Jennifer Whistler

Neurobiology of addictive disorders and their comorbidities. The majority of drugs used in human medicine target G protein coupled receptors (GPCRs). The focus in the Whistler laboratory is elucidating how altering the signaling "bias" of a GPCR for its various downstream signaling partners contributes to drug responsiveness and side effect profile. Dr. Whistler is particularly interested in the role of biased versus balanced GPCR signaling in modulating responsiveness to drugs of abuse and the co-morbidities of anxiety, depression and altered decision making that accompany drug use/abuse. Starting with the opioid receptors, the laboratory demonstrated the in vivo relevance of altered signaling bias in addiction disorders. Specifically, her team demonstrated that altering the signaling bias of morphine so that it mimicked that of endorphin, one of our body's endogenous opioids, could prevent the development of tolerance, dependence and addiction to this drug without adversely affecting analgesia. They have since extended these studies to other clinically important GPCR targets and their ligands/drugs that are important for the treatment of psychosis, depression, Parkinson's disease, anxiety, asthma and metabolic disease. These receptors, including the dopamine receptors and the incretin receptors, and the clinically important drugs that target them, are, as yet, poorly characterize for their signaling bias. The Labs future goals follow four main paths: 1) They are determining the changes in the brain that are responsible for addiction to opioid drugs 2) They are optimizing and providing preclinical in vivo data to stimulate the clinical development of a "balanced" opioid analgesic with reduced abuse liability. 3) They are examining a number of other clinically important GPCR drugs for their signaling bias, and evaluating the consequences of altering their bias. 4) They are determining whether naturally occurring genetic variation at clinically important GPCR targets in the human population affects signaling bias in response to endogenous ligand and clinically important drugs that target these receptors.