Impairments in cognitive function are among the ?hallmark? characteristics of addiction. In this regard, alcoholism is associated with dysfunction of multiple cognitive faculties that may underlie the difficulties in reversing alcohol- seeking behaviors during extended periods of abstinence. Repeated cycles of alcohol intoxication and withdrawal dysregulate brain amino acid systems, an effect that is thought to impart a hyperexcitable state. Whereas acute withdrawal mobilizes signaling of the primary excitatory neurotransmitter glutamate, over time these neurological disturbances subside. The emergence of cognitive disruptions during protracted withdrawal suggests an underlying dysfunction in the medial prefrontal cortex (mPFC). In this regard, drugs of abuse mobilize protein kinases that, over the course of repeated exposures, produce long-term changes in synaptic function and molecular signaling networks that coincide with addictive phenotypes. We propose that withdrawal- induced cognitive impairments relate to an undercurrent of dysfunctional kinase signaling pathways that preserve aberrant glutamate receptor signaling in discrete regions of the mPFC. To this end, the K99 phase will involve training in novel proteomic enrichment strategies to broadly evaluate the mPFC proteome, as isolated by dorsal and ventral regions, towards the goal of identifying novel protein signaling targets in alcohol-dependent rats experiencing protracted withdrawal. We will then seek to characterize the molecular and cognitive behavioral relevance of these targets throughout the R00 phase using novel peptidomimetic strategies that target the disruption of specific protein-protein interactions. This study will provide novel insight into distinct signaling pathways that underlie alcohol-induced cognitive dysfunction.

Public Health Relevance

Alcoholism remains a pervasive societal problem, partially attributed to disrupted functioning of cognitive centers in the brain during alcohol withdrawal that are thought to promote relapse drinking. This project broadly examines molecular signaling pathways in distinct cognitive regions to identify and elucidate novel biochemical mechanisms that may underlie withdrawal-induced cognitive dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Transition Award (R00)
Project #
4R00AA025393-03
Application #
10088146
Study Section
Special Emphasis Panel (NSS)
Program Officer
Chin, Hemin R
Project Start
2020-02-01
Project End
2023-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78759