Funded Research

Ongoing Research Support – Chavkin (PI):

NIH: National Institute of Mental Health; “Stress Mechanisms Increasing Risk of Mood Disorders” P50 MH106428-02 (4/1/15-3/31/20). C Chavkin is overall PI and PI of Project 1 “Therapeutic Potential of Kappa Antagonists in the Adjunctive Treatment of Psychotic Depression.”

The Silvio O. Conte Center at the University of Washington is designed with a specific goal of understanding how stress-exposure can exacerbate depressive symptoms and increase the risk of a depressive episode in vulnerable individuals. The research aims of this Center are designed to understand 1) how the dynorphins, which are released in response to repeated stress, cause aversive effects in mice that have been suggested to be responsible for a component of stress-induced dysphoria in humans (Project 1, Chavkin); 2) how the serotonergic inputs from the dorsal raphe nucleus (DRN) that regulate the dopaminergic system in the ventral tegmental area (VTA) affect neuronal excitability and are changed by repeated social defeat stress exposure (Project 2, Zweifel); 3) how stress exposure alters gene expression in the serotonergic neurons of the DRN (Project 3, Neumaier); and 4) how repeated stress exposure alters the regulation by CRF of the dopamine release by VTA neurons projecting to the nucleus accumbens (NAc) (Project 5, Phillips). The UW-Conte Center will support basic science and clinical research, as well as community Outreach and Training missions in a coordinated and synergistic manner.

NIH: National Institute on Drug Abuse; “Structure-Function of Opioid Receptors” PO1 DA 035764-03 (4/1/14-3/31/19). Dr. Ray Stevens (University of Southern California) & Dr. Bryan Roth (University of North Carolina, overall co-PIs; C Chavkin, PI Project 3.

Pharmacology of KOR Ligands.” This Program Project Grant represents a collaboration between a group of investigators (Drs. Ray Stevens, Bryan Roth, Charles Chavkin, Ivy Carroll, Seva Katritch & Vadim Cherezov) designed to characterize the structural basis of ligand-directed signaling using novel opioid compounds having distinct functional selectivities. Dr. Carroll’s medicinal chemistry component is developing novel kappa-opioid drugs. C Chavkin’s and Bryan Roth’s components are characterizing the compounds’ pharmacological properties by assessing their arrestin-biased / G-protein-biased profiles using in vitro neurochemical and behavioral assays. Kappa opioid receptors bound to signaling pathway-selective compounds would then be crystalized and molecularly modeled by the team lead by Ray Stevens at USC. C Chavkin’s component is also characterizing the mechanisms of JNK-dependent opioid receptor inactivation.

p38 MAPK Mechanisms of Kappa Opioid-Induced Aversion  R01 DA030074-06A1   The goal of this project is to understand how activation of p38 MAPK by KOR stimulation, either by stress-induced dynorphin release in the DRN or systemic administration of a selective KOR agonist, results in conditioned place aversion.  This award supports ongoing studies of the signal transduction events linking kappa receptor activation to p38a MAPK activation. It further supports studies using in vivo fast scan cyclic voltammetry to define the effects of KOR-p38 of dopamine release and reuptake mechanisms. This award is focused on stress as a risk of developing drug addiction, and current studies supported by this grant are using rat cocaine self-administration methods to characterize the effects of stress-induced dynorphin release on the patterns of self-administration.

Training in Molecular Pharmacology of Abused Drugs  T32 DA07278-22  This institutional training grant currently supports 5 postdoctoral fellows and 5 predoctoral fellows per year. C Chavkin directs this training program, which involves 14 faculty mentors. Training for the fellows includes 2 courses (‘Molecular Basis of Addictive Drug Action’ and ‘Addiction: Mechanisms, Treatment, Prevention’ offered in alternate years), 2 journal clubs, and a monthly research progress meeting for members of the ‘UW-Center for Drug Addiction Research’ each of which is organized by C Chavkin. Trainees attend these lectures, participate in discussions, and present talks in these sessions. Trainees participate in the Biomedical Research Integrity Series organized by the UW department of Bioethics, and C Chavkin participates as a mentor and small-group discussion leader in this series.

Therapeutic Potential of Kappa Opioids     R13 DA031536-03
This award provided support for a scientific conference held July 10-13, 2011 in Seattle. C Chavkin was chair of the program committee, and the conference involved 130 registrants, 45 talks, 22 posters. The grant was renewed to support a 2nd Kappa-Therapeutics conference held in Boston April 24-27, 2013 that was co-organized by C Chavkin, Bill Carlezon & Elena Chartoff. The 3rd conference in this series was held in Chapel Hill, NC (4/20-23/2015) co-organized by C Chavkin, Bryan Roth, Ivy Carroll and Tom Kash. The planning for future meetings in Philadelphia, PA (4/2017) and Ventura, CA (4/2019) are in progress.