The Hypothalamopituitary-adrenal axis and alcohol preference

Matthew J. O’Callaghan, Adam P. Croft, Catherine Jacquot, Hillary J. Little

Presented by Muharema Mustic

Hypothalamus

Pituitary Gland

Adrenal

CRF (CRH)

ACTH

Corticosterone

Introduction

• Hypothalamic-pituitary adrenal (HPA) hormones play a role in drug dependence

• stress increases alcohol consumption i.e. altering stress hormones increases EtOH preference

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?”

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

Adrenalectomy Experiments

• Male Wistar Rats

• Alcohol and Water

• Adrenalectomy

• Alcohol preference

• Experiment 1: Corticosterone, Dexamethasone, Blank

Removing Corticosterone (B) reduces EtOH intake

AdX AdX + B AdX + Dex Sham

Corticosterone effects EtOH intake

Back to O’Callaghan Paper

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

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

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

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

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

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?

Experiment 1:Spironolactone and RU38486

• One daily intraperitoneal injection to mice of both preference groups– 3 weeks

• Fluid consumed measured 3x/week

Mice with a high preference for EtOH are not usually affected

Type II Glucocorticoid Receptor Antagonist

But Low Preference Mice are…

Type II GR Antagonist

Do Glucocorticoids influence Preference?

Type II Glucocorticoid Receptor Antagonist

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

Corticosterone has an effect

Metyrapone decreases alcohol intake

Corticosterone Concentration prior to alcohol preference

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

ACTH did not have an effect

Corticosterone-no effect on low preference mice

Experiment 4

• Corticotropin Releasing Factor (CRF)

• CRF antagonist

• Low and high preference groups– Intracerebroventricular injection

Alpha-helical CRF does not induce higher intake

Alpha-helical CRF and low preference mice group

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

Discussion

• Spironolactone– No change in either group

• Metyrapone– Decreased alcohol consumption – metyrapone inhibits synthesis of glucocorticoids

Discussion

• ACTH and CRF administration- no change on alcohol preference

• Alpha-helical CRF (antagonist)- brief increase in intake in low preference mice

Conclusion

• Corticosterone influences drinking preferences

• CRF activity perhaps neuronal?

Thank You!