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.
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.
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.
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.
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
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
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.
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.
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.
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.
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.