title: Differential glutamate AMPA-receptor plasticity in subpopulations of VTA neurons in the presence or absence of residual cocaine: implications for the development of addiction.
abstract: Cocaine-induced plasticity of mesocorticolimbic dopamine (DA) neurons, originating in the ventral tegmental area (VTA), persists in the absence of cocaine and may contribute to both drug-craving and relapse. Glutamate AMPA receptors (AMPARs) in these neurons are implicated in this plasticity. However, there is no ultrastructural evidence that the absence of cocaine following repeated administrations affects the critical surface/synaptic availability of AMPAR GluR1 subunits in either DA or non-DA, putative GABAergic neurons within the VTA. To assess this, we used electron microscopic immunolabeling in the VTA of adult male mice sacrificed at 30 min or 72 h after receiving the final of six (15 mg/kg) cocaine injections, a dosing paradigm that resulted in development of locomotor sensitization. At each time point, both cocaine- and saline-injected mice showed AMPAR GluR1 immunogold labeling in somatodendritic profiles, many of which contained immunoperoxidase labeling for the DA-synthesizing enzyme, tyrosine hydroxylase (TH). At 30 min after the last injection, when cocaine was systemically present, only the non-TH labeled dendrites showed a significant increase in the synaptic/plasmalemmal density of GluR1 immunogold particles. At 72 h, when systemic cocaine was depleted, synaptic GluR1 labeling was greatly enhanced in TH-containing dendrites throughout the VTA and in non-TH dendrites of the limbic-associated paranigral VTA. Our results demonstrate that systemic cocaine produces GluR1 trafficking specifically in non-DA neurons of the VTA, which may subsequently contribute to the abstinent-induced enhancement of AMPA receptor synaptic transmission in mesocorticolimbic DA neurons leading to heightened drug seeking behavior.
authors.affiliation: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA. dal2021@med.cornell.edu
authors.forename: D A
authors.initials: DA
authors.lastname: Lane
authors.forename: B
authors.initials: B
authors.lastname: Reed
authors.forename: M J
authors.initials: MJ
authors.lastname: Kreek
authors.forename: V M
authors.initials: VM
authors.lastname: Pickel
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000097:blood; D019970:Cocaine-Related Disorders / Q000097:blood / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D059330:GABAergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D057146:Multivesicular Bodies / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects*; D021122:Protein Subunits / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011897:Random Allocation; D018091:Receptors, AMPA / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology / Q000648:ultrastructure
chemical_list: D003042:Cocaine; D018765:Dopamine Uptake Inhibitors; D009419:Nerve Tissue Proteins; D021122:Protein Subunits; D018091:Receptors, AMPA; D014446:Tyrosine 3-Monooxygenase; C005618:benzoylecgonine