Modulation of sensitivity to alcohol by cortical and thalamic brain regions

Anel A. Jaramillo; Patrick A. Randall; Suzanne Frisbee; Joyce Besheer

doi:10.1111/ejn.13374

Modulation of sensitivity to alcohol by cortical and thalamic brain regions

Anel A. Jaramillo, Patrick A. Randall, Suzanne Frisbee, Joyce Besheer

Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

Abstract

The nucleus accumbens core (AcbC) is a key brain region known to regulate the discriminative stimulus/interoceptive effects of alcohol. As such, the goal of the present work was to identify AcbC projection regions that may also modulate sensitivity to alcohol. Accordingly, AcbC afferent projections were identified in behaviorally naïve rats using a retrograde tracer which led to the focus on the medial prefrontal cortex (mPFC), insular cortex (IC) and rhomboid thalamic nucleus (Rh). Next, to examine the possible role of these brain regions in modulating sensitivity to alcohol, neuronal response to alcohol in rats trained to discriminate alcohol (1 g/kg, intragastric [IG]) vs. water was examined using a two-lever drug discrimination task. As such, rats were administered water or alcohol (1 g/kg, IG) and brain tissue was processed for c-Fos immunoreactivity (IR), a marker of neuronal activity. Alcohol decreased c-Fos IR in the mPFC, IC, Rh and AcbC. Lastly, site-specific pharmacological inactivation with muscimol + baclofen (GABA_A agonist + GABA_B agonist) was used to determine the functional role of the mPFC, IC and Rh in modulating the interoceptive effects of alcohol in rats trained to discriminate alcohol (1 g/kg, IG) vs. water. mPFC inactivation resulted in full substitution for the alcohol training dose, and IC and Rh inactivation produced partial alcohol-like effects, demonstrating the importance of these regions, with known projections to the AcbC, in modulating sensitivity to alcohol. Together, these data demonstrate a site of action of alcohol and the recruitment of cortical/thalamic regions in modulating sensitivity to the interoceptive effects of alcohol.

Original language	English
Pages (from-to)	2569-2580
Number of pages	12
Journal	European Journal of Neuroscience
Volume	44
Issue number	8
DOIs	https://doi.org/10.1111/ejn.13374
State	Published - Oct 1 2016

Bibliographical note

Funding Information:
This work was supported, in part, by grant AA019682 to JB from the National Institute on Alcohol Abuse and Alcoholism and by the Bowles Center for Alcohol Studies at the University of North Carolina at Chapel Hill. AAJ was supported, in part, by an NSF Graduate Research Fellowship (DGE-1144081) and then by F31AA024973 while working on the writing of this manuscript. The authors would like to thank Dr. Thomas Kash for helpful discussions regarding the utilization of the retrograde tracer and to Dr. Reginald Cannady for help with the conduct of that study.Abbreviations AcbC nucleus accumbens core FG Fluoro-Gold FR Fixed Ratio GABAA [gamma]-aminobutyric acid type A GABAB [gamma]-aminobutyric acid type B IC insular cortex IG intragastric IHC immunohistochemistry IR immunoreactivity mPFC medial prefrontal cortex NMDA n-methyl-d-aspartate Rh rhomboid thalamic nucleus RM anova repeated measures analysis of variance Re reuniens ventral thalamic nucleus

Publisher Copyright:
© 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd

Keywords

addiction
discriminative stimulus
drug-discrimination
interoception

ASJC Scopus subject areas

Neuroscience (all)

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10.1111/ejn.13374

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title = "Modulation of sensitivity to alcohol by cortical and thalamic brain regions",

abstract = "The nucleus accumbens core (AcbC) is a key brain region known to regulate the discriminative stimulus/interoceptive effects of alcohol. As such, the goal of the present work was to identify AcbC projection regions that may also modulate sensitivity to alcohol. Accordingly, AcbC afferent projections were identified in behaviorally na{\"i}ve rats using a retrograde tracer which led to the focus on the medial prefrontal cortex (mPFC), insular cortex (IC) and rhomboid thalamic nucleus (Rh). Next, to examine the possible role of these brain regions in modulating sensitivity to alcohol, neuronal response to alcohol in rats trained to discriminate alcohol (1 g/kg, intragastric [IG]) vs. water was examined using a two-lever drug discrimination task. As such, rats were administered water or alcohol (1 g/kg, IG) and brain tissue was processed for c-Fos immunoreactivity (IR), a marker of neuronal activity. Alcohol decreased c-Fos IR in the mPFC, IC, Rh and AcbC. Lastly, site-specific pharmacological inactivation with muscimol + baclofen (GABAA agonist + GABAB agonist) was used to determine the functional role of the mPFC, IC and Rh in modulating the interoceptive effects of alcohol in rats trained to discriminate alcohol (1 g/kg, IG) vs. water. mPFC inactivation resulted in full substitution for the alcohol training dose, and IC and Rh inactivation produced partial alcohol-like effects, demonstrating the importance of these regions, with known projections to the AcbC, in modulating sensitivity to alcohol. Together, these data demonstrate a site of action of alcohol and the recruitment of cortical/thalamic regions in modulating sensitivity to the interoceptive effects of alcohol.",

keywords = "addiction, discriminative stimulus, drug-discrimination, interoception",

author = "Jaramillo, {Anel A.} and Randall, {Patrick A.} and Suzanne Frisbee and Joyce Besheer",

note = "Funding Information: This work was supported, in part, by grant AA019682 to JB from the National Institute on Alcohol Abuse and Alcoholism and by the Bowles Center for Alcohol Studies at the University of North Carolina at Chapel Hill. AAJ was supported, in part, by an NSF Graduate Research Fellowship (DGE-1144081) and then by F31AA024973 while working on the writing of this manuscript. The authors would like to thank Dr. Thomas Kash for helpful discussions regarding the utilization of the retrograde tracer and to Dr. Reginald Cannady for help with the conduct of that study.Abbreviations AcbC nucleus accumbens core FG Fluoro-Gold FR Fixed Ratio GABAA [gamma]-aminobutyric acid type A GABAB [gamma]-aminobutyric acid type B IC insular cortex IG intragastric IHC immunohistochemistry IR immunoreactivity mPFC medial prefrontal cortex NMDA n-methyl-d-aspartate Rh rhomboid thalamic nucleus RM anova repeated measures analysis of variance Re reuniens ventral thalamic nucleus Publisher Copyright: {\textcopyright} 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd",

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doi = "10.1111/ejn.13374",

language = "English",

volume = "44",

pages = "2569--2580",

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T1 - Modulation of sensitivity to alcohol by cortical and thalamic brain regions

AU - Jaramillo, Anel A.

AU - Randall, Patrick A.

AU - Frisbee, Suzanne

AU - Besheer, Joyce

N1 - Funding Information: This work was supported, in part, by grant AA019682 to JB from the National Institute on Alcohol Abuse and Alcoholism and by the Bowles Center for Alcohol Studies at the University of North Carolina at Chapel Hill. AAJ was supported, in part, by an NSF Graduate Research Fellowship (DGE-1144081) and then by F31AA024973 while working on the writing of this manuscript. The authors would like to thank Dr. Thomas Kash for helpful discussions regarding the utilization of the retrograde tracer and to Dr. Reginald Cannady for help with the conduct of that study.Abbreviations AcbC nucleus accumbens core FG Fluoro-Gold FR Fixed Ratio GABAA [gamma]-aminobutyric acid type A GABAB [gamma]-aminobutyric acid type B IC insular cortex IG intragastric IHC immunohistochemistry IR immunoreactivity mPFC medial prefrontal cortex NMDA n-methyl-d-aspartate Rh rhomboid thalamic nucleus RM anova repeated measures analysis of variance Re reuniens ventral thalamic nucleus Publisher Copyright: © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd

PY - 2016/10/1

Y1 - 2016/10/1

N2 - The nucleus accumbens core (AcbC) is a key brain region known to regulate the discriminative stimulus/interoceptive effects of alcohol. As such, the goal of the present work was to identify AcbC projection regions that may also modulate sensitivity to alcohol. Accordingly, AcbC afferent projections were identified in behaviorally naïve rats using a retrograde tracer which led to the focus on the medial prefrontal cortex (mPFC), insular cortex (IC) and rhomboid thalamic nucleus (Rh). Next, to examine the possible role of these brain regions in modulating sensitivity to alcohol, neuronal response to alcohol in rats trained to discriminate alcohol (1 g/kg, intragastric [IG]) vs. water was examined using a two-lever drug discrimination task. As such, rats were administered water or alcohol (1 g/kg, IG) and brain tissue was processed for c-Fos immunoreactivity (IR), a marker of neuronal activity. Alcohol decreased c-Fos IR in the mPFC, IC, Rh and AcbC. Lastly, site-specific pharmacological inactivation with muscimol + baclofen (GABAA agonist + GABAB agonist) was used to determine the functional role of the mPFC, IC and Rh in modulating the interoceptive effects of alcohol in rats trained to discriminate alcohol (1 g/kg, IG) vs. water. mPFC inactivation resulted in full substitution for the alcohol training dose, and IC and Rh inactivation produced partial alcohol-like effects, demonstrating the importance of these regions, with known projections to the AcbC, in modulating sensitivity to alcohol. Together, these data demonstrate a site of action of alcohol and the recruitment of cortical/thalamic regions in modulating sensitivity to the interoceptive effects of alcohol.

AB - The nucleus accumbens core (AcbC) is a key brain region known to regulate the discriminative stimulus/interoceptive effects of alcohol. As such, the goal of the present work was to identify AcbC projection regions that may also modulate sensitivity to alcohol. Accordingly, AcbC afferent projections were identified in behaviorally naïve rats using a retrograde tracer which led to the focus on the medial prefrontal cortex (mPFC), insular cortex (IC) and rhomboid thalamic nucleus (Rh). Next, to examine the possible role of these brain regions in modulating sensitivity to alcohol, neuronal response to alcohol in rats trained to discriminate alcohol (1 g/kg, intragastric [IG]) vs. water was examined using a two-lever drug discrimination task. As such, rats were administered water or alcohol (1 g/kg, IG) and brain tissue was processed for c-Fos immunoreactivity (IR), a marker of neuronal activity. Alcohol decreased c-Fos IR in the mPFC, IC, Rh and AcbC. Lastly, site-specific pharmacological inactivation with muscimol + baclofen (GABAA agonist + GABAB agonist) was used to determine the functional role of the mPFC, IC and Rh in modulating the interoceptive effects of alcohol in rats trained to discriminate alcohol (1 g/kg, IG) vs. water. mPFC inactivation resulted in full substitution for the alcohol training dose, and IC and Rh inactivation produced partial alcohol-like effects, demonstrating the importance of these regions, with known projections to the AcbC, in modulating sensitivity to alcohol. Together, these data demonstrate a site of action of alcohol and the recruitment of cortical/thalamic regions in modulating sensitivity to the interoceptive effects of alcohol.

KW - addiction

KW - discriminative stimulus

KW - drug-discrimination

KW - interoception

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Modulation of sensitivity to alcohol by cortical and thalamic brain regions

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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