Depression is a major cause of mortality and morbidity worldwide. Its etiology is unknown. Current therapeutic treatments are effective in only half of patients and, when effective, work slowly. There is increasing evidence that a weakening of excitatory synaptic transmission between cells in multiple cortico-mesolimbic reward circuits is induced in rodents by chronic stress, perhaps underlying the wide range of behaviors affected by stress. Innovation: We discovered in the previous grant cycle that selective serotonin reuptake inhibitors act slowly to restore this weakened synaptic excitation. Based on the rapid antidepressant actions of ketamine, we identified a novel class of compounds that we predict will act rapidly to strengthen pathologically weakened excitatory synapses and can thus be predicted to exert a fast acting antidepressant action with fewer side effects than ketamine. Specifically, we will test the hypotheses that Partial inverse agonists of the benzodiazepine binding site of GABAA receptors containing a5 subunits (PIAGRA) will produce a rapid and persistent restoration of a range of behaviors that are affected by chronic stress paradigms in rats and mice and that they will restore the strength of pathologically weakened excitatory synapses, as measured in electrophysiological and biochemical assays. Approach: Our preliminary data show that a unique PIAGRA compound (L-655,078) restores normal sucrose preference and social interaction within 24hrs in rats subjected to two chronic stress paradigms and restores the strength of AMPAR-mediated synaptic excitation and GluA1 expression in hippocampal synapses in rats subjected to chronic stress. We also observed that synapses formed by hippocampal projections to neurons in the nucleus accumbens display activity-dependent long-term potentiation. We propose to test the following specific aims. 1: Determine the persistence and generality of PIAGRA's antidepressant actions on a range of appetitive and innate behaviors (food, social interactions, sex). 2: Determine the mechanism of action of PIAGRA at the level of synaptic circuits. 3: Determine the effects of stress and PIAGRA on hippocampal-NAc excitatory synapses. We will use multiple chronic stress paradigms to produce changes in reward behavior, then test whether PIAGRA compounds produce rapid (<24 hrs) and persistent normalization of these behaviors and determine how long these beneficial actions persist. We will then use electrophysiological recording to test the strength of excitatory interactions, along with several biochemical and molecular correlates, in brain tissue taken from these animals 24 hrs after injection of the compounds. Outcome: Our study will provide a thorough proof-of-concept test of a novel class of AD compounds at several levels of analysis from behavior to molecules, as encouraged by the NIMH's Research Domain Criteria initiative. Evidence of a beneficial therapeutic action in rodents after chronic stress, and the identification of key circuits at which they act, will encourage a test of their therapeutic effect in depressed patients.

Public Health Relevance

The cause(s) of depression are not known and current medications work in only half of all patients. We subject rats and mice to various forms of chronic mild stress, which is known to cause changes in behavior and in the function of brain connections which resemble those seen in human depression. We will then test a new class of drugs that exert rapid antidepressant-like effects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH086828-10
Application #
9692039
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Nadler, Laurie S
Project Start
2009-07-01
Project End
2020-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
10
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Physiology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
LeGates, Tara A; Kvarta, Mark D; Tooley, Jessica R et al. (2018) Reward behaviour is regulated by the strength of hippocampus-nucleus accumbens synapses. Nature 564:258-262
Zanos, Panos; Thompson, Scott M; Duman, Ronald S et al. (2018) Convergent Mechanisms Underlying Rapid Antidepressant Action. CNS Drugs 32:197-227
Zanos, Panos; Nelson, Mackenzie E; Highland, Jaclyn N et al. (2017) A Negative Allosteric Modulator for ?5 Subunit-Containing GABA Receptors Exerts a Rapid and Persistent Antidepressant-Like Action without the Side Effects of the NMDA Receptor Antagonist Ketamine in Mice. eNeuro 4:
Zanos, Panos; Moaddel, Ruin; Morris, Patrick J et al. (2017) Reply to: Antidepressant Actions of Ketamine Versus Hydroxynorketamine. Biol Psychiatry 81:e69-e71
Zhang, Ke; Yamaki, Vitor Nagai; Wei, Zhisheng et al. (2017) Differential regulation of GluA1 expression by ketamine and memantine. Behav Brain Res 316:152-159
Le, Nhat T T; Chang, Lydia; Kovlyagina, Irina et al. (2016) Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS-FTD-linked UBQLN2 mutations. Proc Natl Acad Sci U S A 113:E7580-E7589
Zanos, Panos; Moaddel, Ruin; Morris, Patrick J et al. (2016) NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533:481-6
Yang, Linjie; Xu, Ting; Zhang, Ke et al. (2016) The essential role of hippocampal alpha6 subunit-containing GABAA receptors in maternal separation stress-induced adolescent depressive behaviors. Behav Brain Res 313:135-143
Fischell, Jonathan; Van Dyke, Adam M; Kvarta, Mark D et al. (2015) Rapid Antidepressant Action and Restoration of Excitatory Synaptic Strength After Chronic Stress by Negative Modulators of Alpha5-Containing GABAA Receptors. Neuropsychopharmacology 40:2499-509
Thompson, Scott M; Kallarackal, Angy J; Kvarta, Mark D et al. (2015) An excitatory synapse hypothesis of depression. Trends Neurosci 38:279-94

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