title: Fragile X mental retardation protein regulates synaptic and behavioral plasticity to repeated cocaine administration.
abstract: Repeated cocaine exposure causes persistent, maladaptive alterations in brain and behavior, and hope for effective therapeutics lies in understanding these processes. We describe here an essential role for fragile X mental retardation protein (FMRP), an RNA-binding protein and regulator of dendritic protein synthesis, in cocaine conditioned place preference, behavioral sensitization, and motor stereotypy. Cocaine reward deficits in FMRP-deficient mice stem from elevated mGluR5 (or GRM5) function, similar to a subset of fragile X symptoms, and do not extend to natural reward. We find that FMRP functions in the adult nucleus accumbens (NAc), a critical addiction-related brain region, to mediate behavioral sensitization but not cocaine reward. FMRP-deficient mice also exhibit several abnormalities in NAc medium spiny neurons, including reduced presynaptic function and premature changes in dendritic morphology and glutamatergic neurotransmission following repeated cocaine treatment. Together, our findings reveal FMRP as a critical mediator of cocaine-induced behavioral and synaptic plasticity.
authors.affiliation: Department of Psychiatry, Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA; Department of Psychiatry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, USA.
authors.forename: Laura N
authors.initials: LN
authors.lastname: Smith
authors.affiliation: Department of Psychiatry, Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA; Department of Neuroscience and Department of Psychology, University of Minnesota, 321 Church Street SE, Minneapolis, MN 55455, USA.
authors.forename: Jakub P
authors.initials: JP
authors.lastname: Jedynak
authors.affiliation: Medical Science Training Program, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, USA.
authors.forename: Miles R
authors.initials: MR
authors.lastname: Fontenot
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, USA.
authors.forename: Carly F
authors.initials: CF
authors.lastname: Hale
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, USA.
authors.forename: Karen C
authors.initials: KC
authors.lastname: Dietz
authors.affiliation: Department of Psychiatry, Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA; Department of Psychiatry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, USA.
authors.forename: Makoto
authors.initials: M
authors.lastname: Taniguchi
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, USA.
authors.forename: Feba S
authors.initials: FS
authors.lastname: Thomas
authors.affiliation: Department of Psychiatry, Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA; Department of Psychiatry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, USA.
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Zirlin
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, USA.
authors.forename: Shari G
authors.initials: SG
authors.lastname: Birnbaum
authors.affiliation: Department of Neuroscience, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Huber
authors.affiliation: Department of Neuroscience and Department of Psychology, University of Minnesota, 321 Church Street SE, Minneapolis, MN 55455, USA; Institute for Translational Neuroscience, University of Minnesota, Wallin Medical Biosciences Building, 2101 Sixth Street SE, Minneapolis, MN 55455, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Thomas
authors.affiliation: Department of Psychiatry, Harvard Medical School, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA; Department of Psychiatry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, USA. Electronic address: cwcowan@mclean.harvard.edu.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Cowan
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology*; D012646:Self Administration; D013569:Synapses / Q000187:drug effects* / Q000502:physiology*
chemical_list: D003042:Cocaine; D051860:Fragile X Messenger Ribonucleoprotein 1; C497684:Fmr1 protein, mouse