Dopamine and norepinephrine receptors participate in methylphenidate enhancement of in vivo hippocampal synaptic plasticity

Neuropharmacology. 2015 Mar;90:23-32. doi: 10.1016/j.neuropharm.2014.10.029. Epub 2014 Nov 11.


Attention-deficit hyperactive disorder (ADHD) is the most commonly studied and diagnosed psychiatric disorder in children. Methylphenidate (MPH, e.g., Ritalin) has been used to treat ADHD for over 50 years. It is the most commonly prescribed treatment for ADHD, and in the past decade it was the drug most commonly prescribed to teenagers. In addition, MPH has become one of the most widely abused drugs on college campuses. In this study, we examined the effects of MPH on hippocampal synaptic plasticity, which serves as a measurable quantification of memory mechanisms. Field potentials were recorded with permanently implanted electrodes in freely-moving mice to quantify MPH modulation of perforant path synaptic transmission onto granule cells of the dentate gyrus. Our hypothesis was that MPH affects hippocampal synaptic plasticity underlying learning because MPH boosts catecholamine signaling by blocking the dopamine and norepinephrine transporters (DAT and NET respectively). In vitro hippocampal slice experiments indicated MPH enhances perforant path plasticity, and this MPH enhancement arose from action via D1-type dopamine receptors and β-type adrenergic receptors. Similarly, MPH boosted in vivo initiation of long-term potentiation (LTP). While there was an effect via both dopamine and adrenergic receptors in vivo, LTP induction was more dependent on the MPH-induced action via D1-type dopamine receptors. Under biologically reasonable experimental conditions, MPH enhances hippocampal synaptic plasticity via catecholamine receptors.

Keywords: Dentate gyrus; LTP; Long-term potentiation; Memory; Perforant path; Reward.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Central Nervous System Stimulants / pharmacology*
  • Dentate Gyrus / drug effects*
  • Dentate Gyrus / physiology
  • Dopamine / metabolism
  • Dose-Response Relationship, Drug
  • Electric Stimulation
  • Electrodes, Implanted
  • Female
  • Long-Term Potentiation / drug effects*
  • Long-Term Potentiation / physiology
  • Male
  • Methylphenidate / pharmacology*
  • Mice, Inbred C57BL
  • Neurons / drug effects
  • Neurons / physiology
  • Patch-Clamp Techniques
  • Perforant Pathway / drug effects
  • Perforant Pathway / physiology
  • Receptors, Adrenergic / metabolism*
  • Receptors, Dopamine / metabolism*
  • Theta Rhythm / physiology
  • Tissue Culture Techniques


  • Central Nervous System Stimulants
  • Receptors, Adrenergic
  • Receptors, Dopamine
  • Methylphenidate
  • Dopamine