The%20Hypothalamopituitary-adrenal%20axis%20and%20alcohol%20preference

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The Hypothalamopituitary-adrenal axis and alcohol
preference

• Matthew J. OCallaghan, Adam P. Croft, Catherine
  Jacquot, Hillary J. Little
• Presented by Muharema Mustic

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• Hypothalamus

CRF (CRH)
Pituitary Gland
ACTH
Adrenal
Corticosterone
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Introduction

• Hypothalamic-pituitary adrenal (HPA) hormones
  play a role in drug dependence
• stress increases alcohol consumption i.e.
  altering stress hormones increases EtOH
  preference

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Purpose of the Study

• To what extent are the HPA axis components
  involved in alcohol preference?
• To what extent do agonists and antagonists of the
  HPA axis have an influence?

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Background Paper

• Consequence of Long-Term Exposure to
  Corticosterone or Dexamethasone on Ethanol
  Consumption in the Adrenalectomised Rat, and the
  Effect of Type I and Type II Corticosteroid
  Receptor Antagonists
• By Fahlke, C., Hard, E. Eriksson, J.A., Engel, S.
  Hansen

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Adrenalectomy Experiments

• Male Wistar Rats
• Alcohol and Water
• Adrenalectomy
• Alcohol preference
• Experiment 1 Corticosterone, Dexamethasone,
  Blank

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Removing Corticosterone (B) reduces EtOH intake
AdX AdX B AdX Dex Sham
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Corticosterone effects EtOH intake
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Back to OCallaghan Paper

• HPA axis involved in alcohol preference?
• to what extent do drugs influence preference?
• How do drugs raise alcohol preference?

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Materials and Methods

• In house bred animals
• Housed at 21 degrees Celsius
• Housed in single sex groups of 10/cage
• Free access to water and rodent chow
• 12 hour light/dark cycle
• Light phase between 8am-8pm
• Dark phase 8pm-8am

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Alcohol Preference Measurements

• Preference tests preformed on mice individually
  housed
• Two fluid bottles available-tap H2O and EtOH
• Available 24/7
• 3 week long period

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Alcohol Preference Measurements

• Fluid intake measurement made 3x week
• Alcohol preference measured
• Ratios of last week used to assign categories
• High preference mice- ratio of 0.75 and higher
• Low preference mice-ratio of 0.34 and lower

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Drug Administration
RU 38486-glucocorticoid Type II Receptor ant.
Spironolactone-glucocorticoid Type I Receptor ant.
Metyrapone- inhibits synthesis of corticosterone
ACTH1-39-
Corticosterone
CRF
CRF antagonist
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Experiment 1

• RU 38486-100mg/kg
• Spironolactone-50mg/kg
• Purpose of the experiment
• 1. Do these two drugs decrease alcohol
  preference in high preference mice when given for
  1 week?
• 2. Do these drugs prevent increase in
  preference that was due to vehicle injections
  that occurred over the 3 week period?

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Experiment 1Spironolactone and RU38486

• One daily intraperitoneal injection to mice of
  both preference groups
• 3 weeks
• Fluid consumed measured 3x/week

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Mice with a high preference for EtOH are not
usually affected
Type II Glucocorticoid Receptor Antagonist
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But Low Preference Mice are
Type II GR Antagonist
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Do Glucocorticoids influence Preference?
Type II Glucocorticoid Receptor Antagonist
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Experiment 2

• Metyrapone
• Intraperitoneal injection
• Single and repeated intraperitoneal injections
• 100mg/kg
• 1 week long for high preference mice
• Fluid consumption measured daily
• 3 weeks long for low preference mice

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Corticosterone has an effect
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Metyrapone decreases alcohol intake
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Corticosterone Concentration prior to alcohol
preference
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Experiment 3

• ACTH1-39
• Tested on low preference alcohol group only
• Fluid measured prior to daily after injections
  started
• Administration for 4 days
• Once daily
• Intraperitoneal injection

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ACTH did not have an effect
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Corticosterone-no effect on low preference mice
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Experiment 4

• Corticotropin Releasing Factor (CRF)
• CRF antagonist
• Low and high preference groups
• Intracerebroventricular injection

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Alpha-helical CRF does not induce higher intake
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Alpha-helical CRF and low preference mice group
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Discussion

• Stress hormones are not involved in the
  underlying preference response in high or low
  preference mice
• no effect on glucocorticoid receptors of either
  type
• Except central CRF

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Discussion

• Spironolactone
• No change in either group
• Metyrapone
• Decreased alcohol consumption
• metyrapone inhibits synthesis of glucocorticoids

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Discussion

• ACTH and CRF administration- no change on alcohol
  preference
• Alpha-helical CRF (antagonist)- brief increase in
  intake in low preference mice

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Conclusion

• Corticosterone influences drinking preferences
• CRF activity perhaps neuronal?

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Thank You!