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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. Withdrawal. Acute actions. ?. Tolerance.

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alcohol and stress hormones
Alcohol and Stress Hormones

Hilary J. Little

Institute of Psychiatry,

University of London,

United Kingdom

effects of alcohol
Effects of alcohol

i) Acute effects

ii) Long term effects

- dependence

iii) Interactions with stress hormones

1

slide3

Withdrawal

Acute actions

?

Tolerance

Alcohol Dependence

Effect

on brain

normal

range

Relapse

2

Time

Alcohol intake

slide4

Acute effects of alcohol

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?)

3

slide5

Acute effects of alcohol

Increases release of endogenous opiates

Increases mesolimbic dopamine transmission

Activates the hypothalamo-pituitary adrenal system (HPA)

4

slide6

Drug dependence

1. Withdrawal symptoms

2. Compulsion to take drug

5

the alcohol withdrawal syndrome
The Alcohol Withdrawal Syndrome

Anxiety, irritability

Tremor, convulsions (can be fatal)

Hallucinations, confusion (‘DT’s’)

6

slide8

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

slide9

Clinical evidence for importance of glucocorticoids in alcohol dependence

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

8

cognitive deficits in alcoholics
Cognitive deficits in alcoholics

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

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

No current effective treatment

9

cognitive deficits in alcoholics1
Cognitive deficits in alcoholics

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

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

10

slide12

Stress and drug dependence

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

11

slide13

T

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p

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l

a

m

i

c

-

P

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i

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r

y

-

A

d

r

e

n

a

l

A

x

i

s

The HPA axis

`C

F

R

P

I

T

U

I

T

A

R

Y

ACTH

a

d

r

e

n

a

l

s

cortisol (or corticosterone)

12

slide14

Type I

(mineralocorticoid) receptors

Corticosterone

Type II

glucocorticoid receptors

Corticosterone in the brain

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

slide15

VTA

NMDA activation

Mesolimbic dopamine system

Initial target sites differ, but some common neuronal actions

e.g dopamine release

Mesolimbic dopamine pathway activated by natural rewards

This pathway also activated by stress

nucleus

accumben

DA

Alcohol, nicotine, opiates

Cocaine, amphetamine

14

slide16

**

4

*

3

2

Firing rate (Hz)

1

0

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

Basal

firing

5 µM

NMDA

15 µM

NMDA

Corticosterone 100 nM

aCSF

*P < 0.05 **P < 0.01

15

corticosterone concentrations in rodent brain
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

**

Blood corticosterone, nM

150

*

*

100

**

50

0

Total Free

Regional brain concentrations of corticosterone

C57 strain mice

Alcohol drinking for

20 weeks

Samples 6 days after withdrawal

Corticosterone

ng/g

300

250

200

150

100

50

0

Brain

Hypoth.

PFC

Hipp.

Thal.

Cortex

Striat.

Cereb.

stem

When alcohol not withdrawn, no changes in brain corticosterone

17

regional brain corticosterone concentrations

*

*

30

*

*

20

*

*

10

0

Chronic

alcohol

Regional brain corticosterone concentrations

Lister Hooded rats, 8 months drinking, 2 months abstinence

Corticosterone ng/g

Hypoth Hipp Midbrain PFC Cortex Striatum

Plasma concentrations not significantly different

Controls

18

summary brain corticosterone and alcohol
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
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

slide22

Relevance of brain glucocorticoid changes?

i) Involved in alcohol-induced brain damage?

ii) Responsible for cognitive deficits after long term

alcohol intake?

iii) Alter feedback mechanisms for control of adrenal

hormone release?

iv) Involved in continued desire to drink alcohol?

21

current drug treatments for alcohol dependence
Current drug treatments for alcohol dependence
  • Naltrexone
  • Opiate antagonist
  • Decreases continuation of drinking once relapse occurs
  • Acamprosate
  • Mechanism unknown
  • Sole 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 drinking

22

slide24

?

Effect

on brain

Withdrawal

normal

range

Relapse

?

Time

Alcohol withdrawal = window of opportunity?

Alcohol intake

23

slide25

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

slide26

Vehicle/alcohol withdrawal

Mifepristone /alcohol withdrawal

Vehicle/control

4

3

2

1

0

3

4

5

6

7

8

9

Effects of Mifepristone on Alcohol

Withdrawal Hyperexcitability in Mice

Median

response score

3 weeks alcohol via

liquid diet

Mifepristone/control

Injections of vehicle

or mifepristone just

prior to withdrawal

Response to handling

measured

Time (h)

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

25

slide28

Vehicle/control

Vehicle/alcohol withdrawal

Mifepristone /alcohol withdrawal

Mifepristone/control

0.5

0.4

0.3

0.2

0.1

0.0

-0.1

Effects of Mifepristone on Memory Deficit in Mice

after Alcohol Withdrawal - Object Recognition Test

22 weeks alcohol via

drinking fluid

*

Injections of vehicle

or mifepristone just

prior 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

27

slide29

Effects of Mifepristone on Neuronal Damage in Organotypic Hippocampal Cultures

20X

5X

Propidium iodide fluorescence

Mifepristone + corticosterone +

alcohol withdrawal

Spironolactone + corticosterone +

alcohol withdrawal

Alcohol withdrawal

Corticosterone +

alcohol withdrawal

Control

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

28

Collaboration with University of Kentucky

slide30

Alcohol

preference

ratio

0.6

0.5

0.4

0.3

0.2

0.1

0.0

4

6

8

10

12

14

16

18

20

0

2

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

Low alcohol

preferring mice

Saline injections

Mifepristone injections

Choice 8% alcohol

v tap water

Once daily injections of isotonic saline

or Type II receptor antagonist

===

===

===

***

***

***

Day

Slowly developing increase in alcohol preference and consumption

Effect prevented by mifepristone

29

slide31

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

slide32

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
Future treatments for drug dependence?

1980s

Little research on drug dependence was supported by government funding

1990s

Drug dependence becomes a special target area for research

2000s

Possibility accepted of medication treatment for alcohol dependence

Next?

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