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LABORATORY OF MOLECULAR NEUROPHARMACOLOGYMedical School-University of Crete

Head: VANNA ZACHARIOU, PhD

BACKGROUND

Our goal is to establish an understanding of the regulation of G protein coupled receptor(GPCR) signal transduction in the brain. G protein coupled receptor signaling plays an essen-tial role in neuronal function and communication. One of the most important discoveries forthe understanding GPCR deactivation was that of RGS proteins (Regulators of G protein sig-naling). The diverse family of RGS proteins are widely distributed proteins with multiple func-tions, including GAP activity for heterotrimeric G protein alpha subunits. In addition, severalRGSs regulate G protein activity via effector antagonismor via negative regulation of receptorendocytosis. Several RGS proteins are abundant in brain with overlapping yet distinct patternsof expression that includes neural networks associated with several pathological conditions,such as depression, schizophrenia and addiction. Our earlier work revealed that RGS9-2 is anegative modulator of opioidergic and dopaminergic responses in striatum (Zachariou et al.,PNAS 2003, Rahman et al., Neuron, 2003). We are extending this work to better understandhow changes in RGS function/activity in particular brain regions improves drug responsive-ness. We also aim to understand the cellular mechanism via which particular RGS proteinsaffect neuronal function.

RESEARCH

SIGNAL TRANSDUCTION MECHANISMS IN NEUROLOGICAL AND PSYCHIATRIC DISORDERS

1. The lab uses genetic and molecular tools combined with animal behavior toinvestigate how RGS protein dysfunctions in the brain affect different aspects ofdrug addiction, analgesia, and mood disorders. Some of the genetic animal modelscurrently used in the lab include constitutive and conditional knockout mice (for RGS9, RGS4and RGSz genes) and viral mediated gene transfer (used for RGS4 and RGS9-2 overexpressionin particular brain networks.

2. Another part of the lab research concentrates on the cellular and molecu-lar basis of chronic pain. We are particularly interested on the role of RGS9-2, RGS4, RGS2and RGSz in chronic pain. Ongoing studies, evaluate the role of each of these proteins in neu-ropathic pain treatment, and in chronic pain related depression.

FUNDING

Greek Secreteriat for Research and Technology, The Greek Ministry of Education NIDA.

MEMBERS

Kassi Psifogeorgou Maria Papachatzaki Jo Charlton Konstantinos AlfarasDimitra TerziZoe PetrakiPenny FoukaIrini Kamileri

COLLABORATORS

Our laboratory is part of a multi-disciplinary and highly collaborative research group ofUS and European teams.

REPRESENTATIVE PUBLICATIONS

1. Psifogeorgou K., Papakosta P., Russo S. Neve R.L., Kardassis D., Gold S.J., andZachariou V., RGS9-2 is a negative modulator of Mu opioid receptor function J.Neurochemistry, in press

2. Zachariou V, Bolanos CA, Selley DE, Theobald D, Cassidy M, Kelz M, Shaw-LutchmanT, Berton O, Sim-Selley LJ, Dileone RJ, Kumar A, & Nestler EJ (2006) An Essential Role for∆FosB in the Nucleus Accumbens in Morphine Action. Nature Neuroscience, 9(2): 205-211.

3. Allen PB, Zachariou V, Svenningsson P, Centonze D, Costa C, Rossi S, Bender G, ChenG, Feng J, Snyder G, Benradi G, Nestler EJ, Yan Z, & Greengard P (2006) Distinct roles forspinophilin and neurabin in dopamine mediated plasticity. Neuroscience, In press.

4. McClung CA, Nestler EJ, & Zachariou V (2005) Regulation of Gene Expression byChronic Morphine and Morphine Withdrawal in the Locus Coeruleus and Ventral TegmentalArea. Journal of Neuroscience, 25 (25): 6005-6015.

5. Zachariou V, Sgambato-G V, Sasaki T, Svenningsson P, Berton O, Fienberg AA, NairnAC, Greengard P, & Nestler EJ () Phosphorylation of DARPP-32 at Threonine-34 is Requiredfor Cocaine Action. Neuropsychopharmacology, 31 (3):555-562.

6. Rahman Z, Schwarz J, Gold SJ, Zachariou V, Wein M.N., Choi KH, Kovoor A, ChenCK, DiLeone RJ, Schwarz SC, Selley DE, Sim-Selley LJ, Barrot M, Luedtke RR, Self D, NeveRL, Lester HA, Simon MI, & Nestler EJ (2003) RGS9 modulates dopamine signaling in thebasal ganglia. Neuron, 38(6):941-952.

7. Zachariou V, Georgescu D, Sanchez N, Rahman Z, DiLeone R, Berton O, Neve RL, Sim-Selley LJ, Selley DE, Gold SJ, & Nestler EJ (2003) Essential role for RGS9 in opiate action.Proc. Natl. Acad. Sci., 11;100(23):13656-13661.

8. Zachariou V, Brunzell D, Hawes J, Steadman D, Bartfai T, Steiner RA, Wynick D,Langel U, & Picciotto MR (2003) The neuropeptide galanin modulates behavioral and neuro-chemical signs of opiate withdrawal. Proc. Natl. Acad. Sci 100(15):9028-9033.

9. Georgescu D, Zachariou V, Barrot M, Mieda M, Willie JT, Eisch AJ, Yanagisawa M,Nestler EJ, & DiLeone RJ (2003) Involvement of the lateral hypothalamic peptide orexin inmorphine dependence and withdrawal. Journal of Neuroscience, 23(8):3106-3111.

10. Shaw-Lutchman T, Barrot M, Wallace T, Gilden L, Zachariou V, Impey S, DumanRS, Storm D, & Nestler EJ (2002) Regional and cellular mapping of CRE-mediated transcrip-tion during naltrexone-precipitated morphine withdrawal. Journal of Neuroscience,22(9):3663-3672

11. Barrot M, Olivier JDA, Perrotti LI, Di Leone RJ, Berton O, Eisch AJ, Impey S, StormDR, Neve RL, Zachariou V, & Nestler EJ (2002) CREB activity in the nucleus accumbens shellcontrols gating of behavioral responses to emotional stimuli. Proc. Natl. Acad. Sci,99(17):11435-11440.

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CONTACT

Vanna Zachariou, PhD Department of PharmacologyDivision of Basic SciencesUniversity of CreteFaculty of Medicine, 71003 Heraklion, CreteGreece

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