title: Neurotensin Induces Presynaptic Depression of D2 Dopamine Autoreceptor-Mediated Neurotransmission in Midbrain Dopaminergic Neurons.
abstract: Increased dopaminergic signaling is a hallmark of severe mesencephalic pathologies such as schizophrenia and psychostimulant abuse. Activity of midbrain dopaminergic neurons is under strict control of inhibitory D2 autoreceptors. Application of the modulatory peptide neurotensin (NT) to midbrain dopaminergic neurons transiently increases activity by decreasing D2 dopamine autoreceptor function, yet little is known about the mechanisms that underlie long-lasting effects. Here, we performed patch-clamp electrophysiology and fast-scan cyclic voltammetry in mouse brain slices to determine the effects of NT on dopamine autoreceptor-mediated neurotransmission. Application of the active peptide fragment NT8-13 produced synaptic depression that exhibited short- and long-term components. Sustained depression of D2 autoreceptor signaling required activation of the type 2 NT receptor and the protein phosphatase calcineurin. NT application increased paired-pulse ratios and decreased extracellular levels of somatodendritic dopamine, consistent with a decrease in presynaptic dopamine release. Surprisingly, we observed that electrically induced long-term depression of dopaminergic neurotransmission that we reported previously was also dependent on type 2 NT receptors and calcineurin. Because electrically induced depression, but not NT-induced depression, was blocked by postsynaptic calcium chelation, our findings suggest that endogenous NT may act through a local circuit to decrease presynaptic dopamine release. The current research provides a mechanism through which augmented NT release can produce a long-lasting increase in membrane excitability of midbrain dopamine neurons.
  
  
  CONCLUSIONS
  Whereas plasticity of glutamate synapses in the brain has been studied extensively, demonstrations of plasticity at dopaminergic synapses have been more elusive. By quantifying inhibitory neurotransmission between midbrain dopaminergic neurons in brain slices from mice we have discovered that the modulatory peptide neurotensin can induce a persistent synaptic depression by decreasing dopamine release. This depression of inhibitory synaptic input would be expected to increase excitability of dopaminergic neurons. Induction of the plasticity can be pharmacologically blocked by antagonists of either the protein phosphatase calcineurin or neurotensin receptors, and persists surprisingly long after a brief exposure to the peptide. Since neurotensin-dopamine interactions have been implicated in hyperdopaminergic pathologies, these findings describe a synaptic mechanism that could contribute to addiction and/or schizophrenia.
authors.affiliation: Department of Physiology and.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Piccart
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4970.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Courtney
authors.affiliation: Department of Physiology and.
authors.forename: Sarah Y
authors.initials: SY
authors.lastname: Branch
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4970.
authors.forename: Christopher P
authors.identifier: http://orcid.org/0000-0002-4175-2933
authors.initials: CP
authors.lastname: Ford
authors.affiliation: Department of Physiology and Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3904, and beckstead@uthscsa.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Beckstead
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008636:Mesencephalon / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D009496:Neurotensin / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D018028:Receptors, Neurotensin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D010446:Peptide Fragments; D017448:Receptors, Dopamine D2; D018028:Receptors, Neurotensin; D009496:Neurotensin; C054381:neurotensin (8-13); D019703:Calcineurin
keywords: Dopamine; IPSC; calcineurin; neurotensin; plasticity; presynaptic