title: Methylphenidate amplifies long-term potentiation in rat hippocampus CA1 area involving the insertion of AMPA receptors by activation of β-adrenergic and D1/D5 receptors.
abstract: Methylphenidate (MPH, Ritalin©) is widely used in the treatment of Attention Deficit Hyperactivity Disorder and recently as a drug of abuse. Although the effect of MPH has been studied in brain regions such as striatum and prefrontal cortex (PFC), the hippocampus has received relatively little attention. It is known that MPH increases the TBS-dependent Long Term Potentiation (LTP) in the CA1 area. However, the cellular and molecular mechanisms involved in this process are still unknown. Using field potential recordings and western blot analysis in rat hippocampal slices of young rats, we found that acute application of MPH enhances LTP in CA3-CA1 synapses in a dose-dependent manner with an EC50 of 73.44±6.32 nM. Using specific antagonists and paired-pulse facilitation protocols, we observed that the MPH-dependent increase of LTP involves not only β-adrenergic receptors activation but also post-synaptic D1/D5 dopamine receptors. The inhibition of PKA with PKI, suppressed the facilitation of LTP induced by MPH consistent with an involvement of the adenyl cyclase-cAMP-PKA dependent cascade downstream of the activation of D1/D5 receptors. In addition, samples of CA1 areas taken from slices potentiated with MPH presented an increase in the phosphorylation of the Ser845 residue of the GluA1 subunit of AMPA receptors compared to control slices. This effect was reverted by SCH23390, antagonist of D1/D5 receptors, and PKI. Moreover, we found an increase of surface-associated functional AMPA receptors. We propose that MPH increases TBS-dependent LTP in CA3-CA1 synapses through a polysynaptic mechanism involving activation of β-adrenergic and D1/D5 dopaminergic receptors and promoting the trafficking and insertion of functional AMPA receptors to the plasma membrane.
authors.affiliation: Laboratorio de Neurociencia, Departamento de Biología, Universidad de Santiago de Chile, Chile.
authors.forename: C
authors.initials: C
authors.lastname: Rozas
authors.affiliation: Laboratorio de Neurociencia, Departamento de Biología, Universidad de Santiago de Chile, Chile.
authors.forename: C
authors.initials: C
authors.lastname: Carvallo
authors.affiliation: Laboratorio de Neurociencia, Departamento de Biología, Universidad de Santiago de Chile, Chile.
authors.forename: D
authors.initials: D
authors.lastname: Contreras
authors.affiliation: Laboratorio de Neurociencia, Departamento de Biología, Universidad de Santiago de Chile, Chile.
authors.forename: M
authors.initials: M
authors.lastname: Carreño
authors.affiliation: Laboratorio de Neurociencia, Departamento de Biología, Universidad de Santiago de Chile, Chile.
authors.forename: G
authors.initials: G
authors.lastname: Ugarte
authors.affiliation: Laboratorio de Neurociencia, Departamento de Biología, Universidad de Santiago de Chile, Chile.
authors.forename: R
authors.initials: R
authors.lastname: Delgado
authors.affiliation: Escuela de Psicología, Universidad de Santiago de Chile, Chile.
authors.forename: M L
authors.initials: ML
authors.lastname: Zeise
authors.affiliation: Laboratorio de Neurociencia, Departamento de Biología, Universidad de Santiago de Chile, Chile. Electronic address: bernardo.morales@usach.cl.
authors.forename: B
authors.initials: B
authors.lastname: Morales
mesh_terms: D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000502:physiology*; D002462:Cell Membrane / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology*; D008774:Methylphenidate / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D010766:Phosphorylation / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D050641:Receptors, Dopamine D5 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D046509:Tissue Culture Techniques
chemical_list: D000697:Central Nervous System Stimulants; D018091:Receptors, AMPA; D011943:Receptors, Adrenergic, beta; D017447:Receptors, Dopamine D1; D050641:Receptors, Dopamine D5; D008774:Methylphenidate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: D1/D5 receptors; Glutamate receptors; Hippocampus; LTP; MPH