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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
Alcohol Dependence
Effect
on brain
normal
range
Withdrawal
Acute
actions
?
Relapse
Tolerance
2
Alcohol intake
Time
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
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
The Alcohol Withdrawal Syndrome
Anxiety, irritability
Tremor, convulsions (can be fatal)
Hallucinations, confusion (‘DT’s’)
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
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
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 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
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
The H ypo thalam ic-Pitu itary -Ad renal A xis
The HPA axis
`CRF
P ITUI TARY
ACTH
adren als
cortisol (or
corticosterone)
12
Corticosterone in the brain
Type I
(mineralocorticoid) receptors
Corticosterone
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 actions
e.g dopamine release
Mesolimbic dopamine pathway activated by natural rewards
This pathway also activated by stress
NMDA activation
VTA
Alcohol, nicotine, opiates
DA
nucleus
accumben
Cocaine, amphetamine
14
Effect of corticosterone on firing of ventral
tegmental neurones from control animals
Firing rate (Hz)
4
**
3
*
2
1
0
Basal
firing
aCSF
5 µM
NMDA
15 µM
NMDA
Corticosterone 100 nM
*P < 0.05 **P < 0.01
15
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
C57 strain mice
Alcohol drinking for Corticosterone
ng/g
20 weeks
Samples 6 days after 300
withdrawal
**
250
Blood corticosterone, nM
200
150
150
100
100
50
*
*
**
50
0
Total
Free
0
Hypoth. Hipp. Brain
stem
PFC Cortex Striat. Thal. Cereb.
When alcohol not withdrawn, no changes in brain corticosterone
17
Regional brain corticosterone concentrations
Corticosterone ng/g
Lister Hooded rats, 8 months drinking, 2 months abstinence
30
*
*
20
*
*
*
*
10
0
Hypoth Hipp
Controls
Midbrain
Chronic
alcohol
PFC
Cortex Striatum
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?
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
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
Alcohol withdrawal = window of opportunity?
Effect
on brain
Withdrawal
?
?
normal
range
Alcohol intake
Relapse
Time
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 via
liquid diet
Injections of vehicle
or mifepristone just
prior to withdrawal
Response to handling
measured
Vehicle/alcohol withdrawal
Vehicle/control
Mifepristone /alcohol withdrawal
Median
response score
Mifepristone/control
4
3
2
1
0
3
4
5
6
7
8
9
Time (h)
Mifepristone, the Type II glucocorticoid receptor antagonist
decreased, but did not prevent, alcohol withdrawal hyperexcitability
25
Object recognition test
26
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
0.5
*
Vehicle/control
Vehicle/alcohol withdrawal
Mifepristone /alcohol withdrawal
Mifepristone/control
0.4
0.3
Difference in time
measured between
exploration of novel and
familiar objects, 1 week
after withdrawal
0.2
0.1
0.0
-0.1
Mifepristone decreased the memory loss seen after withdrawal from
chronic alcohol intake
27
Effects of Mifepristone on Neuronal Damage in Organotypic
Hippocampal Cultures
20X
5X
Propidium iodide fluorescence
Control
Alcohol
withdrawal
Corticosterone +
alcohol withdrawal
Mifepristone +
Spironolactone +
corticosterone +
corticosterone +
alcohol withdrawal alcohol withdrawal
• 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
Choice 8% alcohol
v tap water
Alcohol
preference
ratio
Saline injections
Mifepristone injections
0.6
0.5
0.4
Once daily injections of
isotonic saline
or Type II receptor
antagonist
0.3
===
0.2
=== ===
*** *** ***
0.1
0.0
0
2
4
6
8
10
12
14
16
18
20
Day
Slowly developing increase in alcohol preference and consumption
Effect prevented by mifepristone
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?
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?