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NIAAA P01

Project 3: Rodent Studies

 A Rodent Model of Early Life-Stress Increases Behavioral Risk Factors of Comorbid Anxiety Disorders and Alcoholism

Principal Investigators: Sara Jones, PhD, Brian McCool, PhD, Jeff Weiner, PhD

The primary goals of the rodent P01 project were to evaluate the utility of a rodent adolescent social isolation procedure (aSI) as a model of heightened vulnerability to comorbid anxiety/stressor disorders and AUD, and to use this model to identify neurobiological adaptations that may contribute to the “AUD vulnerable” phenotype engendered by this model. Prior work suggested that this model promoted the expression of many behaviors linked with increased vulnerability to AUD and mood disorders, including increases in unconditioned anxiety-like behaviors and measures of voluntary drinking (for review see:(Butler et al., 2016)). However, no studies had sought to systematically evaluate the validity of aSI as a model of heightened vulnerability to AUD and anxiety disorders. This project involved a successful collaboration between Drs. Jones, McCool, and Weiner. Extensive behavioral characterization of the aSI model confirmed and extended earlier studies and showed that, in male rats, aSI leads to numerous  behavioral changes linked with heightened risk of anxiety/stressor disorders and/or AUD, including increased anxiety measures on assays like the elevated plus-maze, hyperactivity in a novel environment, deficits in sensory gating, and extinction of fear learning (McCool and Chappell, 2009, Chappell et al., 2013, Skelly et al., 2015). Importantly, this model also promotes persistent increases in several measures of ethanol drinking (McCool and Chappell, 2009, Chappell et al., 2013, Skelly et al., 2015, Karkhanis et al., 2016). Using this model, these investigators uncovered novel aSI-mediated alterations in mesolimbic catecholamine signaling and measures of neuronal excitability in the basolateral amygdala (BLA) and nucleus accumbens (NAc). They used pharmacological approaches to demonstrate that some adaptations may contribute to the increased anxiety-like behaviors and higher ethanol intake observed in aSI rats (Fig. 1) (Yorgason et al., 2013, Karkhanis et al., 2014, Karkhanis et al., 2015, Rau et al., 2015, Karkhanis et al., 2016, Yorgason et al., 2016). Collectively, these studies have provided strong initial evidence for the face, construct and predictive validity of aSI as a model of heightened vulnerability to comorbid AUD and anxiety disorders. 

Proj3Fig1

References Cited

Butler TR, Karkhanis AN, Jones SR, Weiner JL (2016) Adolescent Social Isolation as a Model of Heightened Vulnerability to Comorbid Alcoholism and Anxiety Disorders. Alcoholism, clinical and experimental research 40:1202-1214.

Chappell AM, Carter E, McCool BA, Weiner JL (2013) Adolescent rearing conditions influence the relationship between initial anxiety-like behavior and ethanol drinking in male Long Evans rats. Alcoholism, clinical and experimental research 37 Suppl 1:E394-403.

Karkhanis AN, Alexander NJ, McCool BA, Weiner JL, Jones SR (2015) Chronic social isolation during adolescence augments catecholamine response to acute ethanol in the basolateral amygdala. Synapse 69:385-395.

Karkhanis AN, Locke JL, McCool BA, Weiner JL, Jones SR (2014) Social isolation rearing increases nucleus accumbens dopamine and norepinephrine responses to acute ethanol in adulthood. Alcoholism, clinical and experimental research 38:2770-2779.

Karkhanis AN, Rose JH, Weiner JL, Jones SR (2016) Early-Life Social Isolation Stress Increases Kappa Opioid Receptor Responsiveness and Downregulates the Dopamine System. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 41:2263-2274.

McCool BA, Chappell AM (2009) Early social isolation in male Long-Evans rats alters both appetitive and consummatory behaviors expressed during operant ethanol self-administration. Alcoholism, clinical and experimental research 33:273-282.

Rau AR, Chappell AM, Butler TR, Ariwodola OJ, Weiner JL (2015) Increased Basolateral Amygdala Pyramidal Cell Excitability May Contribute to the Anxiogenic Phenotype Induced by Chronic Early-Life Stress. The Journal of neuroscience : the official journal of the Society for Neuroscience 35:9730-9740.

Skelly MJ, Chappell AE, Carter E, Weiner JL (2015) Adolescent social isolation increases anxiety-like behavior and ethanol intake and impairs fear extinction in adulthood: Possible role of disrupted noradrenergic signaling. Neuropharmacology.

Yorgason JT, Calipari ES, Ferris MJ, Karkhanis AN, Fordahl SC, Weiner JL, Jones SR (2016) Social isolation rearing increases dopamine uptake and psychostimulant potency in the striatum. Neuropharmacology 101:471-479.

Yorgason JT, Espana RA, Konstantopoulos JK, Weiner JL, Jones SR (2013) Enduring increases in anxiety-like behavior and rapid nucleus accumbens dopamine signaling in socially isolated rats. The European journal of neuroscience. 

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