The development and progression of alcohol use disorders is thought to involve adaptive changes in neural circuits that underlie negative affective states, like anxiety. One hypothesis that is garnering increasing support is that these adaptive changes gradually shift motivation for alcohol away from positive reinforcement (e.g. euphoria) toward negative reinforcement (e.g. relief from negative affective states). Although much is known about the neural underpinning of alcohol's positive reinforcing effects, the neural substrates linking negative reinforcement and alcoholism remain less clearly defined. The lateral/basolateral amygdala (BLA) plays a major role in anxiety-like behaviors and alcohol drinking and there is growing evidence that dysregulation of this brain region contributes to the pathophysiology of both anxiety disorders and addiction. Surprisingly, much remains unknown about the intrinsic circuitry of this brain region or the neuromodulatory systems that influence BLA synaptic transmission. During the last funding period, we discovered that beta3-adrenoceptor activation enhances a novel GABA circuit in the BLA and that this effect can decrease anxiety-like behaviors and ethanol seeking behaviors. We have also recently identified powerful effects of the neuromodulator adenosine on BLA synaptic transmission. In other studies, we demonstrated that a rodent early life stress model engenders several behavioral and neurobiological alterations that have also been associated with increased vulnerability to alcoholism. The first two aims of this proposal will determine the neurobiological effects of adenosine A1 and A2a receptor activation on excitatory and inhibitory neurotransmission in the rat basolateral amygdala (BLA) and whether intra-BLA activation of these receptors reduces measures of anxiety-like behavior.
Aims 3 and 4 will employ the early life stress model to identify enduring perturbations in norepinephrine and adenosine modulation of BLA synaptic transmission that may contribute to increased vulnerability (and resilience) to excessive alcohol drinking behaviors. Other experiments will determine if pharmacological manipulations that restore normal BLA function can reduce the increases in anxiety-like behavior and ethanol drinking that result from early life stress.

Public Health Relevance

The proposed studies are designed to identify novel neurobiological mechanisms linking early life stress and increased vulnerability to alcohol use disorders. These studies may also lead to the discovery of more effective pharmacotherapies for the treatment of alcoholism, particularly in individuals where anxiety and negative reinforcement play a major role in the disease.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Cui, Changhai
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wake Forest University Health Sciences
Schools of Medicine
United States
Zip Code
Deal, Alex L; Konstantopoulos, Joanne K; Weiner, Jeff L et al. (2018) Exploring the consequences of social defeat stress and intermittent ethanol drinking on dopamine dynamics in the rat nucleus accumbens. Sci Rep 8:332
Almonte, Antoine G; Ewin, Sarah E; Mauterer, Madelyn I et al. (2017) Enhanced ventral hippocampal synaptic transmission and impaired synaptic plasticity in a rodent model of alcohol addiction vulnerability. Sci Rep 7:12300
Skelly, M J; Ariwodola, O J; Weiner, J L (2017) Fear conditioning selectively disrupts noradrenergic facilitation of GABAergic inhibition in the basolateral amygdala. Neuropharmacology 113:231-240
Gilpin, N W; Weiner, J L (2017) Neurobiology of comorbid post-traumatic stress disorder and alcohol-use disorder. Genes Brain Behav 16:15-43
Skelly, M J; Chappell, A M; Ariwodola, O J et al. (2016) Behavioral and neurophysiological evidence that lateral paracapsular GABAergic synapses in the basolateral amygdala contribute to the acquisition and extinction of fear learning. Neurobiol Learn Mem 127:10-6
Mikhailova, Maria A; Bass, Caroline E; Grinevich, Valentina P et al. (2016) Optogenetically-induced tonic dopamine release from VTA-nucleus accumbens projections inhibits reward consummatory behaviors. Neuroscience 333:54-64
Karkhanis, Anushree N; Rose, Jamie H; Weiner, Jeffrey L et al. (2016) Early-Life Social Isolation Stress Increases Kappa Opioid Receptor Responsiveness and Downregulates the Dopamine System. Neuropsychopharmacology 41:2263-74
Yorgason, Jordan T; Calipari, Erin S; Ferris, Mark J et al. (2016) Social isolation rearing increases dopamine uptake and psychostimulant potency in the striatum. Neuropharmacology 101:471-9
Rau, Andrew R; Chappell, Ann M; Butler, Tracy R et al. (2015) Increased Basolateral Amygdala Pyramidal Cell Excitability May Contribute to the Anxiogenic Phenotype Induced by Chronic Early-Life Stress. J Neurosci 35:9730-40
Budygin, E A; Weiner, J L (2015) Exploring the Neurochemical Basis of Alcohol Addiction-Related Behaviors: Translational Research. Transl Biomed 6:

Showing the most recent 10 out of 23 publications