title: Brief mitochondrial inhibition causes lasting changes in motor behavior and corticostriatal synaptic physiology in the Fischer 344 rat.
abstract: The striatum is particularly vulnerable to mitochondrial dysfunction and this problem is linked to pathology created by environmental neurotoxins, stimulants like amphetamine, and metabolic disease and ischemia. We studied the course of recovery following a single systemic injection of the mitochondrial complex II inhibitor 3-nitropropionic acid (3-NP) and found 3-NP caused lasting changes in motor behavior that were associated with altered activity-dependent plasticity at corticostriatal synapses in Fischer 344 rats. The changes in synapse behavior varied with the time after exposure to the 3-NP injection. The earliest time point studied, 24h after 3-NP, revealed 3-NP-induced an exaggeration of D1 Dopamine (DA) receptor dependent long-term potentiation (LTP) that reversed to normal by 48 h post-3-NP exposure. Thereafter, the likelihood and degree of inducing D2 DA receptor dependent long-term depression (LTD) gradually increased, relative to saline controls, peaking at 1 month after the 3-NP exposure. NMDA receptor binding did not change over the same post 3-NP time points. These data indicate even brief exposure to 3-NP can have lasting behavioral effects mediated by changes in the way DA and glutamate synapses interact.
authors.affiliation: Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089-0191, USA.
authors.forename: G
authors.initials: G
authors.lastname: Akopian
authors.forename: C
authors.initials: C
authors.lastname: Crawford
authors.forename: G
authors.initials: G
authors.lastname: Petzinger
authors.forename: M W
authors.initials: MW
authors.lastname: Jakowec
authors.forename: J P
authors.initials: JP
authors.lastname: Walsh
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001703:Biophysics; D002540:Cerebral Cortex / Q000166:cytology*; D003342:Corpus Striatum / Q000166:cytology*; D016291:Dizocilpine Maleate / Q000493:pharmacokinetics; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000493:pharmacokinetics; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D007839:Functional Laterality; D066298:In Vitro Techniques; D009068:Movement / Q000187:drug effects*; D009574:Nitro Compounds / Q000494:pharmacology*; D016627:Oxidopamine / Q000633:toxicity; D011422:Propionates / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D013378:Substantia Nigra / Q000293:injuries / Q000502:physiology; D013469:Sulpiride / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects*; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D018663:Adrenergic Agents; D001552:Benzazepines; D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D009574:Nitro Compounds; D011422:Propionates; C534628:SCH 23390; D014316:Tritium; D016291:Dizocilpine Maleate; D013469:Sulpiride; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; C015392:3-nitropropionic acid