title: Region-specific changes in the subcellular distribution of AMPA receptor GluR1 subunit in the rat ventral tegmental area after acute or chronic morphine administration.
abstract: Opiate addiction is characterized by progressive increases in drug intake over time suggesting maladaptive changes in motivational and reward systems. These behaviors are mediated by dopaminergic neurons originating from the ventral tegmental area (VTA), and long-term changes of these dopaminergic neurons are attributed to increased postsynaptic glutamatergic activation. Indeed, chronic morphine administration is known to increase AMPA receptor glutamate receptor 1 (GluR1) subunit in the VTA. However, there is no ultrastructural evidence that morphine affects the expression or surface availability of GluR1 subunits in VTA neurons of defined distribution or transmitter phenotype. Therefore, we examined electron microscopic immunolabeling of GluR1 and tyrosine hydroxylase (TH) in two VTA regions of rats perfused 1 h after a single injection of morphine, or chronic morphine in intermittent-escalating doses for 14 d, and appropriate saline controls. Acute morphine administration produced a significant increase in GluR1 immunogold particles at the plasma membrane and postsynaptic densities in both TH- and non-TH-containing dendrites in the parabrachial VTA, a region that contains mainly prefrontal-cortical-projecting dopaminergic neurons involved in motivation and drug-seeking behavior. Chronic morphine administration maintained the increased synaptic GluR1 labeling in the parabrachial VTA, but also increased the number of GluR1-labeled synapses and TH immunoreactivity in dendrites of the paranigral VTA where substantially more dopaminergic neurons project to limbic structures implicated in locomotor activation and reward. These results demonstrate a region- and dose-dependent redistribution of GluR1-containing AMPA receptors, which is consistent with acute morphine activation of cortical-projecting VTA neurons and chronic morphine activation of limbic-projecting VTA neurons.
authors.affiliation: Department of Neurology and Neuroscience, Division of Neurobiology, Weill Medical College of Cornell University, New York, New York 10021, USA. dal2021@med.cornell.edu
authors.forename: Diane A
authors.initials: DA
authors.lastname: Lane
authors.forename: Andree A
authors.initials: AA
authors.lastname: Lessard
authors.forename: June
authors.initials: J
authors.lastname: Chan
authors.forename: Eric E O
authors.initials: EE
authors.lastname: Colago
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Stefan D
authors.initials: SD
authors.lastname: Schlussman
authors.forename: Mary Jeanne
authors.initials: MJ
authors.lastname: Kreek
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Pickel
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D008297:Male; D016253:Microscopy, Immunoelectron / Q000379:methods; D009020:Morphine / Q000008:administration & dosage*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D013266:Stilbamidines / Q000378:metabolism; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000166:cytology* / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D009020:Morphine; D018091:Receptors, AMPA; D013266:Stilbamidines; D014446:Tyrosine 3-Monooxygenase; C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt