SPECIFIC AIMSIn classical pharmacology, an agonist activates a single linear signal transduction pathway, whereas anantagonist blocks the action of the agonist and possesses no intrinsic activity. Over the past few years, it hasbecome clear that signal transduction pathways are not merely linear cascades for signaling. Instead, they areorganized into complex signaling networks that require high levels of regulation to generate precise and uniquecellular responses. Hence, a given receptor, through various ligand-induced functional conformations, canengage multiple modalities through interaction with different signaling partners. In this way, a given ligand canbind a receptor and act as an antagonist for one signaling pathway while serving as an agonist at another or theconverse. This property is established for several G protein-coupled receptors (GPCRs) - the most importanttargets for therapeutic intervention. Importantly, none of the drugs in clinical use have been developed withthese multiple signaling considerations in mind. Additionally, agonists and antagonists are rarely completelyselective and, for a given receptor, may alter signaling by influencing various receptor-mediated processes suchas interaction with G proteins, desensitization, internalization, down-regulation, and receptor-mediatedscaffolding of non-G protein signaling components. Unfortunately, the physiological relevance of theseproperties is not fully appreciated. Thus, identifying the functional selectivity of compounds may help reveal notonly distinct biological processes, but also specific functional outcomes. Currently, the relevance of functionalselectivity to psychiatry is unknown. This is particularly important for antipsychotic drugs, where dopamine (DA)D2 receptor (D2R) antagonism is essentially a prerequisite for all these drugs; however, their other intrinsicactivities are obscure. The overall goal of the proposed research is to examine behavioral responses toantipsychotic compounds and to elucidate signal transduction mechanisms that are essential forantipsychotic efficacy in preclinical genetic and pharmacological mouse models of schizophrenia-likebehaviors. For behavior, effects of antipsychotic compounds on motor activity, prepulse inhibition (PPI), latentinhibition (LI), and social behavior in DA transporter (DAT) knockout (KO), N-methyl-D-aspartate (NMDA)receptor NR1-subunit knockdown (KD), and C57BL/6 mice treated with amphetamine (AMPH) or phencyclidine(PCP) to reproduce schizophrenia-like states. Molecular fingerprinting of signal transduction pathways(MFSTP) will be performed to analyze effects of antipsychotic compounds on various signal transductionmodalities that include the protein kinase A (PKA) and DA and cAMP-regulated phosphoprotein 32 (DARPP-32), Akt/protein kinase B (PKB or Akt) and glycogen synthase kinase 33 (GSK3), phospholipase C (PLC), andextracellular signal-regulated mitogen activated protein kinase (ERK) pathways. The experiments in the presentProject #3 will complement those in Projects #1 and #2 by providing preclinical models to test the in vivoselectivities and efficacies of various antipsychotic compounds on amelioration of schizophrenia-like behaviorsand will correlate these responses to alterations in signal transduction. Our Project #3 will complement also theCore Project from Wyeth where antipsychotic responses will be analyzed in rat models of schizophrenia-like andantipsychotic-treated behaviors. Understanding the relevance of functional selectivity of antipsychotic drugsmay provide novel targets with fewer side-effects, greater therapeutic selectivity, and enhanced efficacy fortreating individuals with schizophrenia. Our Project #3 has three Specific Aims.
Aim I. Role of hyperdopaminergia in responses to antipsychotic compounds in DAT-KO mice.A. To compare behavioral responses of DAT-KO mice to different antipsychotic compounds.B. To apply MFSTP to various brain regions to define the hyperdopaminergic phenotype and analyzeresponses to antipsychotic compounds.
Aim II. Role of reduced NMD A receptor expression in responses to antipsychotics in NR1-KD mice.A. To compare behavioral responses of NR1 hypomorphic mice to different antipsychotic compounds.B. To apply MFSTP to various brain regions to define the phenotype of the NMDA receptor hypomorphicmice and analyze responses to antipsychotic compounds.
Aim III. Roles of pharmacologically-induced hyperdopaminergia or hypoglutamatergia in responses toantipsychotic compounds in C57BU6 mice.A. To compare behavioral responses of mice treated with AMPH or PCP to different antipsychotics.B. To apply MFSTP to various brain regions to define pharmacologically-induced hyperdopaminergic orhypoglutamatergic states and analyze responses to antipsychotic compounds.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19MH082441-02
Application #
7623086
Study Section
Special Emphasis Panel (ZMH1)
Project Start
2008-05-01
Project End
2012-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
2
Fiscal Year
2008
Total Cost
$488,745
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Che, Tao; Majumdar, Susruta; Zaidi, Saheem A et al. (2018) Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor. Cell 172:55-67.e15
Wang, Sheng; Che, Tao; Levit, Anat et al. (2018) Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone. Nature 555:269-273
Rose, Samuel J; Pack, Thomas F; Peterson, Sean M et al. (2018) Engineered D2R Variants Reveal the Balanced and Biased Contributions of G-Protein and ?-Arrestin to Dopamine-Dependent Functions. Neuropsychopharmacology 43:1164-1173
McCorvy, John D; Butler, Kyle V; Kelly, Brendan et al. (2018) Structure-inspired design of ?-arrestin-biased ligands for aminergic GPCRs. Nat Chem Biol 14:126-134
McCorvy, John D; Wacker, Daniel; Wang, Sheng et al. (2018) Structural determinants of 5-HT2B receptor activation and biased agonism. Nat Struct Mol Biol 25:787-796
Peng, Yao; McCorvy, John D; Harpsøe, Kasper et al. (2018) 5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology. Cell 172:719-730.e14
Wacker, Daniel; Wang, Sheng; McCorvy, John D et al. (2017) Crystal Structure of an LSD-Bound Human Serotonin Receptor. Cell 168:377-389.e12
Wacker, Daniel; Stevens, Raymond C; Roth, Bryan L (2017) How Ligands Illuminate GPCR Molecular Pharmacology. Cell 170:414-427
Arnsten, Amy F T; Girgis, Ragy R; Gray, David L et al. (2017) Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia. Biol Psychiatry 81:67-77
Pappas, Andrea L; Bey, Alexandra L; Wang, Xiaoming et al. (2017) Deficiency of Shank2 causes mania-like behavior that responds to mood stabilizers. JCI Insight 2:

Showing the most recent 10 out of 136 publications