The proposed studies are designed to investigate physiological and neurobiological consequences related to HPA axis dysfunction and corticosterone (CORT) in a well-established model of chronic early life stress produced by adolescent social isolation (SI). This model promotes increased anxiety-like behaviors and greater ethanol intake in SI rodents compared to their group housed (GH) counterparts. HPA-axis dysfunction is a hallmark of many disease states, including affective disorders and alcohol dependence, and alleviation of the stress response has been shown to reduce craving in currently abstinent alcohol dependent individuals. Therefore, it is hypothesized that HPA axis dysfunction will result from SI to contribute to increased anxiety-like behaviors, and also to alcohol intake, which may be reduced by blockade of CORT effects.
Aim 1 of this proposal will establish this SI model as one which engenders dysfunction of HPA axis activity.
This aim will be achieved using of a variety of measurements to comprehensively assess HPA axis function in a within-subject manner, including a dexamethasone suppression test (DST), assessment of plasma CORT following an acute stressor, the effect of pharmacological blockade of CORT receptors or CORT synthesis on anxiety-like behaviors and ethanol intake, and glucocorticoid receptor expression. It is hypothesized that SI will result in HPA axis dysfunction that will manifest as failure to respond on the DST, higher basal CORT, a blunted CORT response to an acute stressor, and greater anxiety-like behavior in SI rats that will be reduced by blockade of CORT receptors or blockade of CORT synthesis. Further, previous studies from our lab have shown that SI rats'ethanol consumption is greater in a model of home cage ethanol self-administration, and therefore Aim 1 will replicate this phenomenon and continue to monitor HPA axis dysfunction, as well as test the effect of GR blockade systemically and within the basolateral amygdala (BLA) on ethanol intake.
Aim 2 will investigate effects of SI/GH on glutamatergic neuroplasticity in the BLA, with or without acute CORT application, using whole cell patch clamp electrophysiology. It is hypothesized that SI will facilitate glutamatergic signaling and occlude CORT-related plasticity at glutamatergic synapses in the BLA, thus contributing to an overall increase in excitability of BLA neurons. Together, these aims seek to understand effects of CORT in a rodent model of chronic stress that engenders a phenotype relevant to the clinical alcohol dependent population. An understanding of how stress systems and neuroplasticity are affected by, or may predispose, an individual for alcohol abuse are of critical importance in the development of new therapeutic strategies targeted at treatment of alcohol use disorders.

Public Health Relevance

The proposed studies will examine physiological and neurobiological consequences of chronic early life stress in a rodent model of adolescent social isolation that promotes greater anxiety-like behavior and greater alcohol intake as compared to rats that are grouped housed throughout adolescence. Dysfunction of stress systems may predispose, and/or occur as a consequence of alcohol dependence. Therefore, an understanding of how stress systems are affected by and may predispose an individual for future alcohol abuse are of critical importance in the development of new therapeutic strategies targeted at prevention or relapse reduction.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZAA1-DD (04))
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Grandison, Lindsey
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Wake Forest University Health Sciences
Schools of Medicine
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Butler, Tracy R; Carter, Eugenia; Weiner, Jeffrey L (2014) Adolescent social isolation does not lead to persistent increases in anxiety- like behavior or ethanol intake in female long-evans rats. Alcohol Clin Exp Res 38:2199-207
Butler, T R; Chappell, A M; Weiner, J L (2014) Effect of ?3 adrenoceptor activation in the basolateral amygdala on ethanol seeking behaviors. Psychopharmacology (Berl) 231:293-303