Dopaminergic modulation of long‐lasting direct current‐induced cortical excitability changes in the human motor cortex

Dopaminergic mechanisms participate in N‐methyl‐d‐aspartate (NMDA) receptor‐dependent neuroplasticity, as animal experiments have shown. This may be similar in humans, where dopamine influences learning and memory. We tested the role of dopamine in human cortical neuroplasticity. Changes of excitability were induced by transcranial direct current stimulation (tDCS). D2 receptor blocking by sulpiride abolished the induction of after‐effects nearly completely. D1 activation alone in the presence of D2 receptor blocking induced by co‐administration of sulpiride and pergolide did not re‐establish the excitability changes induced by tDCS. This suggests that D2 receptors play a major supporting role in inducing neuroplasticity in the human motor cortex. Enhancement of D2 and, to a lesser degree, D1 receptors by pergolide consolidated tDCS‐generated excitability diminution until the morning after stimulation. The readiest explanation for this pattern of results is that D2 receptor activation has a consolidation‐enhancing effect on tDCS‐induced changes of excitability in the human cortex. The results of this study underscore the importance of the dopaminergic system for human neuroplasticity, suggest a first pharmacological add‐on mechanism to prolong the excitability‐diminishing effects of cathodal tDCS for up to 24 h after stimulation, and thus render the application of tDCS practicable in diseases displaying enhanced cortical excitability, e.g. migraine and epilepsy.

[1]  R. D'Hooge,et al.  Amphetamine enhances human-memory consolidation , 1993, Neuroscience Letters.

[2]  J. Desce,et al.  Dopamine facilitates long-term depression of glutamatergic transmission in rat prefrontal cortex , 1998, Neuroscience.

[3]  P. Calabresi,et al.  Abnormal Synaptic Plasticity in the Striatum of Mice Lacking Dopamine D2 Receptors , 1997, The Journal of Neuroscience.

[4]  L. Cohen,et al.  Dopaminergic influences on formation of a motor memory , 2005, Annals of neurology.

[5]  M. Nitsche,et al.  Facilitation of Implicit Motor Learning by Weak Transcranial Direct Current Stimulation of the Primary Motor Cortex in the Human , 2003, Journal of Cognitive Neuroscience.

[6]  L. Cohen,et al.  Enhancement of use-dependent plasticity by d-amphetamine , 2002, Neurology.

[7]  J. Clemens,et al.  Pergolide: a dopamine agonist at both D1 and D2 receptors. , 1991, Life sciences.

[8]  K. Hoffmann,et al.  Direct Current Stimulation over V5 Enhances Visuomotor Coordination by Improving Motion Perception in Humans , 2004, Journal of Cognitive Neuroscience.

[9]  M. Mauri,et al.  l-Sulpiride in young and elderly negative schizophrenics: Clinical and pharmacokinetic variables , 1994, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[10]  E. Kandel,et al.  Genetic evidence for the bidirectional modulation of synaptic plasticity in the prefrontal cortex by D1 receptors. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[11]  M. Nitsche,et al.  Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans , 2001, Neurology.

[12]  D. Deleu,et al.  Clinical Pharmacokinetic and Pharmacodynamic Properties of Drugs Used in the Treatment of Parkinson’s Disease , 2002, Clinical pharmacokinetics.

[13]  J. Rothwell,et al.  Level of action of cathodal DC polarisation induced inhibition of the human motor cortex , 2003, Clinical Neurophysiology.

[14]  Walter Paulus,et al.  Facilitation of visuo‐motor learning by transcranial direct current stimulation of the motor and extrastriate visual areas in humans , 2004, The European journal of neuroscience.

[15]  Walter Paulus,et al.  Enhancement of human motor cortex inhibition by the dopamine receptor agonist pergolide: evidence from transcranial magnetic stimulation , 1996, Neuroscience Letters.

[16]  M. Nitsche,et al.  Catecholaminergic consolidation of motor cortical neuroplasticity in humans. , 2004, Cerebral Cortex.

[17]  M. Nitsche,et al.  Pharmacological Modulation of Cortical Excitability Shifts Induced by Transcranial Direct Current Stimulation in Humans , 2003, The Journal of physiology.

[18]  J. Lisman,et al.  D1/D5 Dopamine Receptors Inhibit Depotentiation at CA1 Synapses via cAMP-Dependent Mechanism , 1998, The Journal of Neuroscience.

[19]  J. Spencer,et al.  Bi-directional changes in synaptic plasticity induced at corticostriatal synapses in vitro , 2000, Experimental Brain Research.

[20]  M. Wolf,et al.  Dopamine Receptor Stimulation Modulates AMPA Receptor Synaptic Insertion in Prefrontal Cortex Neurons , 2005, The Journal of Neuroscience.

[21]  L. Cohen,et al.  Effects of non-invasive cortical stimulation on skilled motor function in chronic stroke. , 2005, Brain : a journal of neurology.

[22]  E. Kandel,et al.  Is Heterosynaptic modulation essential for stabilizing hebbian plasiticity and memory , 2000, Nature Reviews Neuroscience.

[23]  T. Jay,et al.  Essential Role of D1 But Not D2 Receptors in the NMDA Receptor-Dependent Long-Term Potentiation at Hippocampal-Prefrontal Cortex Synapses In Vivo , 2000, The Journal of Neuroscience.

[24]  H. Miyakawa,et al.  Roles of dopamine receptors in long-term depression: enhancement via D1 receptors and inhibition via D2 receptors. , 1996, Receptors & channels.

[25]  Y. Izumi,et al.  Noradrenergic regulation of synaptic plasticity in the hippocampal CA1 region. , 1997, Journal of neurophysiology.

[26]  F. Müller,et al.  Effect of levodopa in combination with physiotherapy on functional motor recovery after stroke: a prospective, randomised, double-blind study , 2001, The Lancet.

[27]  M. Nitsche,et al.  GABAergic modulation of DC stimulation‐induced motor cortex excitability shifts in humans , 2004, The European journal of neuroscience.

[28]  T. Jay Dopamine: a potential substrate for synaptic plasticity and memory mechanisms , 2003, Progress in Neurobiology.

[29]  Walter Paulus,et al.  Consolidation of Human Motor Cortical Neuroplasticity by D-Cycloserine , 2004, Neuropsychopharmacology.

[30]  H Matthies,et al.  Domperidone, an inhibitor of the D2-receptor, blocks a late phase of an electrically induced long-term potentiation in the CA1-region in rats. , 1989, Biomedica biochimica acta.

[31]  J. Stewart,et al.  Development of both conditioning and sensitization of the behavioral activating effects of amphetamine is blocked by the non-competitive NMDA receptor antagonist, MK-801 , 2005, Psychopharmacology.

[32]  P. Calabresi,et al.  Long-term synaptic depression in the striatum: physiological and pharmacological characterization , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[33]  D. Walker-Batson,et al.  Amphetamine paired with physical therapy accelerates motor recovery after stroke. Further evidence. , 1995, Stroke.

[34]  J. Donoghue,et al.  Learning-induced LTP in neocortex. , 2000, Science.

[35]  J. Donoghue,et al.  Strengthening of horizontal cortical connections following skill learning , 1998, Nature Neuroscience.

[36]  E. Kandel,et al.  Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[37]  H. Dinse,et al.  Pharmacological Modulation of Perceptual Learning and Associated Cortical Reorganization , 2003, Science.

[38]  R. D'Hooge,et al.  Effect of amphetamine on long-term retention of verbal material , 1995, Psychopharmacology.

[39]  T. Robbins,et al.  Systemic sulpiride in young adult volunteers simulates the profile of cognitive deficits in Parkinson’s disease , 1999, Psychopharmacology.

[40]  Antonio Pisani,et al.  Receptor Subtypes Involved in the Presynaptic and Postsynaptic Actions of Dopamine on Striatal Interneurons , 2003, The Journal of Neuroscience.

[41]  Paul Greengard,et al.  Loss of bidirectional striatal synaptic plasticity in L-DOPA–induced dyskinesia , 2003, Nature Neuroscience.

[42]  M. Nitsche,et al.  Pharmacological approach to the mechanisms of transcranial DC-stimulation-induced after-effects of human motor cortex excitability. , 2002, Brain : a journal of neurology.

[43]  M. Nitsche,et al.  Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation , 2000, The Journal of physiology.

[44]  L. Cohen,et al.  Modulation of use‐dependent plasticity by d‐amphetamine , 2002, Supplements to Clinical neurophysiology.

[45]  Jon A. Mukand,et al.  Dopaminergic therapy with carbidopa L-dopa for left neglect after stroke: a case series. , 2001, Archives of physical medicine and rehabilitation.

[46]  D. Manahan‐Vaughan,et al.  Regulation of depotentiation and long-term potentiation in the dentate gyrus of freely moving rats by dopamine D2-like receptors. , 2003, Cerebral cortex.

[47]  W Paulus,et al.  Changes in human motor cortex excitability induced by dopaminergic and anti-dopaminergic drugs. , 1997, Electroencephalography and clinical neurophysiology.

[48]  DelainaWalker-Batson,et al.  Amphetamine Paired With Physical Therapy Accelerates Motor Recovery After Stroke , 1995 .

[49]  S. Knecht,et al.  Dopaminergic effects on encoding of a motor memory in chronic stroke , 2005, Neurology.

[50]  Denise Manahan-Vaughan,et al.  Hippocampal long-term depression and long-term potentiation encode different aspects of novelty acquisition. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[51]  E. Ringelstein,et al.  Levodopa: Faster and better word learning in normal humans , 2004, Annals of neurology.