title: Strengthening the accumbal indirect pathway promotes resilience to compulsive cocaine use.
abstract: A hallmark of addiction is the loss of control over drug intake, which is seen in only a fraction of those exposed to stimulant drugs such as cocaine. The cellular mechanisms underlying vulnerability or resistance to compulsive drug use remain unknown. We found that individual variability in the development of highly motivated and perseverative behavior toward cocaine is associated with synaptic plasticity in medium spiny neurons expressing dopamine D2 receptors (D2-MSNs) in the nucleus accumbens (NAc) of mice. Potentiation of glutamatergic inputs onto indirect pathway D2-MSNs was associated with resilience toward compulsive cocaine seeking. Inhibition of D2-MSNs using a chemicogenetic approach enhanced the motivation to obtain cocaine, whereas optogenetic activation of D2-MSNs suppressed cocaine self-administration. These results indicate that recruitment of D2-MSNs in NAc functions to restrain cocaine self-administration and serves as a natural protective mechanism in drug-exposed individuals.
authors.affiliation: Laboratory for Integrative Neuroscience, National Institute of Alcohol Abuse and Alcoholism, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Roland
authors.initials: R
authors.lastname: Bock
authors.forename: J Hoon
authors.initials: JH
authors.lastname: Shin
authors.forename: Alanna R
authors.initials: AR
authors.lastname: Kaplan
authors.forename: Alice
authors.initials: A
authors.lastname: Dobi
authors.forename: Eric
authors.initials: E
authors.lastname: Markey
authors.forename: Paul F
authors.initials: PF
authors.lastname: Kramer
authors.forename: Christina M
authors.initials: CM
authors.lastname: Gremel
authors.forename: Christine H
authors.initials: CH
authors.lastname: Christensen
authors.forename: Martin F
authors.initials: MF
authors.lastname: Adrover
authors.forename: Veronica A
authors.initials: VA
authors.lastname: Alvarez
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D000075402:Channelrhodopsins; D003024:Clozapine / Q000031:analogs & derivatives / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage*; D003192:Compulsive Behavior / Q000235:genetics / Q000503:physiopathology*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000378:metabolism; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000235:genetics; D012201:Reward; D012646:Self Administration; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D000075402:Channelrhodopsins; D018765:Dopamine Uptake Inhibitors; D008164:Luminescent Proteins; D017448:Receptors, Dopamine D2; C485184:enhanced green fluorescent protein; C054562:yellow fluorescent protein, Bacteria; D049452:Green Fluorescent Proteins; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D003042:Cocaine; D003024:Clozapine; C079149:clozapine N-oxide
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