Goals: Our primary goals are to: 1) shed new light on the neural mechanisms that drive the positive reinforcing effects of alcohol and other drugs of abuse; and 2) investigate the impact of alcohol use on neurodegenerative disorders including Alzheimer’s disease.

Strategy: Our preclinical studies take a “discovery-to-mechanistic” approach: 1) we seek to discover novel neural targets of alcohol use (changes in gene and protein expression); and 2) experimentally manipulate key targets using pharmacological or genetic strategies to determine if specific targets mechanistically regulate excessive alcohol self-administration and related behavioral pathologies.

Significance: Understanding the neural mechanisms of drug-induced maladaptive plasticity in brain and behavioral functions is important for development of new pharmacotherapeutic strategies for treating problems associated with alcohol and drug abuse, and neurodegenerative disorders.

Discovery: The figure shows a model of CaMKII in glutamate synapse. We discovered that moderate (nondependent) alcohol self-administration produces major effects on the neuro-proteome, including maladaptive alterations in cell signaling proteins that controls neuroplasticity. Accordingly, our work identified CaMKII (a.k.a. the molecular memory switch) as a primary target of alcohol that, in turn, drives the positive reinforcing effects of the drug. Now, we are focused on TARP gamma-8, which is required for CaMKII modulation of AMPAR-mediated glutamate signaling. Based on Salling et al., 2016.

Mechanism: This figure shows a summary of our preclinical medications development work. Glutamate AMPAR function is modulated by TARP γ-8. We evaluated JNJ-55511118, a novel inhibitor of TARP γ-8 bound AMPARs, for preclinical efficacy in reducing chronic alcohol self-administration. JNJ-55511118 decreased operant alcohol self-administration in C57BL/6J mice, demonstrating TARP γ-8 bound AMPAR activity is required for alcohol reinforcement. This discovery shows for the first time that TARP γ-8 regulates behavioral pathology associated with addiction. From Hoffman et al., 2021.

Neurodegeneration: The figure at left shows an experimental model of human Tau propagation in the mouse amygdala after “seeding” in the entorhinal cortex via an AAV approach. Human tau (red), AAV-GFP (green), DAPI (blue). In this ongoing study, we are evaluating the hypothesis that alcohol use exacerbates Tau propagation in the brain.