Advertisement

The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex

Published:September 25, 2014DOI:https://doi.org/10.1016/j.biopsych.2014.09.013

      Abstract

      Psychostimulants are highly effective in the treatment of attention-deficit/hyperactivity disorder. The clinical efficacy of these drugs is strongly linked to their ability to improve cognition dependent on the prefrontal cortex (PFC) and extended frontostriatal circuit. The procognitive actions of psychostimulants are only associated with low doses. Surprisingly, despite nearly 80 years of clinical use, the neurobiology of the procognitive actions of psychostimulants has only recently been systematically investigated. Findings from this research unambiguously demonstrate that the cognition-enhancing effects of psychostimulants involve the preferential elevation of catecholamines in the PFC and the subsequent activation of norepinephrine α2 and dopamine D1 receptors. In contrast, while the striatum is a critical participant in PFC-dependent cognition, where examined, psychostimulant action within the striatum is not sufficient to enhance cognition. At doses that moderately exceed the clinical range, psychostimulants appear to improve PFC-dependent attentional processes at the expense of other PFC-dependent processes (e.g., working memory, response inhibition). This differential modulation of PFC-dependent processes across dose appears to be associated with the differential involvement of noradrenergic α2 versus α1 receptors. Collectively, this evidence indicates that at low, clinically relevant doses, psychostimulants are devoid of the behavioral and neurochemical actions that define this class of drugs and instead act largely as cognitive enhancers (improving PFC-dependent function). This information has potentially important clinical implications as well as relevance for public health policy regarding the widespread clinical use of psychostimulants and for the development of novel pharmacologic treatments for attention-deficit/hyperactivity disorder and other conditions associated with PFC dysregulation.

      Keywords

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

      Purchase one-time access:

      Academic and Personal
      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

        • Segal D.S.
        Behavioral and neurochemical correlates of repeated d-amphetamine administration.
        Adv Biochem Psychopharmacol. 1975; 13: 247-262
        • Rebec G.V.
        • Bashore T.R.
        Critical issues in assessing the behavioral effects of amphetamine.
        Neurosci Biobehav Rev. 1984; 8: 153-159
        • McGaughy J.
        • Sarter M.
        Behavioral vigilance in rats: Task validation and effects of age, amphetamine, and benzodiazepine receptor ligands.
        Psychopharmacology (Berl). 1995; 117: 340-357
        • Berridge C.W.
        • Stalnaker T.A.
        Relationship between low-dose amphetamine-induced arousal and extracellular norepinephrine and dopamine levels within prefrontal cortex.
        Synapse. 2002; 46: 140-149
        • 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
        • Devilbiss D.M.
        • Berridge C.W.
        Cognition-enhancing doses of methylphenidate preferentially increase prefrontal cortex neuronal responsiveness.
        Biol Psychiatry. 2008; 64: 626-635
        • Bradley C.
        The behavior of children receiving benzadrine.
        Am J Psychiatry. 1937; 94: 577-585
        • Greenhill L.L.
        Clinical effects of stimulant medication in ADHD.
        in: Solanto M.V. Arnsten A.F.T. Castellanos F.X. Stimulant Drugs and ADHD: Basic and Clinical Neuroscience. Oxford University Press, New York2001: 31-71
        • Hechtman L.
        • Abikoff H.
        • Klein R.G.
        • Weiss G.
        • Respitz C.
        • Kouri J.
        • et al.
        Academic achievement and emotional status of children with ADHD treated with long-term methylphenidate and multimodal psychosocial treatment.
        J Am Acad Child Adolesc Psychiatry. 2004; 43: 812-819
        • Scheffler R.M.
        • Brown T.T.
        • Fulton B.D.
        • Hinshaw S.P.
        • Levine P.
        • Stone S.
        Positive association between attention-deficit/ hyperactivity disorder medication use and academic achievement during elementary school.
        Pediatrics. 2009; 123: 1273-1279
        • Rapoport J.L.
        • Buchsbaum M.S.
        • Weingartner H.
        • Zahn T.P.
        • Ludlow C.
        • Mikkelsen E.J.
        Dextroamphetamine. Its cognitive and behavioral effects in normal and hyperactive boys and normal men.
        Arch Gen Psychiatry. 1980; 37: 933-943
        • Vaidya C.J.
        • Austin G.
        • Kirkorian G.
        • Ridlehuber H.W.
        • Desmond J.E.
        • Glover G.H.
        • Gabrieli J.D.
        Selective effects of methylphenidate in attention deficit hyperactivity disorder: A functional magnetic resonance study.
        Proc Natl Acad Sci U S A. 1998; 95: 14494-14499
        • Mehta M.A.
        • Owen A.M.
        • Sahakian B.J.
        • Mavaddat N.
        • Pickard J.D.
        • Robbins T.W.
        Methylphenidate enhances working memory by modulating discrete frontal and parietal lobe regions in the human brain.
        J Neurosci. 2000; 20: RC65
        • Rapoport J.L.
        • Inoff-Germain G.
        Responses to methylphenidate in attention-deficit/hyperactivity disorder and normal children: Update 2002.
        J Atten Disord. 2002; 6: S57-S60
        • Elliott R.
        • Sahakian B.J.
        • Matthews K.
        • Bannerjea A.
        • Rimmer J.
        • Robbins T.W.
        Effects of methylphenidate on spatial working memory and planning in healthy young adults.
        Psychopharmacology (Berl). 1997; 131: 196-206
        • Setlik J.
        • Bond G.R.
        • Ho M.
        Adolescent prescription ADHD medication abuse is rising along with prescriptions for these medications.
        Pediatrics. 2009; 124: 875-880
        • McCabe S.E.
        • Knight J.R.
        • Teter C.J.
        • Wechsler H.
        Non-medical use of prescription stimulants among US college students: Prevalence and correlates from a national survey.
        Addiction. 2005; 100: 96-106
        • Maher B.
        Poll results: Look who׳s doping.
        Nature. 2008; 452: 674-675
        • Barkley R.A.
        Attention-deficit/hyperactivity disorder, self-regulation, and time: Toward a more comprehensive theory.
        J Dev Behav Pediatr. 1997; 18: 271-279
        • Castellanos F.X.
        • Tannock R.
        Neuroscience of attention-deficit/hyperactivity disorder: The search for endophenotypes.
        Nat Rev Neurosci. 2002; 3: 617-628
        • Casey B.J.
        • Epstein J.N.
        • Buhle J.
        • Liston C.
        • Davidson M.C.
        • Tonev S.T.
        • et al.
        Frontostriatal connectivity and its role in cognitive control in parent-child dyads with ADHD.
        Am J Psychiatry. 2007; 164: 1729-1736
        • Bush G.
        • Valera E.M.
        • Seidman L.J.
        Functional neuroimaging of attention-deficit/hyperactivity disorder: A review and suggested future directions.
        Biol Psychiatry. 2005; 57: 1273-1284
        • Swanson J.
        • Volkow N.
        Pharmacokinetic and pharmacodynamic properties of methylphenidate in humans.
        in: Solanto M.V. Arnsten A.F.T. Castellanos F.X. Stimulant Drugs and ADHD: Basic and Clinical Neuroscience. Oxford University Press, New York2001
        • 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
        • Berridge C.W.
        • Devilbiss D.M.
        Psychostimulants as cognitive enhancers: The prefrontal cortex, catecholamines, and attention-deficit/hyperactivity disorder.
        Biol Psychiatry. 2011; 69: e101-e111
        • 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
        • Kuczenski R.
        • Segal D.S.
        Regional norepinephrine response to amphetamine using dialysis: Comparison with caudate dopamine.
        Synapse. 1992; 11: 164-169
        • Kuczenski R.
        • Segal D.S.
        • Cho A.K.
        • Melega W.
        Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioral responses to the stereoisomers of amphetamine and methamphetamine.
        J Neurosci. 1995; 15: 1308-1317
        • Kuczenski R.
        • Segal D.S.
        Neurochemistry of amphetamine.
        in: Cho A.K. Segal D.S. Amphetamine and Its Analogues: Psychopharmacology, Toxicology and Abuse. Academic Press, San Diego1994: 81-113
        • Florin S.M.
        • Kuczenski R.
        • Segal D.S.
        Regional extracellular norepinephrine responses to amphetamine and cocaine and effects of clonidine pretreatment.
        Brain Res. 1994; 654: 53-62
        • Kuczenski R.
        • Segal D.S.
        Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: Comparison with amphetamine.
        J Neurochem. 1997; 68: 2032-2037
        • 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
        • Gamo N.J.
        • Wang M.
        • Arnsten A.F.
        Methylphenidate and atomoxetine enhance prefrontal function through alpha2-adrenergic and dopamine D1 receptors.
        J Am Acad Child Adolesc Psychiatry. 2010; 49: 1011-1023
        • Arnsten A.F.
        • Pliszka S.R.
        Catecholamine influences on prefrontal cortical function: Relevance to treatment of attention deficit/hyperactivity disorder and related disorders.
        Pharmacol Biochem Behav. 2011; 99: 211-216
        • Delfs J.M.
        • Schreiber L.
        • Kelley A.E.
        Microinjection of cocaine into the nucleus accumbens elicits locomotor activation in the rat.
        J Neurosci. 1990; 10: 303-310
        • Berridge C.W.
        Neural substrates of psychostimulant-induced arousal.
        Neuropsychopharmacology. 2006; 31: 2332-2340
        • Kelly P.H.
        • Seviour P.W.
        • Iversen S.D.
        Amphetamine and apomorphine responses in the rat following 6-OHDA lesions of the nucleus accumbens septi and corpus striatum.
        Brain Res. 1975; 94: 507-522
        • Wise R.A.
        • Bozarth M.A.
        A psychomotor stimulant theory of addiction.
        Psychol Rev. 1987; 94: 469-492
        • Drouin C.
        • Page M.
        • Waterhouse B.
        Methylphenidate enhances noradrenergic transmission and suppresses mid- and long-latency sensory responses in the primary somatosensory cortex of awake rats.
        J Neurophysiol. 2006; 96: 622-632
        • Biederman J.
        Pharmacotherapy for attention-deficit/hyperactivity disorder (ADHD) decreases the risk for substance abuse: Findings from a longitudinal follow-up of youths with and without ADHD.
        J Clin Psychiatry. 2003; 64: 3-8
        • Wilens T.E.
        • Faraone S.V.
        • Biederman J.
        • Gunawardene S.
        Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature.
        Pediatrics. 2003; 111: 179-185
        • Schmeichel B.E.
        • Berridge C.W.
        Neurocircuitry underlying the preferential sensitivity of prefrontal catecholamines to low-dose psychostimulants.
        Neuropsychopharmacology. 2013; 38: 1078-1084
        • Meyers B.
        • Kritzer M.F.
        In vitro binding assays using (3)H nisoxetine and (3)H WIN 35,428 reveal selective effects of gonadectomy and hormone replacement in adult male rats on norepinephrine but not dopamine transporter sites in the cerebral cortex.
        Neuroscience. 2009; 159: 271-282
        • Sesack S.R.
        • Hawrylak V.A.
        • Matus C.
        • Guido M.A.
        • Levey A.I.
        Dopamine axon varicosities in the prelimbic division of the rat prefrontal cortex exhibit sparse immunoreactivity for the dopamine transporter.
        J Neurosci. 1998; 18: 2697-2708
        • Giros B.
        • Wang Y.M.
        • Suter S.
        • McLeskey S.B.
        • Pifl C.
        • Caron M.G.
        Delineation of discrete domains for substrate, cocaine, and tricyclic antidepressant interactions using chimeric dopamine-norepinephrine transporters.
        J Biol Chem. 1994; 269: 15985-15988
        • Gu H.
        • Wall S.C.
        • Rudnick G.
        Stable expression of biogenic amine transporters reveals differences in inhibitor sensitivity, kinetics, and ion dependence.
        J Biol Chem. 1994; 269: 7124-7130
        • Moron J.A.
        • Brockington A.
        • Wise R.A.
        • Rocha B.A.
        • Hope B.T.
        Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: Evidence from knock-out mouse lines.
        J Neurosci. 2002; 22: 389-395
        • Bymaster F.P.
        • Katner J.S.
        • Nelson D.L.
        • Hemrick-Luecke S.K.
        • Threlkeld P.G.
        • Heiligenstein J.H.
        • et al.
        Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: A potential mechanism for efficacy in attention deficit/hyperactivity disorder.
        Neuropsychopharmacology. 2002; 27: 699-711
        • Carboni E.
        • Tanda G.L.
        • Frau R.
        • Di C.G.
        Blockade of the noradrenaline carrier increases extracellular dopamine concentrations in the prefrontal cortex: Evidence that dopamine is taken up in vivo by noradrenergic terminals.
        J Neurochem. 1990; 55: 1067-1070
        • Carboni E.
        • Silvagni A.
        • Vacca C.
        • Di C.G.
        Cumulative effect of norepinephrine and dopamine carrier blockade on extracellular dopamine increase in the nucleus accumbens shell, bed nucleus of stria terminalis and prefrontal cortex.
        J Neurochem. 2006; 96: 473-481
        • Cass W.A.
        • Gerhardt G.A.
        In vivo assessment of dopamine uptake in rat medial prefrontal cortex: Comparison with dorsal striatum and nucleus accumbens.
        J Neurochem. 1995; 65: 201-207
        • Schmeichel B.
        • Zemlan F.
        • Berridge C.W.
        A selective dopamine reuptake inhibitor improves prefrontal cortex-dependent cognitive function: Potential relevant to attention deficit hyperactivity disorder.
        Neuropharmacology. 2012; 64: 321-328
        • Kesner R.P.
        Subregional analysis of mnemonic functions of the prefrontal cortex in the rat.
        Psychobiology. 2000; 28: 219-228
        • Mehta M.A.
        • Goodyer I.M.
        • Sahakian B.J.
        Methylphenidate improves working memory and set-shifting in AD/HD: Relationships to baseline memory capacity.
        J Child Psychol Psychiatry. 2004; 45: 293-305
        • Dalley J.W.
        • Cardinal R.N.
        • Robbins T.W.
        Prefrontal executive and cognitive functions in rodents: Neural and neurochemical substrates.
        Neurosci Biobehav Rev. 2004; 28: 771-784
        • Vertes R.P.
        Differential projections of the infralimbic and prelimbic cortex in the rat.
        Synapse. 2004; 51: 32-58
        • Spencer R.C.
        • Klein R.M.
        • Berridge C.W.
        Psychostimulants act within the prefrontal cortex to improve cognitive function.
        Biol Psychiatry. 2012; 72: 221-227
        • Armario A.
        Activation of the hypothalamic-pituitary-adrenal axis by addictive drugs: different pathways, common outcome.
        Trends Pharmacol Sci. 2010; 31: 318-325
        • Barsegyan A.
        • Mackenzie S.M.
        • Kurose B.D.
        • McGaugh J.L.
        • Roozendaal B.
        Glucocorticoids in the prefrontal cortex enhance memory consolidation and impair working memory by a common neural mechanism.
        Proc Natl Acad Sci U S A. 2010; 107: 16655-16660
        • Balleine B.W.
        • Delgado M.R.
        • Hikosaka O.
        The role of the dorsal striatum in reward and decision-making.
        J Neurosci. 2007; 27: 8161-8165
        • Balleine B.W.
        • O׳Doherty J.P.
        Human and rodent homologies in action control: Corticostriatal determinants of goal-directed and habitual action.
        Neuropsychopharmacology. 2010; 35: 48-69
        • Clatworthy P.L.
        • Lewis S.J.
        • Brichard L.
        • Hong Y.T.
        • Izquierdo D.
        • Clark L.
        • et al.
        Dopamine release in dissociable striatal subregions predicts the different effects of oral methylphenidate on reversal learning and spatial working memory.
        J Neurosci. 2009; 29: 4690-4696
        • Volkow N.D.
        • Wang G.J.
        • Fowler J.S.
        • Logan J.
        • Franceschi D.
        • Maynard L.
        • et al.
        Relationship between blockade of dopamine transporters by oral methylphenidate and the increases in extracellular dopamine: Therapeutic implications.
        Synapse. 2002; 43: 181-187
        • Volkow N.D.
        • Wang G.J.
        • Tomasi D.
        • Kollins S.H.
        • Wigal T.L.
        • Newcorn J.H.
        • et al.
        Methylphenidate-elicited dopamine increases in ventral striatum are associated with long-term symptom improvement in adults with attention deficit hyperactivity disorder.
        J Neurosci. 2012; 32: 841-849
        • Gabbott P.L.
        • Warner T.A.
        • Jays P.R.
        • Salway P.
        • Busby S.J.
        Prefrontal cortex in the rat: Projections to subcortical autonomic, motor, and limbic centers.
        J Comp Neurol. 2005; 492: 145-177
        • Floresco S.B.
        • Braaksma D.N.
        • Phillips A.G.
        Thalamic-cortical-striatal circuitry subserves working memory during delayed responding on a radial arm maze.
        J Neurosci. 1999; 19: 11061-11071
        • Smith A.
        • Cubillo A.
        • Barrett N.
        • Giampietro V.
        • Simmons A.
        • Brammer M.
        • Rubia K.
        Neurofunctional effects of methylphenidate and atomoxetine in boys with attention-deficit/hyperactivity disorder during time discrimination.
        Biol Psychiatry. 2013; 74: 615-622
        • Rubia K.
        • Halari R.
        • Cubillo A.
        • Mohammad A.M.
        • Brammer M.
        • Taylor E.
        Methylphenidate normalises activation and functional connectivity deficits in attention and motivation networks in medication-naive children with ADHD during a rewarded continuous performance task.
        Neuropharmacology. 2009; 57: 640-652
        • Rubia K.
        • Halari R.
        • Cubillo A.
        • Smith A.B.
        • Mohammad A.M.
        • Brammer M.
        • Taylor E.
        Methylphenidate normalizes fronto-striatal underactivation during interference inhibition in medication-naive boys with attention-deficit hyperactivity disorder.
        Neuropsychopharmacology. 2011; 36: 1575-1586
        • Marquand A.F.
        • O׳Daly O.G.
        • De Simoni S.
        • Alsop D.C.
        • Maguire R.P.
        • Williams S.C.
        • et al.
        Dissociable effects of methylphenidate, atomoxetine and placebo on regional cerebral blood flow in healthy volunteers at rest: A multi-class pattern recognition approach.
        Neuroimage. 2012; 60: 1015-1024
        • Marquand A.F.
        • De Simoni S.
        • O׳Daly O.G.
        • Williams S.C.
        • Mourao-Miranda J.
        • Mehta M.A.
        Pattern classification of working memory networks reveals differential effects of methylphenidate, atomoxetine, and placebo in healthy volunteers.
        Neuropsychopharmacology. 2011; 36: 1237-1247
        • Pauls A.M.
        • O׳Daly O.G.
        • Rubia K.
        • Riedel W.J.
        • Williams S.C.
        • Mehta M.A.
        Methylphenidate effects on prefrontal functioning during attentional-capture and response inhibition.
        Biol Psychiatry. 2012; 72: 142-149
        • Cubillo A.
        • Smith A.B.
        • Barrett N.
        • Giampietro V.
        • Brammer M.
        • Simmons A.
        • Rubia K.
        Drug-specific laterality effects on frontal lobe activation of atomoxetine and methylphenidate in attention deficit hyperactivity disorder boys during working memory.
        Psychol Med. 2014; 44: 633-646
        • Mehta M.A.
        • Sahakian B.J.
        • Robbins T.W.
        Comparative psycholpharmacology of methylphenidate and related drugs in human volunteers, patients with ADHD, and experimental animals.
        in: Solanto M.V. Arnsten A.F.T. Castellanos F.X. Stimulant Drugs and ADHD: Basic and Clinical Neuroscience. Oxford University Press, New York2001: 303-331
        • Clark L.
        • Blackwell A.D.
        • Aron A.R.
        • Turner D.C.
        • Dowson J.
        • Robbins T.W.
        • Sahakian B.J.
        Association between response inhibition and working memory in adult ADHD: A link to right frontal cortex pathology?.
        Biol Psychiatry. 2007; 61: 1395-1401
        • Lundqvist T.
        Imaging cognitive deficits in drug abuse.
        Springer-Verlag, Berlin2009
        • Vijayraghavan S.
        • Wang M.
        • Birnbaum S.G.
        • Williams G.V.
        • Arnsten A.F.
        Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory.
        Nat Neurosci. 2007; 10: 376-384
        • Arnsten A.F.
        Through the looking glass: Differential noradenergic modulation of prefrontal cortical function.
        Neural Plast. 2000; 7: 133-146
        • Hunt R.D.
        • Minderaa R.B.
        • Cohen D.J.
        Clonidine benefits children with attention deficit disorder and hyperactivity: Report of a double-blind placebo-crossover therapeutic trial.
        J Am Acad Child Psychiatry. 1985; 24: 617-629
        • Scahill L.
        • Chappell P.B.
        • Kim Y.S.
        • Schultz R.T.
        • Katsovich L.
        • Shepherd E.
        • et al.
        A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder.
        Am J Psychiatry. 2001; 158: 1067-1074
        • Biederman J.
        • Melmed R.D.
        • Patel A.
        • McBurnett K.
        • Konow J.
        • Lyne A.
        • et al.
        A randomized, double-blind, placebo-controlled study of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder.
        Pediatrics. 2008; 121: e73-e84
        • Franowicz J.S.
        • Arnsten A.F.
        The alpha-2a noradrenergic agonist, guanfacine, improves delayed response performance in young adult rhesus monkeys.
        Psychopharmacology (Berl). 1998; 136: 8-14
        • Berridge C.W.
        • Arnsten A.F.
        • Foote S.L.
        Noradrenergic modulation of cognitive function: Clinical implications of anatomical, electrophysiological and behavioural studies in animal models [editorial].
        Psychol Med. 1993; 23: 557-564
        • Tanila H.
        • Rama P.
        • Carlson S.
        The effects of prefrontal intracortical microinjections of an alpha-2 agonist, alpha-2 antagonist and lidocaine on the delayed alternation performance of aged rats.
        Brain Res Bull. 1996; 40: 117-119
      1. Spencer RC, Berridge CW (2013): Receptor and frontostriatal circuit mechanisms underlying the cognition-enhancing actions of psychostimulants. Soc Neurosci Abst 288.16:KKK14

        • Wang Y.
        • Liu J.
        • Gui Z.H.
        • Ali U.
        • Fan L.L.
        • Hou C.
        • et al.
        alpha2-Adrenoceptor regulates the spontaneous and the GABA/glutamate modulated firing activity of the rat medial prefrontal cortex pyramidal neurons.
        Neuroscience. 2011; 182: 193-202
        • Salgado H.
        • Garcia-Oscos F.
        • Patel A.
        • Martinolich L.
        • Nichols J.A.
        • Dinh L.
        • et al.
        Layer-specific noradrenergic modulation of inhibition in cortical layer II/III.
        Cereb Cortex. 2011; 21: 212-221
        • Cheng J.
        • Xiong Z.
        • Duffney L.J.
        • Wei J.
        • Liu A.
        • Liu S.
        • et al.
        Methylphenidate exerts dose-dependent effects on glutamate receptors and behaviors [published online ahead of print April 12].
        Biol Psychiatry. 2014;
        • Seamans J.K.
        • Gorelova N.
        • Durstewitz D.
        • Yang C.R.
        Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons.
        J Neurosci. 2001; 21: 3628-3638
        • Seamans J.K.
        • Durstewitz D.
        • Christie B.R.
        • Stevens C.F.
        • Sejnowski T.J.
        Dopamine D1/D5 receptor modulation of excitatory synaptic inputs to layer V prefrontal cortex neurons.
        Proc Natl Acad Sci U S A. 2001; 98: 301-306
        • 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
        • Sprague R.L.
        • Sleator E.K.
        Methylphenidate in hyperkinetic children: Differences in dose effects on learning and social behavior.
        Science. 1977; 198: 1274-1276
        • 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
        • Rapport M.D.
        • Kelly K.L.
        Psychostimulant effects on learning and cognitive function: Findings and implications for children with attention deficit hyperactivity disorder.
        Clin Psychol Rev. 1991; 11: 61-92
        • Tannock R.
        • Schachar R.
        • Logan G.
        Methylphenidate and cognitive flexibility: Dissociated dose effects in hyperactive children.
        J Abnorm Child Psychol. 1995; 23: 235-266
        • Granon S.
        • Passetti F.
        • Thomas K.L.
        • Dalley J.W.
        • Everitt B.J.
        • Robbins T.W.
        Enhanced and impaired attentional performance after infusion of D1 dopaminergic receptor agents into rat prefrontal cortex.
        J Neurosci. 2000; 20: 1208-1215
        • Berridge C.
        • Shumsky J.S.
        • Andrzejewski M.E.
        • McGaughy J.
        • Spencer R.C.
        • Devilbiss D.
        • Waterhouse B.D.
        Differential sensitivity to psychostimulants across prefrontal cognitive tasks: Differential involvement of noradrenergic α1- vs. α2-receptors.
        Biol Psychiatry. 2012; 71: 467-473
      2. Spencer RC, Waterhouse BD, Berridge CW (in press): Neurocircuitry and receptor mechanisms underlying the differential sensitivity of prefrontal cognitive processes to psychostimulants. Soc Neurosci Abst.

        • Lapiz M.D.
        • Morilak D.A.
        Noradrenergic modulation of cognitive function in rat medial prefrontal cortex as measured by attentional set shifting capability.
        Neuroscience. 2006; 137: 1039-1049
        • Aston-Jones G.
        • Rajkowski J.
        • Cohen J.
        Locus coeruleus and regulation of behavioral flexibility and attention.
        Prog Brain Res. 2000; 126: 165-182
        • Birrell J.M.
        • Brown V.J.
        Medial frontal cortex mediates perceptual attentional set shifting in the rat.
        J Neurosci. 2000; 20: 4320-4324
        • Owen A.M.
        • Roberts A.C.
        • Polkey C.E.
        • Sahakian B.J.
        • Robbins T.W.
        Extra-dimensional versus intra-dimensional set shifting performance following frontal lobe excisions, temporal lobe excisions or amygdalo-hippocampectomy in man.
        Neuropsychologia. 1991; 29: 993-1006
        • Arnsten A.F.
        • Li B.M.
        Neurobiology of executive functions: Catecholamine influences on prefrontal cortical functions.
        Biol Psychiatry. 2005; 57: 1377-1384
        • Arnsten A.F.
        The use of α-2A adrenergic agonists for the treatment of attention-deficit/hyperactivity disorder.
        Expert Rev Neurother. 2010; 10: 1595-1605
        • Doerge D.R.
        • Fogle C.M.
        • Paule M.G.
        • McCullagh M.
        • Bajic S.
        Analysis of methylphenidate and its metabolite ritalinic acid in monkey plasma by liquid chromatography/electrospray ionization mass spectrometry.
        Rapid Commun Mass Spectrom. 2000; 14: 619-623
        • Navarra R.
        • Graf R.
        • Huang Y.
        • Logue S.
        • Comery T.
        • Hughes Z.
        • Day M.
        Effects of atomoxetine and methylphenidate on attention and impulsivity in the 5-choice serial reaction time test.
        Prog Neuropsychopharmacol Biol Psychiatry. 2008; 32: 34-41
        • Milstein J.A.
        • Dalley J.W.
        • Robbins T.W.
        Methylphenidate-induced impulsivity: Pharmacological antagonism by beta-adrenoreceptor blockade.
        J Psychopharmacol. 2010; 24: 309-321