Northwestern University

May
6
Mon 4:00 PM

Autophagic Regulation of Cocaine-Induced Behaviors

When: Monday, May 6, 2019
4:00 PM - 5:00 PM  

Where: Ward Building, 5-230, 303 E. Chicago Avenue, Chicago, IL 60611 map it

Audience: Faculty/Staff - Student - Public - Post Docs/Docs - Graduate Students

Contact: Alexa Nash   312.503.4893

Group: Department of Pharmacology Seminars

Category: Lectures & Meetings

Description:

CongCong He, Ph.D.
Assistant Professor
Department of Cell and Molecular Biology
Northwestern University

Abstract:
Drug abuse is one of the most important health and societal issues of our time. Cocaine is one of the most widely abused recreational drugs throughout the world, and produces a variety of behaviors, including psychostimulation, addiction, and death from overdose. The mechanisms that underlie cocaine-induced disordersare unresolved and effective treatments are lacking. We used a combination of mouse genetics, cell biology, animal behavior, and pharmacological approaches, linking cocaine stimulation and addiction to the autophagy pathway, a stress-induced lysosomal degradation process that breaks down damaged or unnecessary structures in the cell. Although emerging evidence indicates that autophagy proteins are implicated in several diseases, whether and how they play a role in drug abuse and addiction is essentially unknown. We discovered that an autophagy-related protein Becn2 is a novel regulator and druggable target for the prevention of cocaine-induced behaviors. Knockout of Becn2 protects mice from cocaine-induced stimulant and addictive effects, as well as cocaine-amplified dopamine release and signaling, due to an increase in the striatal presynaptic dopamine receptor 2 (D2R), an autoreceptor that inhibits dopamine release. We further found that Becn2 regulates D2R trafficking, degradation, and cocaine-induced behaviors via binding to an adaptor protein GASP1. In addition, translationally, we found that targeting Becn2 by upstream small-molecule autophagy inhibitors stabilizes striatal presynaptic D2R andprevents physiological and behavioral responsiveness to cocaine. Thus, these results link dopaminergic transmission to an entirely new and potentially druggable pathwayto prevent behavioral responses to cocaine, and also suggest that besides cocaine, Becn2 and the autophagy machinery may play an important role in other substance-related and/or mental disorders caused by altered dopamine transmission.

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