (2009) The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci 10(3):211–223. https://doi.org/10.1038/nrn2573. (Epub 2009 Feb 4. PMID: 19190638)
Stevens T, Sangkuhl K, Brown JT, Altman RB, Klein TE (2019) PharmGKB summary: methylphenidate pathway, pharmacokinetics/pharmacodynamics. Pharmacogenet Genomics 29(6):136–154. https://doi.org/10.1097/FPC.0000000000000376. (PMID: 30950912; PMCID: PMC6581573)
Svetlov SI, Kobeissy FH, Gold MS (2007) Performance enhancing, non-prescription use of Ritalin: a comparison with amphetamines and cocaine. J Addict Dis 26(4):1–6. https://doi.org/10.1300/J069v26n04_01. (PMID: 18032226)
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. https://doi.org/10.1016/j.brainresbull.2013.06.004. (Epub 2013 Jul 22. PMID: 23886570)
Tao R, Auerbach SB (1995) Involvement of the dorsal raphe but not median raphe nucleus in morphine-induced increases in serotonin release in the rat forebrain. Neuroscience 68(2):553–561. https://doi.org/10.1016/0306-4522(95)00154-b. (PMID: 7477965)
Venkataraman SS, Claussen CM, Kharas N, Dafny N (2020) The prefrontal cortex and the caudate nucleus respond conjointly to methylphenidate (Ritalin). Concomitant behavioral and neuronal recording study. Brain Res Bull 157:77–89. https://doi.org/10.1016/j.brainresbull.2019.10.009. (Epub 2020 Jan 24. PMID: 31987926)
Volkow ND, Swanson JM (2013) Clinical practice: adult attention deficit-hyperactivity disorder. N Engl J Med 369(20):1935–1944. https://doi.org/10.1056/NEJMcp1212625. (PMID: 24224626; PMCID: PMC4827421)
Volkow ND, Ding YS, Fowler JS, Wang GJ, Logan J, Gatley JS, Dewey S, Ashby C, Liebermann J, Hitzemann R et al. (1995) Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in the human brain. Arch Gen Psychiatry 52(6):456–463. https://doi.org/10.1001/archpsyc.1995.03950180042006. (PMID: 7771915)
Volkow ND, Gatley SJ, Fowler JS, Wang GJ, Swanson J (2000) Serotonin and the therapeutic effects of ritalin. Science 288(5463):11. https://doi.org/10.1126/science.288.5463.11a. (PMID: 10766624)
Volkow ND, Fowler JS, Wang GJ (2002) Role of dopamine in drug reinforcement and addiction in humans: results from imaging studies. Behav Pharmacol 13(5–6):355–366. https://doi.org/10.1097/00008877-200209000-00008. (PMID: 12394411)
Wanchoo SJ, Swann AC, Dafny N (2009) Descending glutamatergic pathways of PFC are involved in acute and chronic action of methylphenidate. Brain Res 1301:68–79. https://doi.org/10.1016/j.brainres.2009.08.095. (Epub 2009 Sep 9. PMID: 19747456; PMCID: PMC3271787)
Weinshenker D, Holmes PV (2016) Regulation of neurological and neuropsychiatric phenotypes by locus coeruleus-derived galanin. Brain Res 1641(Pt B):320–337. https://doi.org/10.1016/j.brainres.2015.11.025. (Epub 2015 Nov 20. PMID: 26607256; PMCID: PMC4874918)
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. https://doi.org/10.1016/s0006-8993(02)04240-3. (PMID: 12706230)
Yang PB, Swann AC, Dafny N (2006a) Chronic methylphenidate modulates locomotor activity and sensory evoked responses in the VTA and NAc of freely behaving rats. Neuropharmacology 51(3):546–556. https://doi.org/10.1016/j.neuropharm.2006.04.014. (Epub 2006 Jul 7. PMID: 16824558)
Yang PB, Swann AC, Dafny N (2006b) 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. https://doi.org/10.1016/j.brainres.2005.12.055. (Epub 2006 Feb 10. PMID: 16473326)
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 17(2):3. https://doi.org/10.1186/1744-9081-2-3. (PMID: 16417623; PMCID: PMC1360669)
Yang PB, Swann AC, Dafny N (2007) Chronic administration of methylphenidate produces neurophysiological and behavioral sensitization. Brain Res 1145:66–80. https://doi.org/10.1016/j.brainres.2007.01.108. (Epub 2007 Feb 2. PMID: 17335781; PMCID: PMC1902809)
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This work was supported by the National Institute on Drug Abuse (Grant No. NIH RO1 DA 027022).
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Yuan, A., Claussen, C., Jones, Z. et al. Methylphenidate induces a different response in the dorsal raphe as compared to ventral tegmental area and locus coeruleus: behavioral and concomitant neuronal recordings in adult rats. J Neural Transm 130, 1579–1599 (2023). https://doi.org/10.1007/s00702-023-02665-y
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DOI: https://doi.org/10.1007/s00702-023-02665-y