RGS9 modulates dopamine signaling in the basal ganglia

被引:219
作者
Rahman, Z
Schwarz, J
Gold, SJ
Zachariou, V
Wein, MN
Choi, KH
Kovoor, A
Chen, CK
DiLeone, RJ
Schwarz, SC
Selley, DE
Sim-Selley, LJ
Barrot, M
Luedtke, RR
Self, D
Neve, RL
Lester, HA
Simon, MI
Nestler, EJ
机构
[1] Univ Texas, SW Med Ctr, Dept Psychiat, Dallas, TX 75390 USA
[2] Univ Texas, SW Med Ctr, Ctr Basic Neurosci, Dallas, TX 75390 USA
[3] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06508 USA
[4] Yale Univ, Lab Mol Psychiat, New Haven, CT 06508 USA
[5] CALTECH, Dept Biol, Pasadena, CA 91125 USA
[6] Virginia Commonwealth Univ, Dept Pharmacol, Richmond, VA 23298 USA
[7] Univ N Texas, Ctr Hlth Sci, Dept Pharmacol & Neurosci, Ft Worth, TX 76107 USA
[8] Harvard Univ, Sch Med, Dept Genet, Belmont, MA 02478 USA
关键词
D O I
10.1016/S0896-6273(03)00321-0
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Regulators of G protein signaling (FIGS) modulate heterotrimeric G proteins in part by serving as GTPase-activating proteins for Galpha subunits. We examined a role for RGS9-2, an FIGS subtype highly enriched in striatum, in modulating dopamine D2 receptor function. Viral-mediated overexpression of RGS9-2 in rat nucleus accumbens (ventral striatum) reduced locomotor responses to cocaine (an indirect dopamine agonist) and to D2 but not to D1 receptor agonists. Conversely, RGS9 knockout mice showed heightened locomotor and rewarding responses to cocaine and related psychostimulants. In vitro expression of RGS9-2 in Xenopus oocytes accelerated the off-kinetics of D2 receptor-induced GIRK currents, consistent with the in vivo data. Finally, chronic cocaine exposure increased RGS9-2 levels in nucleus accumbens. Together, these data demonstrate a functional interaction between RGS9-2 and D2 receptor signaling and the behavioral actions of psychostimulants and suggest that psychostimulant induction of RGS9-2 represents a compensatory adaptation that diminishes drug responsiveness.
引用
收藏
页码:941 / 952
页数:12
相关论文
共 52 条
  • [1] Anatomical and physiological evidence for D1 and D2 dopamine receptor colocalization in neostriatal neurons
    Aizman, O
    Brismar, H
    Uhlén, P
    Zettergren, E
    Levey, AI
    Forssberg, H
    Greengard, P
    Aperia, A
    [J]. NATURE NEUROSCIENCE, 2000, 3 (03) : 226 - 230
  • [2] Mammalian RGS proteins: Barbarians at the gate
    Berman, DM
    Gilman, AG
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (03) : 1269 - 1272
  • [3] μ-Opioid receptor desensitization by β-arrestin-2 determines morphine tolerance but not dependence
    Bohn, LM
    Gainetdinov, RR
    Lin, FT
    Lefkowitz, RJ
    Caron, MG
    [J]. NATURE, 2000, 408 (6813) : 720 - 723
  • [4] Enhanced morphine analgesia in mice lacking β-arrestin 2
    Bohn, LM
    Lefkowitz, RJ
    Gainetdinov, RR
    Peppel, K
    Caron, MG
    Lin, FT
    [J]. SCIENCE, 1999, 286 (5449) : 2495 - 2498
  • [5] Regulation of cocaine reward by CREB
    Carlezon, WA
    Thome, J
    Olson, VG
    Lane-Ladd, SB
    Brodkin, ES
    Hiroi, N
    Duman, RS
    Neve, RL
    Nestler, EJ
    [J]. SCIENCE, 1998, 282 (5397) : 2272 - 2275
  • [6] Sensitization to morphine induced by viral-mediated gene transfer
    Carlezon, WA
    Boundy, VA
    Haile, CN
    Lane, SB
    Kalb, RG
    Neve, RL
    Nestler, EJ
    [J]. SCIENCE, 1997, 277 (5327) : 812 - 814
  • [7] Slowed recovery of rod photoresponse in mice lacking the GTPase accelerating protein RGS9-1
    Chen, CK
    Burns, ME
    He, W
    Wensel, TG
    Baylor, DA
    Simon, MI
    [J]. NATURE, 2000, 403 (6769) : 557 - 560
  • [8] ATRIAL G-PROTEIN-ACTIVATED K+-CHANNEL - EXPRESSION CLONING AND MOLECULAR-PROPERTIES
    DASCAL, N
    SCHREIBMAYER, W
    LIM, NF
    WANG, WZ
    CHAVKIN, C
    DIMAGNO, L
    LABARCA, C
    KIEFFER, BL
    GAVERIAUXRUFF, C
    TROLLINGER, D
    LESTER, HA
    DAVIDSON, N
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (21) : 10235 - 10239
  • [9] The regulator of G protein signaling family
    De Vries, L
    Zheng, B
    Fischer, T
    Elenko, E
    Farquhar, MG
    [J]. ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, 2000, 40 : 235 - 271
  • [10] RGS proteins: more than just GAPs for heterotrimeric G proteins
    De Vries, L
    Farquhar, MG
    [J]. TRENDS IN CELL BIOLOGY, 1999, 9 (04) : 138 - 144