Psychostimulants Act Within the Prefrontal Cortex to Improve Cognitive Function


      At low and clinically relevant doses, psychostimulants enhance cognitive and behavioral function dependent on the prefrontal cortex (PFC) and extended frontostriatal circuitry. These actions are observed in individuals with attention-deficit/hyperactivity disorder, as well as in normal human and animal subjects. Despite the widespread use of these drugs, the sites of action involved in their cognition-enhancing and therapeutic effects are poorly understood. Indirect and/or correlative evidence suggests the cognition-enhancing/therapeutic effects of psychostimulants may involve actions directly within the PFC or extended frontostriatal circuitry. The current studies examined the degree to which methylphenidate (MPH) (Ritalin) acts within distinct frontostriatal subfields to improve PFC-dependent cognition as measured in a delayed-response test of spatial working memory.


      Working memory performance was assessed following microinfusion of vehicle or varying doses of MPH (.03–8.0 μg/500 nL) directly into the dorsomedial PFC (dorsal prelimbic and dorsal anterior cingulate cortex), the ventromedial PFC (infralimbic), and the dorsomedial striatum of rats (n = 69).


      Methylphenidate infusion into the dorsomedial PFC, but not ventromedial PFC, elicited an inverted U-shaped facilitation of PFC-dependent cognition as measured in this task. The magnitude of this improvement was comparable with that seen with systemic administration. Additional studies demonstrated that although the dorsomedial striatum is necessary for accurate performance in this task, MPH infusion into this region did not affect working memory performance.


      These observations provide the first definitive evidence that the PFC is a site of action in the cognition-enhancing and presumably therapeutic actions of low-dose psychostimulants.

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


        • Greenhill L.L.
        Clinical effects of stimulant medication in ADHD.
        in: Stimulant Drugs and ADHD: Basic and Clinical Neuroscience. Oxford University Press, New York2001: 31-71
        • 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
        • 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
        • Castellanos F.X.
        • Tannock R.
        Neuroscience of attention-deficit/hyperactivity disorder: The search for endophenotypes.
        Nat Rev Neurosci. 2002; 3: 617-628
        • Shaw P.
        • Lalonde F.
        • Lepage C.
        • Rabin C.
        • Eckstrand K.
        • Sharp W.
        • et al.
        Development of cortical asymmetry in typically developing children and its disruption in attention-deficit/hyperactivity disorder.
        Arch Gen Psychiatry. 2009; 66: 888-896
        • Mehta M.A.
        • Sahakian B.J.
        • Robbins T.W.
        Comparative psychopharmacology of methylphenidate and related drugs in human volunteers, patients with ADHD, and experimental animals.
        in: Stimulant Drugs and ADHD: Basic and Clinical Neuroscience. Oxford University Press, New York2001: 303-331
        • 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
        • 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
        • Gamo N.J.
        • Wang M.
        • Arnsten A.F.T.
        Methylphenidate and atomoxetine enhance prefrontal function through α2-adrenergic and dopamine D1 receptors.
        J Am Acad Child Adolesc Psychiatry. 2010; 49: 1011-1023
        • Wilens T.E.
        • Adler L.A.
        • Adams J.
        • Sgambati S.
        • Rotrosen J.
        • Sawtelle R.
        • et al.
        Misuse and diversion of stimulants prescribed for ADHD: A systematic review of the literature.
        J. Am Acad Child Adolesc Psychiatry. 2008; 47: 21-31
        • Dickstein S.G.
        • Bannon K.
        • Castellanos F.X.
        • Milham M.P.
        The neural correlates of attention deficit hyperactivity disorder: An ALE meta-analysis.
        J Child Psychol Psychiatry. 2006; 47: 1051-1062
        • Devilbiss D.M.
        • Berridge C.W.
        Cognition-enhancing doses of methylphenidate preferentially increase prefrontal cortex neuronal responsiveness.
        Biol Psychiatry. 2008; 64: 626-635
        • Rubia K.
        • Overmeyer S.
        • Taylor E.
        • Brammer M.
        • Williams S.C.R.
        • Simmons A.
        • Bullmore E.T.
        Hypofrontality in attention deficit hyperactivity disorder during higher-order motor control: A study with functional MRI.
        Am J Psychiatry. 1999; 156: 891-896
        • Sheridan M.A.
        • Hinshaw S.
        • D'Esposito M.
        Efficiency of the prefrontal cortex during working memory in attention-deficit/hyperactivity disorder.
        J Am Acad Child Adolesc Psychiatry. 2007; 46: 1357-1366
        • 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
        • Seidman L.J.
        • Valera E.M.
        • Makris N.
        Structural brain imaging of attention-deficit/hyperactivity disorder.
        Biol Psychiatry. 2005; 57: 1263-1272
        • 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.G.
        • 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
        • Kesner R.P.
        Subregional analysis of mnemonic functions of the prefrontal cortex in the rat.
        Psychobiology. 2000; 28: 219-228
        • 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
        • Berridge C.W.
        • Shumsky J.S.
        • Andrzejewski M.E.
        • McGaughy J.A.
        • Spencer R.C.
        • Devilbiss D.M.
        • Waterhouse B.D.
        Differential sensitivity to psychostimulants across prefrontal cognitive tasks: Differential involvement of noradrenergic α(1)- and α(2)-receptors.
        Biol Psychiatry. 2011; ([published online ahead of print September 2])
        • 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
        • Ragozzino M.E.
        The contribution of the medial prefrontal cortex, orbitofrontal cortex, and dorsomedial striatum to behavioral flexibility.
        Ann N Y Acad Sci. 2007; 1121: 355-375
        • Voorn P.
        • Vanderschuren L.J.
        • Groenewegen H.J.
        • Robbins T.W.
        • Pennartz C.M.
        Putting a spin on the dorsal-ventral divide of the striatum.
        Trends Neurosci. 2004; 27: 468-474
        • España R.A.
        • Reis K.M.
        • Valentino R.J.
        • Berridge C.W.
        Organization of hypocretin/orexin efferents to locus coeruleus and basal forebrain arousal-related structures.
        J Comp Neurol. 2005; 481: 160-178
        • 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
        • Vertes R.P.
        Interactions among the medial prefrontal cortex, hippocampus and midline thalamus in emotional and cognitive processing in the rat.
        Neuroscience. 2006; 142: 1-20
        • Seidman L.J.
        • Valera E.M.
        • Makris N.
        • Monuteaux M.C.
        • Boriel D.L.
        • Kelkar K.
        • et al.
        Dorsolateral prefrontal and anterior cingulate cortex volumetric abnormalities in adults with attention-deficit/hyperactivity disorder identified by magnetic resonance imaging.
        Biol Psychiatry. 2006; 60: 1071-1080
        • Bush G.
        • Frazier J.A.
        • Rauch S.L.
        • Seidman L.J.
        • Whalen P.J.
        • Jenike M.A.
        • et al.
        Anterior cingulate cortex dysfunction in attention-deficit/hyperactivity disorder revealed by fMRI and the counting Stroop.
        Biol Psychiatry. 1999; 45: 1542-1552
        • Seamans J.K.
        • Lapish C.C.
        • Durstewitz D.
        Comparing the prefrontal cortex of rats and primates: Insights from electrophysiology.
        Neurotox Res. 2008; 14: 249-262
        • Arnsten A.F.
        Fundamentals of attention-deficit/hyperactivity disorder: Circuits and pathways.
        J Clin Psychiatry. 2006; 67: 7-12
        • Floresco S.B.
        • Braaksma D.N.
        • Phillips A.G.
        Involvement of the ventral pallidum in working memory tasks with or without a delay.
        Ann N Y Acad Sci. 1999; 877: 711-716
        • Wang G.-W.
        • Cai J.-X.
        Disconnection of the hippocampal-prefrontal cortical circuits impairs spatial working memory performance in rats.
        Behav Brain Res. 2006; 175: 329-336
        • Robbins T.W.
        • Arnsten A.F.T.
        The neuropsychopharmacology of fronto-executive function: Monoaminergic modulation.
        Annu Rev Neurosci. 2009; 32: 267-287
        • Arnsten A.F.
        • Li B.M.
        Neurobiology of executive functions: Catecholamine influences on prefrontal cortical functions.
        Biol Psychiatry. 2005; 57: 1377-1384
        • 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.
        • Mathew R.
        • Ubriani R.
        • Taylor J.R.
        • Li B.M.
        Alpha-1 noradrenergic receptor stimulation impairs prefrontal cortical cognitive function.
        Biol Psychiatry. 1999; 45: 26-31
        • Arnsten A.F.
        • Steere J.C.
        • Hunt R.D.
        The contribution of alpha 2-noradrenergic mechanisms of prefrontal cortical cognitive function.
        Arch Gen Psychiatry. 1996; 53: 448-455
        • Arnsten A.F.
        Through the looking glass: Differential noradrenergic modulation of prefrontal cortical function.
        Neural Plast. 2000; 7: 133-146
        • 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
        • Birnbaum S.G.
        • Yuan P.X.
        • Wang M.
        • Vijayraghavan S.
        • Bloom A.K.
        • Davis D.J.
        • et al.
        Protein kinase C overactivity impairs prefrontal cortical regulation of working memory.
        Science. 2004; 306: 882-884
        • Cardinal R.N.
        • Pennicott D.R.
        • Sugathapala C.L.
        • Robbins T.W.
        • Everitt B.J.
        Impulsive choice induced in rats by lesions of the nucleus accumbens core.
        Science. 2001; 292: 2499-2501
        • Volkow N.D.
        • Wang G.-J.
        • Newcorn J.H.
        • Kollins S.H.
        • Wigal T.L.
        • Telang F.
        • et al.
        Motivation deficit in ADHD is associated with dysfunction of the dopamine reward pathway.
        Mol Psychiatry. 2011; 16: 1147-1154
        • Volkow N.D.
        • Wang G.-J.
        • Kollins S.H.
        • Wigal T.L.
        • Newcorn J.H.
        • Telang F.
        • et al.
        Evaluating dopamine reward pathway in ADHD.
        JAMA. 2009; 302: 1084-1091
        • Scheres A.
        • Milham M.P.
        • Knutson B.
        • Castellanos F.X.
        Ventral striatal hyporesponsiveness during reward anticipation in attention-deficit/hyperactivity disorder.
        Biol Psychiatry. 2007; 61: 720-724
        • Dodds C.M.
        • Muller U.
        • Clark L.
        • van Loon A.
        • Cools R.
        • Robbins T.W.
        Methylphenidate has differential effects on blood oxygenation level-dependent signal related to cognitive subprocesses of reversal learning.
        J Neurosci. 2008; 28: 5976-5982
        • Mair R.G.
        • Koch J.K.
        • Newman J.B.
        • Howard J.R.
        • Burk J.A.
        A double dissociation within striatum between serial reaction time and radial maze delayed nonmatching performance in rats.
        J Neurosci. 2002; 22: 6756-6765
        • Seamans J.K.
        • Phillips A.G.
        Selective memory impairments produced by transient lidocaine-induced lesions of the nucleus accumbens in rats.
        Behav Neurosci. 1994; 108: 456-468
        • Swanson L.W.
        Brain Maps: Structure of the Rat Brain.
        Elsevier, Amsterdam1992