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PMID: 15999146 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Methylphenidate increases cortical excitability via activation of alpha-2 noradrenergic receptors.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology ·Vol. 31 ·No. 3 ·2006-03-00 ·Pages 594-601

Andrews GD, Lavin A

Abstract

Although methylphenidate (MPH), a catecholaminergic reuptake blocker, is prescribed for attention-deficit/hyperactivity disorder, there is a dearth of information regarding the cellular basis of its actions. To address this issue, we used whole-cell patch-clamp recordings to investigate the roles of various catecholamine receptors in MPH-induced changes in cortical neuron excitability. We bath-applied dopamine or noradrenaline receptor antagonists in combination with MPH to pyramidal cells located in deep layers of the infralimbic and prelimbic prefrontal cortices. Application of MPH (10 microM) by itself increased cortical cell excitability in slices obtained from juvenile rats. This MPH-mediated increase in excitability was lost when catecholamines were depleted with reserpine prior to recording, demonstrating the requirement for a presynaptic monoamine component. Antagonist studies further revealed that stimulation of alpha-2 noradrenergic receptors mediates the MPH-induced increase in intrinsic excitability. Dopamine D1 receptors played no observable role in the actions of MPH. We therefore propose that MPH is acting to increase catecholaminergic tone in the PFC, and thereby increases cortical excitability by mediating the disinhibition of pyramidal cells through mechanisms that may include activation of alpha-2 adrenoreceptors located in interneurons.

MeSH Terms
Adrenergic alpha-Agonists/pharmacology Adrenergic alpha-Antagonists/pharmacology Animals Catecholamines/metabolism Central Nervous System Stimulants/pharmacology Cerebral Cortex/drug effects,metabolism Dopamine/metabolism Dopamine Agonists/pharmacology Electrophysiology In Vitro Techniques Male Methylphenidate/pharmacology Nerve Net/drug effects,physiology Norepinephrine/metabolism,physiology Prefrontal Cortex/drug effects,metabolism Pyramidal Cells/metabolism Rats Receptors, Adrenergic, alpha-2/drug effects
Chemicals
Adrenergic alpha-Agonists Adrenergic alpha-Antagonists Catecholamines Central Nervous System Stimulants Dopamine Agonists Receptors, Adrenergic, alpha-2 Methylphenidate Dopamine Norepinephrine
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Andrews Glenn D
Department of Physiology and Neuroscience, Medical University of South Carolina, Charleston, SC 29425, USA.
Lavin Antonieta
References (34)
34 references, click to expand
  1. Effects of methylphenidate on young adults' performance and event-related potentials in a vigilance and a paired-associates learning test.
    Psychophysiology. 1984 Nov;21(6):609-21 PMID: 6514938
  2. Brainstem innervation of prefrontal and anterior cingulate cortex in the rhesus monkey revealed by retrograde transport of HRP.
    J Comp Neurol. 1982 Feb 10;205(1):63-76 PMID: 6121826
  3. Opiate- and alpha 2-adrenoceptor-induced hyperpolarizations of locus ceruleus neurons in brain slices: reversal by cyclic adenosine 3':5'-monophosphate analogues.
    J Neurosci. 1985 Sep;5(9):2359-64 PMID: 2993542
  4. Effects of methylphenidate on spatial working memory and planning in healthy young adults.
    Psychopharmacology (Berl). 1997 May;131(2):196-206 PMID: 9201809
  5. Methylphenidate enhances working memory by modulating discrete frontal and parietal lobe regions in the human brain.
    J Neurosci. 2000 Mar 15;20(6):RC65 PMID: 10704519
  6. Perikaryal and synaptic localization of alpha 2A-adrenergic receptor-like immunoreactivity.
    Brain Res. 1994 Jul 11;650(2):181-204 PMID: 7953684
  7. Biochemical and histochemical studies on the effects of imipramine-like drugs and (+)-amphetamine on central and peripheral catecholamine neurons.
    Acta Physiol Scand. 1966 Jul-Aug;67(3):481-97 PMID: 5967609
  8. Dopamine D1 receptor mechanisms in the cognitive performance of young adult and aged monkeys.
    Psychopharmacology (Berl). 1994 Oct;116(2):143-51 PMID: 7862943
  9. A comparison of the capacities of isomers of amphetamine, deoxypipradrol and methylphenidate to inhibit the uptake of tritiated catecholamines into rat cerebral cortex slices, synaptosomal preparations of rat cerebral cortex, hypothalamus and striatum and into adrenergic nerves of rabbit aorta.
    J Pharmacol Exp Ther. 1972 Jun;181(3):407-16 PMID: 5033010
  10. Biochemistry of somatodendritic dopamine release in substantia nigra: an in vivo comparison with striatal dopamine release.
    J Neurochem. 1995 Jul;65(1):192-200 PMID: 7790860
  11. Possible change in noradrenergic receptor sensitivity following methylphenidate treatment: growth hormone and MHPG response to clonidine challenge in children with attention deficit disorder and hyperactivity.
    Life Sci. 1984 Aug 20;35(8):885-97 PMID: 6482679
  12. Treatment effects of oral and transdermal clonidine in relation to methylphenidate: an open pilot study in ADD-H.
    Psychopharmacol Bull. 1987;23(1):111-4 PMID: 3602304
  13. Noradrenaline-mediated synaptic inhibition in rat locus coeruleus neurones.
    J Physiol. 1983 Dec;345:477-88 PMID: 6141289
  14. Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: a review and integration.
    Behav Brain Res. 1998 Jul;94(1):127-52 PMID: 9708845
  15. Multiple ionic conductances of the human dopamine transporter: the actions of dopamine and psychostimulants.
    J Neurosci. 1997 Feb 1;17(3):960-74 PMID: 8994051
  16. The distribution of tyrosine hydroxylase-immunoreactive fibers in primate neocortex is widespread but regionally specific.
    J Neurosci. 1987 Jan;7(1):279-90 PMID: 2879896
  17. Dopamine D2 receptor mechanisms contribute to age-related cognitive decline: the effects of quinpirole on memory and motor performance in monkeys.
    J Neurosci. 1995 May;15(5 Pt 1):3429-39 PMID: 7751922
  18. A neurocomputational theory of the dopaminergic modulation of working memory functions.
    J Neurosci. 1999 Apr 1;19(7):2807-22 PMID: 10087092
  19. Antagonism by methylphenidate of the stereotyped behaviour produced by (+)-amphetamine in reserpinized rats.
    J Pharm Pharmacol. 1978 Apr;30(4):253-4 PMID: 24718
  20. Ultrastructural localization of the norepinephrine transporter in superficial and deep layers of the rat prelimbic prefrontal cortex and its spatial relationship to probable dopamine terminals.
    J Comp Neurol. 2003 Nov 24;466(4):478-94 PMID: 14566944
  21. The dopamine mesocorticolimbic pathway is affected by deficiency in n-3 polyunsaturated fatty acids.
    Am J Clin Nutr. 2002 Apr;75(4):662-7 PMID: 11916751
  22. Effects of dopamine antagonists on neuronal activity related to a delayed response task in monkey prefrontal cortex.
    J Neurophysiol. 1990 Jun;63(6):1401-12 PMID: 2358883
  23. Stereoselectivity of catecholamine uptake by brain synaptosomes: studies with ephedrine, methylphenidate and phenyl-2-piperidyl carbinol.
    J Pharmacol Exp Ther. 1972 Oct;183(1):103-16 PMID: 5080026
  24. Ventral tegmental area afferents to the prefrontal cortex maintain membrane potential 'up' states in pyramidal neurons via D(1) dopamine receptors.
    Cereb Cortex. 2000 Dec;10(12):1168-75 PMID: 11073866
  25. Stimulation of D1-type dopamine receptors enhances excitability in prefrontal cortical pyramidal neurons in a state-dependent manner.
    Neuroscience. 2001;104(2):335-46 PMID: 11377838
  26. Regional and cellular fractionation of working memory.
    Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13473-80 PMID: 8942959
  27. Electrophysiological effects of methylphenidate on the coeruleo-cortical noradrenergic system in the rat.
    Eur J Pharmacol. 1988 May 10;149(3):277-85 PMID: 3409954
  28. Cellular and subcellular sites for noradrenergic action in the monkey dorsolateral prefrontal cortex as revealed by the immunocytochemical localization of noradrenergic receptors and axons.
    Cereb Cortex. 1998 Apr-May;8(3):269-77 PMID: 9617922
  29. Anti-hyperactivity medication: methylphenidate and amphetamine.
    Mol Psychiatry. 1998 Sep;3(5):386-96 PMID: 9774771
  30. Dopamine D1 receptor actions in layers V-VI rat prefrontal cortex neurons in vitro: modulation of dendritic-somatic signal integration.
    J Neurosci. 1996 Mar 1;16(5):1922-35 PMID: 8774459
  31. Region-specific distribution of catecholamine afferents in primate cerebral cortex: a fluorescence histochemical analysis.
    J Comp Neurol. 1984 Jul 20;227(1):23-36 PMID: 6470208
  32. Characterization of alpha 2-adrenoceptors which increase potassium conductance in rat locus coeruleus neurones.
    Neuroscience. 1985 Jan;14(1):95-101 PMID: 2579354
  33. Noradrenergic innervation of monkey prefrontal cortex: a dopamine-beta-hydroxylase immunohistochemical study.
    J Comp Neurol. 1989 Apr 15;282(3):317-30 PMID: 2715385
  34. Prefrontal neurons in networks of executive memory.
    Brain Res Bull. 2000 Jul 15;52(5):331-6 PMID: 10922510
Article Info
Journal
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Abbr.
Neuropsychopharmacology
ISSN
0893-133X
DOI
10.1038/sj.npp.1300818
Published
2006-03-00
Pages
594-601
Language
English
Region
England
NLM ID
8904907
PMCID
PMC5509071
Subset
IM
Grants
NIDA NIH HHS · R01 DA014698 · United States
NIDA NIH HHS · R56 DA014698 · United States
NIDA NIH HHS · DA 14698 · United States
External Links
PubMed source DOI: 10.1038/sj.npp.1300818 PMC Full Text View journal details
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