The Hypothalamopituitary-adrenal axis and alcohol preference Matthew J. O’Callaghan, Adam P....
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Transcript of The Hypothalamopituitary-adrenal axis and alcohol preference Matthew J. O’Callaghan, Adam P....
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The Hypothalamopituitary-adrenal axis and alcohol preference
Matthew J. O’Callaghan, Adam P. Croft, Catherine Jacquot, Hillary J. Little
Presented by Muharema Mustic
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Hypothalamus
Pituitary Gland
Adrenal
CRF (CRH)
ACTH
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 O’Callaghan 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 1:Spironolactone 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!