Central administration of cyclosporine a decreases ethanol drinking

Patrick J. Ronan, Sydney A. Strait, Geralyn M. Palmer, Thomas P. Beresford

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Aims: Abstinence among alcohol dependent liver graft recipients is remarkably high. The routine use of anti-immune agents in these patients led to rodent studies showing that immunosuppressants acting through inhibition of calcineurin (CLN) are highly effective in decreasing alcohol consumption. It remained unclear, however, whether the decreased alcohol consumption in rodent models is mediated through peripheral suppression of immune response or centrally through direct inhibition of cyclophilin-CLN in the brain. We tested the hypothesis that direct brain inhibition of CLN with intracerebroventricular (ICV) injections of the immunosuppressant cyclosporine A (CsA) is sufficient to decrease ethanol consumption in a rodent model of binge-like drinking. Methods: Male C57BL/6NHsd mice were put through a modified 'drinking in the dark' (DID) paradigm. Effects of both peripheral (IP) and central (ICV) injections of CsA on ethanol consumption were assessed. Results: Here, as in earlier work, IP CsA administration significantly decreased alcohol consumption. Supporting our hypothesis, central administration of CsA was sufficient to decrease alcohol consumption in a dose-dependent manner. There was no significant effect of CsA on water or sucrose consumption. Conclusions: These results clearly implicate a CLN-mediated mechanism in brain in the inhibitory effects of CsA on ethanol consumption and provide novel targets for investigation of treatment for Alcohol Use Disorders (AUD). These results also add to the growing body of literature implicating neuroimmune mechanisms in the etiology, pathophysiology and behaviors driving AUD. Short Summary: The unusually high abstinence rate and routine use of immunosuppressants in AUD liver graft recipients led us to rodent studies showing that immunosuppressants acting through inhibition of calcineurin (CLN) are highly effective in decreasing drinking. Here we demonstrate that this effect is mediated by brain rather than peripheral immune mechanisms.

Original languageEnglish (US)
Pages (from-to)193-199
Number of pages7
JournalAlcohol and Alcoholism
Volume53
Issue number2
DOIs
StatePublished - Mar 1 2018

Fingerprint

Calcineurin
Cyclosporine
Drinking
Ethanol
Alcohols
Immunosuppressive Agents
Alcohol Drinking
Rodentia
Brain
Neuroimmunomodulation
Grafts
Alcohol Abstinence
Liver
Cyclophilins
Binge Drinking
Transplants
Injections
Proxy
Inbred C57BL Mouse
Sucrose

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology
  • Psychiatry and Mental health

Cite this

Central administration of cyclosporine a decreases ethanol drinking. / Ronan, Patrick J.; Strait, Sydney A.; Palmer, Geralyn M.; Beresford, Thomas P.

In: Alcohol and Alcoholism, Vol. 53, No. 2, 01.03.2018, p. 193-199.

Research output: Contribution to journalArticle

Ronan, Patrick J. ; Strait, Sydney A. ; Palmer, Geralyn M. ; Beresford, Thomas P. / Central administration of cyclosporine a decreases ethanol drinking. In: Alcohol and Alcoholism. 2018 ; Vol. 53, No. 2. pp. 193-199.
@article{9164e2fee4f34623b16e11337080a052,
title = "Central administration of cyclosporine a decreases ethanol drinking",
abstract = "Aims: Abstinence among alcohol dependent liver graft recipients is remarkably high. The routine use of anti-immune agents in these patients led to rodent studies showing that immunosuppressants acting through inhibition of calcineurin (CLN) are highly effective in decreasing alcohol consumption. It remained unclear, however, whether the decreased alcohol consumption in rodent models is mediated through peripheral suppression of immune response or centrally through direct inhibition of cyclophilin-CLN in the brain. We tested the hypothesis that direct brain inhibition of CLN with intracerebroventricular (ICV) injections of the immunosuppressant cyclosporine A (CsA) is sufficient to decrease ethanol consumption in a rodent model of binge-like drinking. Methods: Male C57BL/6NHsd mice were put through a modified 'drinking in the dark' (DID) paradigm. Effects of both peripheral (IP) and central (ICV) injections of CsA on ethanol consumption were assessed. Results: Here, as in earlier work, IP CsA administration significantly decreased alcohol consumption. Supporting our hypothesis, central administration of CsA was sufficient to decrease alcohol consumption in a dose-dependent manner. There was no significant effect of CsA on water or sucrose consumption. Conclusions: These results clearly implicate a CLN-mediated mechanism in brain in the inhibitory effects of CsA on ethanol consumption and provide novel targets for investigation of treatment for Alcohol Use Disorders (AUD). These results also add to the growing body of literature implicating neuroimmune mechanisms in the etiology, pathophysiology and behaviors driving AUD. Short Summary: The unusually high abstinence rate and routine use of immunosuppressants in AUD liver graft recipients led us to rodent studies showing that immunosuppressants acting through inhibition of calcineurin (CLN) are highly effective in decreasing drinking. Here we demonstrate that this effect is mediated by brain rather than peripheral immune mechanisms.",
author = "Ronan, {Patrick J.} and Strait, {Sydney A.} and Palmer, {Geralyn M.} and Beresford, {Thomas P.}",
year = "2018",
month = "3",
day = "1",
doi = "10.1093/alcalc/agx102",
language = "English (US)",
volume = "53",
pages = "193--199",
journal = "Alcohol and alcoholism (Oxford, Oxfordshire). Supplement",
issn = "0735-0414",
publisher = "Oxford University Press",
number = "2",

}

TY - JOUR

T1 - Central administration of cyclosporine a decreases ethanol drinking

AU - Ronan, Patrick J.

AU - Strait, Sydney A.

AU - Palmer, Geralyn M.

AU - Beresford, Thomas P.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - Aims: Abstinence among alcohol dependent liver graft recipients is remarkably high. The routine use of anti-immune agents in these patients led to rodent studies showing that immunosuppressants acting through inhibition of calcineurin (CLN) are highly effective in decreasing alcohol consumption. It remained unclear, however, whether the decreased alcohol consumption in rodent models is mediated through peripheral suppression of immune response or centrally through direct inhibition of cyclophilin-CLN in the brain. We tested the hypothesis that direct brain inhibition of CLN with intracerebroventricular (ICV) injections of the immunosuppressant cyclosporine A (CsA) is sufficient to decrease ethanol consumption in a rodent model of binge-like drinking. Methods: Male C57BL/6NHsd mice were put through a modified 'drinking in the dark' (DID) paradigm. Effects of both peripheral (IP) and central (ICV) injections of CsA on ethanol consumption were assessed. Results: Here, as in earlier work, IP CsA administration significantly decreased alcohol consumption. Supporting our hypothesis, central administration of CsA was sufficient to decrease alcohol consumption in a dose-dependent manner. There was no significant effect of CsA on water or sucrose consumption. Conclusions: These results clearly implicate a CLN-mediated mechanism in brain in the inhibitory effects of CsA on ethanol consumption and provide novel targets for investigation of treatment for Alcohol Use Disorders (AUD). These results also add to the growing body of literature implicating neuroimmune mechanisms in the etiology, pathophysiology and behaviors driving AUD. Short Summary: The unusually high abstinence rate and routine use of immunosuppressants in AUD liver graft recipients led us to rodent studies showing that immunosuppressants acting through inhibition of calcineurin (CLN) are highly effective in decreasing drinking. Here we demonstrate that this effect is mediated by brain rather than peripheral immune mechanisms.

AB - Aims: Abstinence among alcohol dependent liver graft recipients is remarkably high. The routine use of anti-immune agents in these patients led to rodent studies showing that immunosuppressants acting through inhibition of calcineurin (CLN) are highly effective in decreasing alcohol consumption. It remained unclear, however, whether the decreased alcohol consumption in rodent models is mediated through peripheral suppression of immune response or centrally through direct inhibition of cyclophilin-CLN in the brain. We tested the hypothesis that direct brain inhibition of CLN with intracerebroventricular (ICV) injections of the immunosuppressant cyclosporine A (CsA) is sufficient to decrease ethanol consumption in a rodent model of binge-like drinking. Methods: Male C57BL/6NHsd mice were put through a modified 'drinking in the dark' (DID) paradigm. Effects of both peripheral (IP) and central (ICV) injections of CsA on ethanol consumption were assessed. Results: Here, as in earlier work, IP CsA administration significantly decreased alcohol consumption. Supporting our hypothesis, central administration of CsA was sufficient to decrease alcohol consumption in a dose-dependent manner. There was no significant effect of CsA on water or sucrose consumption. Conclusions: These results clearly implicate a CLN-mediated mechanism in brain in the inhibitory effects of CsA on ethanol consumption and provide novel targets for investigation of treatment for Alcohol Use Disorders (AUD). These results also add to the growing body of literature implicating neuroimmune mechanisms in the etiology, pathophysiology and behaviors driving AUD. Short Summary: The unusually high abstinence rate and routine use of immunosuppressants in AUD liver graft recipients led us to rodent studies showing that immunosuppressants acting through inhibition of calcineurin (CLN) are highly effective in decreasing drinking. Here we demonstrate that this effect is mediated by brain rather than peripheral immune mechanisms.

UR - http://www.scopus.com/inward/record.url?scp=85043458580&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85043458580&partnerID=8YFLogxK

U2 - 10.1093/alcalc/agx102

DO - 10.1093/alcalc/agx102

M3 - Article

C2 - 29281037

AN - SCOPUS:85043458580

VL - 53

SP - 193

EP - 199

JO - Alcohol and alcoholism (Oxford, Oxfordshire). Supplement

JF - Alcohol and alcoholism (Oxford, Oxfordshire). Supplement

SN - 0735-0414

IS - 2

ER -