Alcohol and Stress Hormones

Hilary J. Little

Institute of Psychiatry, University of London,

United Kingdom

Effects of alcohol

i) Acute effects

ii) Long term effects- dependence

iii) Interactions with stress hormones

1

Alcohol Dependence

normalrange

Alcohol intake

Withdrawal

Tolerance

?Acute actions

Relapse

Time

Effecton brain

2

Decreases effects of excitatory transmitters, glutamate and aspartate.

- particular effect at NMDA receptors - may be relevant to amnesic actions

Increases effects pf GABA – in some neurons

5-HT transmission altered (?mood changes?)

Acute effects of alcohol

3

Acute effects of alcohol

Increases release of endogenous opiates

Increases mesolimbic dopamine transmission

Activates the hypothalamo-pituitary adrenal system (HPA)

4

Drug dependence

1. Withdrawal symptoms

2. Compulsion to take drug

5

Anxiety, irritabilityTremor, convulsions (can be fatal)Hallucinations, confusion (‘DT’s’)

The Alcohol Withdrawal Syndrome

6

Aims of our experiments

i) Neuronal changes during the acute phase of alcohol withdrawal

ii) Long term neuronal changes during alcohol abstinence

iii) Potential new medication approaches:

- glucocorticoid antagonists

7

Clinical evidence for importance of glucocorticoids in alcohol dependence

“High strain” occupations increase risk for alcohol dependence

Stressful experiences during abstinence increase likelihood of relapse drinking

Stress induces alcohol craving; related to incidence of relapse

More severe life events (“danger” & “loss”) in years preceding alcohol dependence

8

Cognitive deficits in alcoholics

Incidence of cognitive dysfunction in abstinent alcoholics estimated to be 50 to 80%

No current effective treatment

Difficulties in learning new information, retention over long intervals, problems in executive function

9

Cognitive deficits in alcoholics

In high concentrations, glucocorticoid stress hormones (cortisol, corticosterone) cause neurotoxicity and cognitive deficits

Neuronal damage after long term alcohol consumption:- frontal association cortex, hippocampus (rodents), thalamus

Preclinical and clinical evidence that withdrawal of alcohol after long term consumption plays an important role in memory deficits

10

Stress can alter the effects of many drugs

Causes alterations in synaptic plasticity and neuronal survival

Such changes include acute, prolonged and delayed effects

Stress activates the mesolimbic dopamine system

Stress and drug dependence

11

`CRF

PITUITARY

adrenals

The H ypothalam ic-Pitu itary -Ad renal AxisThe HPA axis

cortisol (or corticosterone)

ACTH

12

Corticosterone in the brain

Corticosterone

Type I (mineralocorticoid) receptors

Type II glucocorticoid receptors

What effects does corticosterone have on the brain during alcohol withdrawal?

What are the concentrations of corticosterone in the brain?

Why do the concentrations matter? 13

Mesolimbic dopamine system

Initial target sites differ, but some common neuronal actionse.g dopamine release

Mesolimbic dopamine pathway activated by natural rewards

This pathway also activated by stress

Alcohol, nicotine, opiates Cocaine, amphetamine

nucleus accumbenVTA

DA

NMDA activation

14

Effect of corticosterone on firing of ventral tegmental neurones from control animals

Fir

ing

ra

te (

Hz)

0

1

2

3

4

Basalfiring

5 µM NMDA

15 µM NMDA

Corticosterone 100 nMaCSF

*

**

*P < 0.05 **P < 0.0115

Corticosterone concentrations in rodent brain

Measured corticosterone concentrations in brain regions in rodents after chronic alcohol consumption

Chronic alcohol treatment and withdrawal

Radioimmunoassay after ethanol/DMSO extraction of brain homogenates

Identity of corticosterone verified by HPLC and GC-MS

16

Regional brain concentrations of corticosterone

0

50

100

150

200

250

300

Corticosteroneng/g

Brain stem

Cortex Cereb.Hypoth. Thal.Striat.Hipp. PFC

**

****

0

50

100

150

Blood corticosterone, nM

Total Free

C57 strain miceAlcohol drinking for

20 weeksSamples 6 days after

withdrawal

When alcohol not withdrawn, no changes in brain corticosterone 17

Regional brain corticosterone concentrations

Lister Hooded rats, 8 months drinking, 2 months abstinence

0

10

20

30

Hypoth Hipp Midbrain PFC Cortex Striatum

Co

rtic

ost

ero

ne

ng

/g

Controls

*

*

*

*

**

Chronicalcohol

Plasma concentrations not significantly different

18

Summary: brain corticosterone and alcohol

Chronic alcohol consumption increased brain concentrations of the glucocorticoid, corticosterone

Plasma levels unchanged

Changes seen only after alcohol withdrawal

Largest increases in prefrontal cortex and hippocampus

20

Mechanism of brain corticosterone changes after chronic alcohol treatment

and withdrawal?

Local synthesis of glucocorticoids suggested to occur outside adrenal glands

Demonstrated in adipose tissue

Occurs via the enzyme 11--hydroxysteroid dehydrogenase (HSD-1)

This enzyme is present in brain

20

Relevance of brain glucocorticoid changes?

iii) Alter feedback mechanisms for control of adrenal hormone release?

iv) Involved in continued desire to drink alcohol?

i) Involved in alcohol-induced brain damage?

ii) Responsible for cognitive deficits after long term alcohol intake?

21

Current drug treatments for alcohol dependence

NaltrexoneOpiate antagonistDecreases continuation of drinking once relapse occurs

AcamprosateMechanism unknownSole action apparently to decrease alcohol intake

Disulphiram (“Antabuse”) Prevents metabolism of acetaldehyde- this accumulates, producing unpleasant symptoms. - may help those who really want to stop drinking

Effects: 10 – 20% decrease in relapse drinking22

Alcohol withdrawal = window of opportunity?

Alcohol intake

normalrange

Withdrawal

?

Relapse

Time

Effecton brain

?

23

Alcohol withdrawal = window of opportunity?

Multiple withdrawal episodes, more severe withdrawal, higher risk of relapse, greater cognitive deficits

Evidence cognitive deficits due to withdrawal rather than to direct effects

Acute withdrawal phase offers "window of opportunity" for treatment

Drug studied:-i) glucocorticoid Type II receptor antagonist –

"mifepristone" 25

Effects of Mifepristone on Alcohol Withdrawal Hyperexcitability in Mice

3 weeks alcohol vialiquid diet

Injections of vehicleor mifepristone justprior to withdrawal

Response to handlingmeasured

Mifepristone, the Type II glucocorticoid receptor antagonist decreased, but did not prevent, alcohol withdrawal hyperexcitability

Vehicle/alcohol withdrawal

Mifepristone /alcohol withdrawal

3 4 5 6 7 8 90

1

2

3

4

Time (h)

Medianresponse score

Mifepristone/control

Vehicle/control

25

Object recognition test

26

Effects of Mifepristone on Memory Deficit in Miceafter Alcohol Withdrawal - Object Recognition Test

22 weeks alcohol viadrinking fluid

Injections of vehicleor mifepristone justprior to withdrawal

Difference in time measured between

exploration of novel and familiar objects, 1 week

after withdrawal

Mifepristone decreased the memory loss seen after withdrawal from chronic alcohol intake

Vehicle/alcohol withdrawal

-0.1

0.0

0.1

0.2

0.3

0.4

0.5 *

Vehicle/control

Mifepristone /alcohol withdrawal

Mifepristone/control

27

5X

20X

Control Alcohol withdrawal

Corticosterone +alcohol withdrawal

Mifepristone + corticosterone +

alcohol withdrawal

Spironolactone + corticosterone +

alcohol withdrawal

Effects of Mifepristone on Neuronal Damage in Organotypic Hippocampal Cultures

Propidium iodide fluorescence

• Corticosterone greatly increased the neuronal damage caused by withdrawal of alcohol.• Mifepristone, but not spironolactone prevented this effect of • corticosterone

Collaboration with University of Kentucky

28

Effects of Type II glucocorticoid receptor antagonist mifepristone (RU38486) on alcohol preference in mice

Low alcohol preferring mice

Once daily injections of isotonic saline

or Type II receptor antagonist

Slowly developing increase in alcohol preference and consumption

Choice 8% alcohol v tap water

Effect prevented by mifepristone

0 2 4 6 8 10 12 14 16 18 200.0

0.1

0.2

0.3

0.4

0.5

0.6

Alcoholpreference

ratio

***

******

Day

Saline injections

Mifepristone injections

29

Clinical Trial of Mifepristone in Alcoholics

Participants - alcoholics entering the Alcohol Unit for detoxification

Treatment - mifepristone or placebo for two weeks from cessation of drinking

Testing – depression ratings and cognitive test battery (CANTAB) during weeks 3 and 4

Follow-up – 3,6 and 12 months to record relapse drinking

30

Mifepristone as a Potential Treatment?

• Glucocorticoid Type II receptor antagonist e.g. mifepristone

• Reduced withdrawal severity• Reduced memory loss• Prevented neurotoxicity in vitro• Prevent stress-induced increases in alcohol drinking• ?effective in alcoholics - study in progress

32

Future treatments for drug dependence?

1980sLittle research on drug dependence was supported by government funding

1990sDrug dependence becomes a special target area for research

2000sPossibility accepted of medication treatment for alcohol dependence

? Development of effective treatments to prevent dependence and memory loss?

Next?