title: Endogenous dopamine amplifies ischemic long-term potentiation via D1 receptors.
abstract: OBJECTIVE
  Several observations indicate that, during energy deprivation, endogenous dopamine may become neurotoxic. Accordingly, the nucleus striatum is a preferential site of silent infarcts in humans, and experimental ischemia caused by homolateral carotid occlusion selectively damages this dopamine-enriched brain area. In an attempt to clarify how dopamine takes part in ischemia-induced neuronal damage, we performed in vitro electrophysiological recordings from neurons of the nucleus striatum.
  
  
  METHODS
  Intracellular recordings with sharp microelectrodes were performed from corticostriatal slices. Slices were obtained from both rats and wild-type and dopamine D1 receptor-lacking mice. In some experiments, the striatum was unilaterally denervated by injecting the dopamine-specific neurotoxin 6-hydroxydopamine in the homolateral substantia nigra. Dopamine agonists and antagonists, as well as drugs targeting the intracellular cascade coupled to dopamine receptor stimulation, were applied at known concentrations.
  
  
  RESULTS
  Manipulation of the dopamine system failed to affect the membrane depolarization of striatal neurons exposed to combined oxygen and glucose deprivation of short duration, but it reduced the amplitude of postischemic long-term potentiation (LTP) expressed at corticostriatal synapses. In particular, pharmacological blockade or genetic inactivation of D1/cAMP/protein kinase A pathway prevented the long-term increase of the excitatory postsynaptic potential (EPSP) amplitude caused by a transient ischemic episode, while it failed to prevent the increase of the EPSP half-decay coupled to ischemic LTP.
  
  
  CONCLUSIONS
  The present data suggest that endogenous dopamine, via D1 receptors, selectively facilitates the expression of ischemic LTP on the AMPA-mediated component of the EPSPs, while it does not alter the expression of this form of synaptic plasticity on the N-methyl-D-aspartate-mediated component of corticostriatal synaptic potentials. Understanding the cellular and molecular mechanisms of ischemia-triggered excitotoxicity offers hope for the development of specific treatments able to interfere with this pathological process.
authors.affiliation: Clinica Neurologica, Dipartimento di Neuroscienze, Università "Tor Vergata," and IRCCS Fondazione Santa Lucia, Rome, Italy.
authors.forename: Emilia
authors.initials: E
authors.lastname: Saulle
authors.forename: Diego
authors.initials: D
authors.lastname: Centonze
authors.forename: Ana B
authors.initials: AB
authors.lastname: Martín
authors.forename: Rosario
authors.initials: R
authors.lastname: Moratalla
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002545:Brain Ischemia / Q000503:physiopathology*; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003714:Denervation; D004298:Dopamine / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004734:Energy Metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005947:Glucose / Q000172:deficiency / Q000378:metabolism; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016627:Oxidopamine / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D001552:Benzazepines; D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; D016627:Oxidopamine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose; D004298:Dopamine