The hypothalamopituitary adrenal axis and alcohol preference
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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. Hypothalamus. CRF (CRH). Pituitary Gland. ACTH. Adrenal. Corticosterone. Introduction.

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The hypothalamopituitary adrenal axis and alcohol preference

The Hypothalamopituitary-adrenal axis and alcohol preference

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

Presented by Muharema Mustic


Hypothalamus

CRF (CRH)

Pituitary Gland

ACTH

Adrenal

Corticosterone


Introduction
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
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
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
Adrenalectomy Experiments

  • Male Wistar Rats

  • Alcohol and Water

  • Adrenalectomy

  • Alcohol preference

  • Experiment 1: Corticosterone, Dexamethasone, Blank




Back to o callaghan paper
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
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
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 measurements1
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



Experiment 1
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
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
Mice with a high preference for EtOH are not usually affected

Type II Glucocorticoid Receptor Antagonist


But low preference mice are
But Low Preference Mice are… affected

Type II GR Antagonist


Do glucocorticoids influence preference
Do Glucocorticoids influence Preference? affected

Type II Glucocorticoid Receptor Antagonist


Experiment 2
Experiment 2 affected

  • 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





Experiment 3
Experiment 3 affected

  • 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




Experiment 4
Experiment 4 affected

  • Corticotropin Releasing Factor (CRF)

  • CRF antagonist

  • Low and high preference groups

    • Intracerebroventricular injection




Discussion
Discussion affected

  • 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


Discussion1
Discussion affected

  • Spironolactone

    • No change in either group

  • Metyrapone

    • Decreased alcohol consumption

    • metyrapone inhibits synthesis of glucocorticoids


Discussion2
Discussion affected

  • ACTH and CRF administration- no change on alcohol preference

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


Conclusion
Conclusion affected

  • Corticosterone influences drinking preferences

  • CRF activity perhaps neuronal?



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