Environmental stimuli such as the taste, smell, and sight, of a favorite alcoholic drink can become salient cues that increase craving for alcohol and lead individuals to continue to drink to the point of intoxication (or well beyond). These same cues can also cause craving and relapse in individuals who have abstained from alcohol for long periods of time. Because continued excessive alcohol intake and relapse following abstinence are both hallmarks of alcoholism, understanding the brain regions and processes that regulate cue-evoked alcohol seeking are critical to develop effective treatment strategies for these alcoholic individuals. Interestingly, neural activity within an area of the brain known as th prefrontal cortex (PFC) is now known to be critically involved in regulating how alcohol associated cues elicit craving, alcohol seeking, and intake. However, the exact changes in neural activity that mediate continued excessive alcohol intake and/or craving and relapse are poorly understood. We also have only a very limited understanding of how populations with genetic risk for developing alcoholism might exhibit abnormal neural processing regimes in the PFC, which make them more vulnerable to cue-related craving. We hypothesize that neural networks in the PFC will be more robustly effected by alcohol-paired cues in vulnerable populations than non-vulnerable. We also hypothesize that PFC neuronal networks are more resistant to re-mapping in genetically vulnerable populations during periods of abstinence from alcohol. These abnormal neuronal network processes might contribute to heightened cue-evoked craving and drive both continued excessive alcohol intake, as well as relapse following periods of abstinence. Our broad, long-term objective is to develop a comprehensive understanding of how neuronal networks (ensembles) within the PFC are altered by alcohol associated cues. We will accomplish this by using state-of-the-art electrophysiological recording and analysis techniques of large populations of cells in the awake behaving rodent to determine, for the first time, how instantaneous shifts in PFC ensemble activity evoked by alcohol paired cues: 1) contribute to the maintenance of binge- drinking and are modified during extinction, and 2) initiate relapse-like behavior. We will evaluate these effects in a rat population genetically predisposed to excessive alcohol consumption (Indiana alcohol preferring P rats) and in a rat population with average genetic susceptibility to excessive alcohol consumption (Wistar rats). Determining the neurobiological/neurophysiological causes and consequences of excessive alcohol consumption as well as the role of genetic vulnerability to excessive alcohol intake are directly relevant to the mission of the NIAAA. Specifically, the proposed studies will reveal the neurobiological origins of why genetically vulnerable populations respond to alcohol, and alcohol-paired cues, differently. This will lead us to a better understanding of why and how alcohol can cause addiction and will help us develop strategies to prevent and treat excessive drinking.
The results of this work will contribute to the field by determining how the activity and architecture of neuronal networks within the prefrontal cortex (PFC) interact with alcohol associated cues to 1) maintain and extinguish binge-like alcohol intake and 2) evoke relapse-like behavior following abstinence. Determining how the PFC assigns and integrates information about alcohol associated cues will inform the field of potential avenues for treating those vulnerable to cue-evoked craving and relapse;particularly those with increased risk due to genetic factors.
