Advertisement

Distinct Age-Dependent Effects of Methylphenidate on Developing and Adult Prefrontal Neurons

      Background

      Methylphenidate (MPH) has long been used to treat attention-deficit/hyperactivity disorder (ADHD); however, its cellular mechanisms of action and potential effects on prefrontal cortical circuitry are not well understood, particularly in the developing brain system. A clinically relevant dose range for rodents has been established in the adult animal; however, how this range will translate to juvenile animals has not been established.

      Methods

      Juvenile (postnatal day [PD] 15) and adult (PD90) Sprague Dawley rats were treated with MPH or saline. Whole-cell patch clamp recording was used to examine the neuronal excitability and synaptic transmission in pyramidal neurons of prefrontal cortex. Recovery from MPH treatment was also examined at 1, 5, and 10 weeks following drug cessation.

      Results

      A dose of 1 mg/kg intraperitoneal MPH, either single dose or chronic treatment (well within the accepted therapeutic range for adults), produced significant depressive effects on pyramidal neurons by increasing hyperpolarization-activated currents in juvenile rat prefrontal cortex, while exerting excitatory effects in adult rats. Minimum clinically-relevant doses (.03 to .3 mg/kg) also produced depressive effects in juvenile rats, in a linear dose-dependent manner. Function recovered within 1 week from chronic 1 mg/kg treatment, chronic treatment with 3 and 9 mg/kg resulted in depression of prefrontal neurons lasting 10 weeks and beyond.

      Conclusions

      These results suggest that the juvenile prefrontal cortex is supersensitive to methylphenidate, and the accepted therapeutic range for adults is an overshoot. Juvenile treatment with MPH may result in long-lasting, potentially permanent, changes to excitatory neuron function in the prefrontal cortex of juvenile rats.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Solanto M.V.
        Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: A review and integration.
        Behav Brain Res. 1998; 94: 127-152
        • Swanson J.M.
        • Kinsbourne M.
        • Nigg J.
        • Lanphear B.
        • Stefanatos G.A.
        • Volkow N.
        • et al.
        Etiologic subtypes of attention-deficit/hyperactivity disorder: Brain imaging, molecular genetic and environmental factors and the dopamine hypothesis.
        Neuropsychol Rev. 2007; 17: 39-59
        • Castellanos F.X.
        • Tannock R.
        Neuroscience of attention-deficit/hyperactivity disorder: The search for endophenotypes.
        Nat Rev Neurosci. 2002; 3: 617-628
        • Barkley R.A.
        • Fischer M.
        • Smallish L.
        • Fletcher K.
        Young adult follow-up of hyperactive children: Antisocial activities and drug use.
        J Child Psychol Psychiatry. 2004; 45: 195-211
        • Shaw P.
        • Eckstrand K.
        • Sharp W.
        • Blumenthal J.
        • Lerch J.P.
        • Greenstein D.
        • et al.
        Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation.
        Proc Natl Acad Sci U S A. 2007; 104: 19649-19654
        • Arnsten A.F.
        Fundamentals of attention-deficit/hyperactivity disorder: circuits and pathways.
        J Clin Psychiatry. 2006; 67: 7-12
        • Ohno M.
        The dopaminergic system in attention deficit/hyperactivity disorder.
        Congenit Anom (Kyoto). 2003; 43: 114-122
        • Russell V.A.
        Dopamine hypofunction possibly results from a defect in glutamate-stimulated release of dopamine in the nucleus accumbens shell of a rat model for attention deficit hyperactivity disorder—the spontaneously hypertensive rat.
        Neurosci Biobehav Rev. 2003; 27: 671-682
        • Challman T.D.
        • Lipsky J.J.
        Methylphenidate: Its pharmacology and uses.
        Mayo Clin Proc. 2000; 75: 711-721
        • Berridge C.W.
        • Devilbiss D.M.
        • Andrzejewski M.E.
        • Arnsten A.F.
        • Kelley A.E.
        • Schmeichel B.
        • et al.
        Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function.
        Biol Psychiatry. 2006; 60: 1111-1120
        • Kuczenski R.
        • Segal D.S.
        Locomotor effects of acute and repeated threshold doses of amphetamine and methylphenidate: Relative roles of dopamine and norepinephrine.
        J Pharmacol Exp Ther. 2001; 296: 876-883
        • Kuczenski R.
        • Segal D.S.
        Exposure of adolescent rats to oral methylphenidate: preferential effects on extracellular norepinephrine and absence of sensitization and cross-sensitization to methamphetamine.
        J Neurosci. 2002; 22: 7264-7271
        • Kuczenski R.
        • Segal D.S.
        Stimulant actions in rodents: Implications for attention-deficit/hyperactivity disorder treatment and potential substance abuse.
        Biol Psychiatry. 2005; 57: 1391-1396
        • Greenhill L.
        • Kollins S.
        • Abikoff H.
        • McCracken J.
        • Riddle M.
        • Swanson J.
        • et al.
        Efficacy and safety of immediate-release methylphenidate treatment for preschoolers with ADHD.
        J Am Acad Child Adolesc Psychiatry. 2006; 45: 1284-1293
        • Arnsten A.F.
        Stimulants: Therapeutic actions in ADHD.
        Neuropsychopharmacology. 2006; 31: 2376-2383
        • Arnsten A.F.
        • Dudley A.G.
        Methylphenidate improves prefrontal cortical cognitive function through alpha2 adrenoceptor and dopamine D1 receptor actions: Relevance to therapeutic effects in attention deficit hyperactivity disorder.
        Behav Brain Funct. 2005; 1: 2-10
        • Arnsten A.F.
        Toward a new understanding of attention-deficit hyperactivity disorder pathophysiology: An important role for prefrontal cortex dysfunction.
        CNS Drugs. 2009; 23: 33-41
        • Arnsten A.F.T.
        Stress signalling pathways that impair prefrontal cortex structure and function.
        Nat Rev Neurosci. 2009; 10: 410-422
        • Lagace D.C.
        • Yee J.K.
        • Bolanos C.A.
        • Eisch A.J.
        Juvenile administration of methylphenidate attenuates adult hippocampal neurogenesis.
        Biol Psychiatry. 2006; 60: 1121-1130
        • Algahim M.F.
        • Yang P.B.
        • Burau K.D.
        • Swann A.C.
        • Dafny N.
        Repetitive Ritalin treatment modulates the diurnal activity pattern of young SD male rats.
        Cent Nerv Syst Agents Med Chem. 2010; 10: 247-257
        • Beckman D.A.
        • Schneider M.
        • Youreneff M.
        • Tse F.L.
        Juvenile toxicity assessment of d,l-methylphenidate in rats.
        Birth Defects Res B Dev Reprod Toxicol. 2008; 83: 48-67
        • Gray J.D.
        • Punsoni M.
        • Tabori N.E.
        • Melton J.T.
        • Fanslow V.
        • Ward M.J.
        • et al.
        Methylphenidate administration to juvenile rats alters brain areas involved in cognition, motivated behaviors, appetite, and stress.
        J Neurosci. 2007; 27: 7196-7207
        • Kanyshkova T.
        • Pawlowski M.
        • Meuth P.
        • Dube C.
        • Bender R.A.
        • Brewster A.L.
        • et al.
        Postnatal expression pattern of HCN channel isoforms in thalamic neurons: relationship to maturation of thalamocortical oscillations.
        J Neurosci. 2009; 29: 8847-8857
        • Kirschner J.
        • Moll G.H.
        • Fietzek U.M.
        • Heinrich H.
        • Mall V.
        • Berweck S.
        • et al.
        Methylphenidate enhances both intracortical inhibition and facilitation in healthy adults.
        Pharmacopsychiatry. 2003; 36: 79-82
        • Drouin C.
        • Wang D.
        • Waterhouse B.D.
        Neurophysiological actions of methylphenidate in the primary somatosensory cortex.
        Synapse. 2007; 61: 985-990
        • Hille B.
        Ion Channels of Excitable Membranes.
        3rd ed. Sinauer, Sunderland, MA2001
        • Surges R.
        • Freiman T.M.
        • Feuerstein T.J.
        Input resistance is voltage dependent due to activation of Ih channels in rat CA1 pyramidal cells.
        J Neurosci Res. 2004; 76: 475-480
        • Kessels H.W.M.
        Synaptic AMPA receptor plasticity and behavior.
        Neuron. 2009; 61 (R.): 340-350
        • Franke A.G.
        • Bonertz C.
        • Christmann M.
        • Huss M.
        • Fellgiebel A.
        • Hildt E.
        • et al.
        Non-medical use of prescription stimulants and illicit use of stimulants for cognitive enhancement in pupils and students in Germany.
        Pharmacopsychiatry. 2011; 44: 60-66
        • Linssen A.M.
        • Vuurman E.F.
        • Sambeth A.
        • Riedel W.J.
        Methylphenidate produces selective enhancement of declarative memory consolidation in healthy volunteers [published online ahead of print December 15].
        Psychopharmacology (Berl). 2011;
        • Smith M.E.
        • Farah M.J.
        Are prescription stimulants “smart pills”?.
        Psychol Bull. 2011; 137: 717-741
        • Grund T.
        • Lehmann K.
        • Bock N.
        • Rothenberger A.
        • Teuchert-Noodt G.
        Influence of methylphenidate on brain development—an update of recent animal experiments.
        Behav Brain Funct. 2006; 2: 2
        • Yano M.
        • Steiner H.
        Methylphenidate and cocaine: the same effects on gene regulation?.
        Trends Pharmacol Sci. 2007; 28: 588-596
        • Brandon C.L.
        • Marinelli M.
        • Baker L.K.
        • White F.J.
        Enhanced reactivity and vulnerability to cocaine following methylphenidate treatment in adolescent rats.
        Neuropsychopharmacology. 2001; 25: 651-661
        • Carlezon Jr, W.A.
        • Mague S.D.
        • Andersen S.L.
        Enduring behavioral effects of early exposure to methylphenidate in rats.
        Biol Psychiatry. 2003; 54: 1330-1337
        • Andersen S.L.
        • Arvanitogiannis A.
        • Pliakas A.M.
        • LeBlanc C.
        • Carlezon Jr, W.A.
        Altered responsiveness to cocaine in rats exposed to methylphenidate during development.
        Nat Neurosci. 2002; 5: 13-14
        • Bolanos C.A.
        • Barrot M.
        • Berton O.
        • Wallace-Black D.
        • Nestler E.J.
        Methylphenidate treatment during pre- and periadolescence alters behavioral responses to emotional stimuli at adulthood.
        Biol Psychiatry. 2003; 54: 1317-1329
        • Brandon C.L.
        • Steiner H.
        Repeated methylphenidate treatment in adolescent rats alters gene regulation in the striatum.
        Eur J Neurosci. 2003; 18: 1584-1592
        • Yang P.B.
        • Swann A.C.
        • Dafny N.
        Chronic pretreatment with methylphenidate induces cross-sensitization with amphetamine.
        Life Sci. 2003; 73: 2899-2911
        • Sproson E.J.
        • Chantrey J.
        • Hollis C.
        • Marsden C.A.
        • Fonel K.C.
        Effect of repeated methylphenidate administration on presynaptic dopamine and behaviour in young adult rats.
        J Psychopharmacol. 2001; 15: 67-75
        • Gray J.D.
        • Punsoni M.
        • Tabori N.E.
        • Melton J.T.
        • Fanslow V.
        • Ward M.J.
        • et al.
        Methylphenidate administration to juvenile rats alters brain areas involved in cognition, motivated behaviors, appetite, and stress.
        J Neurosci. 2007; 27: 7196-7207
        • Jezierski G.
        • Zehle S.
        • Bock J.
        • Braun K.
        • Gruss M.
        Early stress and chronic methylphenidate cross-sensitize dopaminergic responses in the adolescent medial prefrontal cortex and nucleus accumbens.
        J Neurochem. 2007; 103: 2234-2244
        • Torres-Reveron A.
        • Gray J.D.
        • Melton J.T.
        • Punsoni M.
        • Tabori N.E.
        • Ward M.J.
        • et al.
        Early postnatal exposure to methylphenidate alters stress reactivity and increases hippocampal ectopic granule cells in adult rats.
        Brain Res Bull. 2009; 78: 175-181
        • Adriani W.
        • Leo D.
        • Greco D.
        • Rea M.
        • di Porzio U.
        • Laviola G.
        • et al.
        Methylphenidate administration to adolescent rats determines plastic changes on reward-related behavior and striatal gene expression.
        Neuropsychopharmacology. 2006; 31: 1946-1956
        • Scaini G.
        • Fagundes A.O.
        • Rezin G.T.
        • Gomes K.M.
        • Zugno A.I.
        • Quevedo J.
        • et al.
        Methylphenidate increases creatine kinase activity in the brain of young and adult rats.
        Life Sci. 2008; 83: 795-800
        • Andersen S.L.
        • Napierata L.
        • Brenhouse H.C.
        • Sonntag K.C.
        Juvenile methylphenidate modulates reward-related behaviors and cerebral blood flow by decreasing cortical D3 receptors.
        Eur J Neurosci. 2008; 27: 2962-2972
        • Martins M.R.
        • Reinke A.
        • Petronilho F.C.
        • Gomes K.M.
        • Dal-Pizzol F.
        • Quevedo J.
        Methylphenidate treatment induces oxidative stress in young rat brain.
        Brain Res. 2006; 1078: 189-197
        • Vendruscolo L.F.
        • Izidio G.S.
        • Takahashi R.N.
        • Ramos A.
        Chronic methylphenidate treatment during adolescence increases anxiety-related behaviors and ethanol drinking in adult spontaneously hypertensive rats.
        Behav Pharmacol. 2008; 19: 21-27
        • Lee M.J.
        • Yang P.B.
        • Wilcox V.T.
        • Burau K.D.
        • Swann A.C.
        • Dafny N.
        Does repetitive Ritalin injection produce long-term effects on SD female adolescent rats?.
        Neuropharmacology. 2009; 57: 201-207
        • Andrews G.D.
        • Lavin A.
        Methylphenidate increases cortical excitability via activation of alpha-2 noradrenergic receptors.
        Neuropsychopharmacology. 2006; 31: 594-601
        • Andersen S.L.
        Changes in the second messenger cyclic AMP during development may underlie motoric symptoms in attention deficit/hyperactivity disorder (ADHD).
        Behav Brain Res. 2002; 130: 197-201
        • Devilbiss D.M.
        • Berridge C.W.
        Cognition-enhancing doses of methylphenidate preferentially increase prefrontal cortex neuronal responsiveness.
        Biol Psychiatry. 2008; 64: 626-635
      1. Waterhouse BD, Agster KL, Calrk BD (2008): The effects of methylphenidate on sensory signal processing in the rodent lateral geniculate nucleus. Presented at the Society for Neuroscience meeting (abstract, program no. 161.165; Washington, DC; 15-19 Nov).

        • Casey B.J.
        • Nigg J.T.
        • Durston S.
        New potential leads in the biology and treatment of attention deficit-hyperactivity disorder.
        Curr Opin Neurol. 2007; 20: 119-124
        • Arnsten A.F.
        Catecholamine and second messenger influences on prefrontal cortical networks of “representational knowledge”: a rational bridge between genetics and the symptoms of mental illness.
        Cereb Cortex. 2007; 17: i6-i15
        • Wu J.
        • Hablitz J.J.
        Cooperative activation of D1 and D2 dopamine receptors enhances a hyperpolarization-activated inward current in layer I interneurons.
        J Neurosci. 2005; 25: 6322-6328
        • Rosenkranz J.A.
        • Johnston D.
        Dopaminergic regulation of neuronal excitability through modulation of Ih in layer V entorhinal cortex.
        J Neurosci. 2006; 26: 3229-3244
        • Surges R.
        • Brewster A.L.
        • Bender R.A.
        • Beck H.
        • Feuerstein T.J.
        • Baram T.Z.
        Regulated expression of HCN channels and cAMP levels shape the properties of the h current in developing rat hippocampus.
        Eur J Neurosci. 2006; 24: 94-104
        • Vasilyev D.V.
        • Barish M.E.
        Postnatal development of the hyperpolarization-activated excitatory current Ih in mouse hippocampal pyramidal neurons.
        J Neurosci. 2002; 22: 8992-9004
        • Ding L.
        • Perkel D.J.
        Dopamine modulates excitability of spiny neurons in the avian basal ganglia.
        J Neurosci. 2002; 22: 5210-5218
        • Rothmond D.A.
        • Weickert C.S.
        • Webster M.J.
        Developmental changes in human dopamine neurotransmission: cortical receptors and terminators.
        BMC Neurosci. 2012; 13: 18-31
        • Surmeier D.J.
        • Ding J.
        • Day M.
        • Wang Z.
        • Shen W.
        D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons.
        Trends Neurosci. 2007; 30: 228-235
        • Volkow N.D.
        • Insel T.R.
        What are the long-term effects of methylphenidate treatment?.
        Biol Psychiatry. 2003; 54: 1307-1309
        • LeBlanc-Duchin D.
        • Taukulis H.K.
        Chronic oral methylphenidate administration to periadolescent rats yields prolonged impairment of memory for objects.
        Neurobiol Learn Mem. 2007; 88: 312-320
        • LeBlanc-Duchin D.
        • Taukulis H.K.
        Chronic oral methylphenidate induces post-treatment impairment in recognition and spatial memory in adult rats.
        Neurobiol Learn Mem. 2009; 91: 218-225

      Linked Article

      • Erratum
        Biological PsychiatryVol. 73Issue 6
        • Preview
          The incorrect grant number was inadvertently reported in the Acknowledgments section of “Distinct Age-Dependent Effects of Methylphenidate on Developing and Adult Prefrontal Neurons” by Urban et al., which appeared in Biological Psychiatry (2012;72:880-888). The listed grant number of R01MH232395 is an internal number of Drexel University. The proper NIH grant number is R01MH085666.
        • Full-Text
        • PDF