Compromised HPA axis function, including dysregulation of glucocorticoid feedback and blunted response to stressors, is a characteristic feature of alcoholism. Impaired HPA axis function is also evident in populations that are at risk for increased alcohol drinking such as nonalcoholic individuals with a family history of alcoholism, and individuals suffering from some forms of depression and other mood and anxiety disorders. Given these key observations that link dysregulated HPA axis function and susceptibility to increased drinking, there is a necessity in the field to understand the mechanisms underlying the interaction. We propose that a possible behavioral mechanism is alteration of the interoceptive effects of alcohol. All drugs of abuse share the common attribute that they produce interoceptive/subjective effects in humans. These interoceptive cues can potently influence drug taking and seeking behaviors. Emerging evidence shows that metabotropic glutamate receptors, specifically subtype 5 (mGluR5) regulate the interoceptive effects of alcohol. Using a model of repeated HPA axis activation (corticosterone (CORT) in the drinking water) that results in HPA axis dysregulation, we show reduced sensitivity to the interoceptive effects of alcohol, and a parallel decrease in both mGluR5 and phosphorylated ERK1/2 immunoreactivity in the nucleus accumbens. These findings suggest the primary hypothesis of this application: repeated HPA axis activation/dysregulation leads to adaptations in mGluR5 in the n. accumbens that functionally regulate the interoceptive effects of alcohol. Given that interoceptive drug effects can influence drug taking behavior, and the associations between compromised HPA axis function and susceptibility to increased alcohol drinking, we also propose the corollary hypothesis that: the CORT-induced reduction in sensitivity to the interoceptive effects of alcohol is associated with increased drinking. The studies in this application have four separate by integrated Specific Aims. First, experiments will characterize the effects of CORT exposure on the interoceptive effects of alcohol. The information gained from these studies will establish a relation between HPA axis activation/dysregulation and the interoceptive effects of alcohol. Second, experiments will examine adaptations within the mGluR5 system that occur after CORT exposure, and will pharmacologically manipulate mGluR5, which will provide novel information as to the relationship between changes in mGluR5 expression, and the expression of ERK1/2 and CREB, which are downstream targets, and the interoceptive of effects of alcohol. Third, using brain site-specific microinjections, studies will assess the functional involvement of mGluR5 in the expression of alcohol's interoceptive effects after repeated HPA axis activation/dysregulation, by evaluating the efficacy of mGluR5 compounds to restore sensitivity to the interoceptive effects of alcohol. Lastly, experiments will address the relation between the interoceptive effects of self-administered alcohol and alcohol self-administration and will determine a functional role for mGluR5 in the nucleus accumbens and amygdala in these behaviors. Together, the studies in this proposal have the potential to move the field forward by providing insight into how HPA axis activation/dysregulation can influence the interoceptive effects of alcohol, a critical mechanism of drug seeking.

Public Health Relevance

Compromised HPA axis function is a characteristic feature of alcoholism and is also evident in populations that are also at risk for increased alcohol drinking such as nonalcoholic individuals with a family history of alcoholism. HPA axis dysregulation can result from chronic HPA axis activation. The purpose of this application is to examine how HPA axis activation/dysregulation alters the interoceptive effects of alcohol (a major controlling process of drug seeking behavior), possible mechanisms underlying the changes, and how these changes can impact alcohol drinking.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA019682-03
Application #
8493911
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Grandison, Lindsey
Project Start
2011-07-15
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$273,950
Indirect Cost
$87,950
Name
University of North Carolina Chapel Hill
Department
Psychiatry
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Jaramillo, Anel A; Randall, Patrick A; Stewart, Spencer et al. (2018) Functional role for cortical-striatal circuitry in modulating alcohol self-administration. Neuropharmacology 130:42-53
Jaramillo, Anel A; Van Voorhies, Kalynn; Randall, Patrick A et al. (2018) Silencing the insular-striatal circuit decreases alcohol self-administration and increases sensitivity to alcohol. Behav Brain Res 348:74-81
Makhijani, Viren H; Van Voorhies, Kalynn; Besheer, Joyce (2018) The mineralocorticoid receptor antagonist spironolactone reduces alcohol self-administration in female and male rats. Pharmacol Biochem Behav 175:10-18
Randall, Patrick A; Stewart, Robert T; Besheer, Joyce (2017) Sex differences in alcohol self-administration and relapse-like behavior in Long-Evans rats. Pharmacol Biochem Behav 156:1-9
Jaramillo, Anel A; Agan, Verda E; Makhijani, Viren H et al. (2017) Functional role for suppression of the insular-striatal circuit in modulating interoceptive effects of alcohol. Addict Biol :
Hwa, Lara; Besheer, Joyce; Kash, Thomas (2017) Glutamate plasticity woven through the progression to alcohol use disorder: a multi-circuit perspective. F1000Res 6:298
Cannady, Reginald; Fisher, Kristen R; Graham, Caitlin et al. (2017) Potentiation of amygdala AMPA receptor activity selectively promotes escalated alcohol self-administration in a CaMKII-dependent manner. Addict Biol 22:652-664
Jaramillo, Anel A; Randall, Patrick A; Frisbee, Suzanne et al. (2016) Modulation of sensitivity to alcohol by cortical and thalamic brain regions. Eur J Neurosci 44:2569-2580
Randall, Patrick A; Cannady, Reginald; Besheer, Joyce (2016) The nicotine + alcohol interoceptive drug state: contribution of the components and effects of varenicline in rats. Psychopharmacology (Berl) 233:3061-74
Besheer, Joyce; Frisbee, Suzanne; Randall, Patrick A et al. (2016) Gabapentin potentiates sensitivity to the interoceptive effects of alcohol and increases alcohol self-administration in rats. Neuropharmacology 101:216-24

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