McLean Hospital 115 Mill Street Belmont, MA 02478
Bill Carlezon, PhD, has received several awards for his research, including an Independent Investigator Award from the National Alliance for Research on Schizophrenia and Depression (NARSAD), the Presidential Early Career Award for Scientists and Engineers (PECASE) from George W. Bush, and the Jacob P. Waletzky Award for Innovative Research in Drug Addiction and Alcoholism from the Society for Neuroscience (SfN).
Bill is editor-in-chief of the journal Neuropsychopharmacology and a member of the Scientific Advisory Board for Autism Speaks.
Dr. Carlezon is primarily interested in the biological basis and treatment of psychiatric illness, specifically nature/nurture issues as they relate to the brain and the basic processes by which the brain develops and is modified in response to experience. His Behavioral Genetics Laboratory, founded in 1998, aims to better understand how the environment affects behavior and the biology of the brain. “Environment” can mean many things, including exposure to stress, drugs, trauma, toxins, or illness. This work is relevant to many types of neuropsychiatric disorders, including depression, anxiety, PTSD, addiction, and autism.
Scientists who are trained in the Carlezon lab develop expertise in the analysis of behavior in rats and mice, the use of genetic engineering to control or modify gene and protein expression, and molecular techniques to measure molecular adaptations. His staff is highly motivated to disseminate their work via publications and to participate in the discovery and development of novel therapeutic agents.
Rather than trying to model neuropsychiatric conditions directly, Dr. Carlezon’s lab uses multiple behavioral tests that capture their key signs, which in people are often overlapping (co-occurring). Ideally, the tests are sensitive to the same signs in animals that psychiatrists use to make diagnoses in people.
The work is performed in rats and mice using various strategies. For example, Dr. Carlezon and his staff might study how exposure to a particular type of stress affects motivated behavior, which is dysregulated in many types of neuropsychiatric disorders. They would then examine brain regions known to regulate motivation for the molecular changes that accompany observed behavioral changes.
To establish cause-effect relationships, genetic engineering techniques are used—for example, viral vectors and mutant mice—to reproduce individual molecular changes to see if they can cause the behavioral changes. Finally, this new information is used to design new medications that can block, reverse, or prevent the behavioral changes.
This strategy has been successful. Dr. Carlezon and his group were the first to report that a class of drugs called kappa-opioid receptor (KOR) antagonists has antidepressant, anti-anxiety, and anti-stress effects in their behavioral tests. These discoveries have led to considerable interest in KOR antagonists, which are now in advanced clinical trials for treatment-resistant depression. The lab is now working with other scientists at McLean and the Broad Institute to develop novel kappa antagonists, using techniques such as high-throughput screening and medicinal chemistry.
Carroll FI, Carlezon WA Jr. Development of Kappa-opioid receptor antagonists. Journal of Medicinal Chemistry 2013;56:2178-2195.
Van’t Veer A, Bechtholt AJ, Onvani S, Potter D, Wang Y, Liu-Chen LY, Schütz G, Chartoff EH, Rudolph U, Cohen BM, Carlezon WA Jr. Ablation of kappa-opioid receptors from brain dopamine neurons has anxiolytic-like effects and enhances cocaine-induced plasticity. Neuropsychopharmacology 2013;38:1585-1597.
Muschamp JW, Hollander JA, Thompson JL, Voren G, Onvani S, Hassinger LC, Kamenecka TM, Borgland SL, Kenny PJ, Carlezon WA Jr. Hypocretin (orexin) facilitates reward by attenuating the anti-reward effects of its co-transmitter dynorphin. Proceedings of the National Academy of Sciences USA 2014;111(16):E1648-55.
Belmont campus - Mailman Research Center, Room 217