Behavioral
Pharmacology Unit
GÖTEBORG
UNIVERSITY
Förebygg.nu
Göteborg 2009
Hur beroendeframkallande medel kidnappar
hjärnan vilket kan medföra ökad risk för
unga att bli knarkare
Jörgen A. Engel
Drug addiction is a complex illness. It is
characterized by compulsive, at times
uncontrollable drug craving, seeking, and use that
persist even in the face of extremely negative
consequences …. with relapses possible even after
long periods of abstinence
Professor emeritus, u-läk. Nordhemskliniken
(A.Leshner, Science 1997)
Beroendekliniken, SU
The Sahlgrenska Academy, Göteborg University, Department of Pharmacology
Box 431, SE 405 30 Göteborg, Sweden
[email protected]
RELAPSE RATES IN ADDICTION PROGRAMS*
WILLIAM A. HUNT, L. WALKER BARNETT, AND LAURENCE G. BRANCH
DRUG ABUSE
Loyola University of Chicago
J. Clin. Psychol., vol. 27, 455-456, 1971.
RELAPSE RATE OVER TIME
ACUTE EFFECTS
% ABSTAINERS
100
J
H
É
90
80
70
É
J
HEROIN
H
SMOKING
É
ALCOHOL
CHRONIC EFFECTS
• reinforcement (reward)
- positive effects
- relieve an unpleasant mental state
• neuroadaptive
- tolerance
- sensitization
8 -10%
RELAPSE
60
ADDICTION
• craving
• poor impulse control
• poor decision making
50
40
É
J
H
30
DETOXIFICATION
É
J
H
• withdrawal
J
H
20
10
0
0
1
2
3
4
5
6
7
8
20 - 30%
9 10 11 12
MONTHS
2 weeks
Behavioral sensitization or reversed tolerance is a phenomenon which occurs
when repeated administration of a drug produces certain behavioral ef fects to
a progressively greater extent in response to the same dose of the drug.
LMA (counts/1h)
CHARACTERISTICS OF SENSITIZATION
14000
12000
Most dependence producing drugs appear to share the ability
10000
to produce sensitization
8000
The phenomenon appears to be long-lasting or persistent
6000
Cross-sensitization between dif ferent drugs of abuse may develop
4000
Stressors can cause sensitization to drugs of abuse
2000
0
veh
Nic 1st day
Nic 10th day
Nic 20th day
1
Korssensitisering har uppstått
när intag av en drog förstärker
svaret på en annan drog
More than 90% of alcoholics are smokers.
Dreher and Fraser 1967
Walton 1972
Bobo et al. 1987
Alcoholism is 10 times more common among smokers than
non-smokers.
Di Franza and Guerrera 1990
Effect of Nicotine on Ethanol Intake in MP Rats
% of baseline
200
175
EtOH
☺
☺
☺
150
125
100
☺
☺
☺
☺
75
Nicotine 0.4 mg/kg/day
25
50
☺
Vehicle
☺
Nic.
0
-10
0
7
14
21
28
35
42
Days
Tidig rökdebut ökar risken för
utveckling av och alkohol- och annat
drogproblem senare i livet
Rökning under graviditet ökar risk
för missbruksproblem för
avkomman
Prevalence of Lifetime Alcohol Use Disorders
QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture.
Grant oa, 1998
Patricia A. Brennan et al, Am J Psychiatry 159:48-54, January 2002
2
Compared to people who have never smoked, those who begin smoking
by age twelve are
• sixteen times likelier to meet the medical criteria for marijuana abuse
or dependence
• almost five times likelier to meet the medical criteria for alcohol abuse
or dependence
• more than three times likelier to binge drink
• almost seven times likelier to use other illegal drugs like cocaine and
heroin
From the National center on Addiction and Substance abuse at Columbia University.
Tobacco: The Smoking Gun. Prepared for the Citizien´s Commission to protect the truth. October 2007
DRUG ABUSE
ACUTE EFFECTS
CHRONIC EFFECTS
• reinforcement (reward)
- positive effects
- relieve an unpleasant mental state
• neuroadaptive
- tolerance
- sensitization
8 -10%
RELAPSE
ADDICTION
• craving
• poor impulse control
• poor decision making
DETOXIFICATION
• withdrawal
20 - 30%
Activation of memory circuits during cue-elicited cocaine craving
STEVEN GRANT, EDYTHE D. LONDON, DAVID B. NEWLIN, VICTOR L. VILLEMAGNE , XIANG LIU,
CARLO CONTOREGGI , ROBERT L. PHILLIPS, ALANE S. KIMES AND ARTHUR MARGOLINE
Proc. Natl. Acad. Sci. USA. Vol. 93, pp. 12040-12045, 1996
Neutral Cues
Cocaine Cues
3
DRUG ABUSE
ACUTE EFFECTS
CHRONIC EFFECTS
• reinforcement (reward)
- positive effects
- relieve an unpleasant mental state
• neuroadaptive
- tolerance
- sensitization
8 -10%
RELAPSE
ADDICTION
• craving
• poor impulse control
• poor decision making
DETOXIFICATION
• withdrawal
20 - 30%
Craving
(Sug, drive)
RELAPS
Impulskontroll
deficit
Kognitiv
deficit
Glädje
HJÄRNANS DOPAMIN BELÖNINGSSYSTEM
Prefrontal
cortex
I hjärnan och endast i hjärnan
uppstår våra njutningar, glädjeämnen, skratt och lustiga infall,
likaväl som vår bedrövelse,
smärta, sorg och våra tårar……
Sorg
Hippokrates
Nucleus
accumbens
Ventral tegmental
area
Från:På spaning efter Spinoza
av A. Damasio
(Modefied from: Wickelgren. Science vol 278, 1997, 35-37)
4
HJÄRNANS DOPAMIN BELÖNINGSSYSTEM
aktiveras av
naturliga belöningar såsom
mat - dryck-sex
Pharmacology Biochemistry & Behavior, Vol. 32, pp. 355-356. © Pergamon Press plc, 1989. Printed in the U.S.A.
0091-3057/89 $3.00 + .00
RAPID COMMUNICATION
The Hedonic Effects of Amphetamine
and Pentobarbital in Goldfish
Prefrontal
cortex
Nucleus
accumbens
BOW TONG LETT AND VIRGINIA L. GRANT
Ventral tegmental
area
Department of Psychology, Memorial University of Newfoundland
St. John’s, Newfoundland A1B 3X9, Canada
” These goldfish would abuse amphetamine
in the same way as these substances are
abused by human.”
Belöning ökar dopaminfrisättningen i ventrala striatum
Belöningssystemens naturliga
funktion är att stimulera inlärning
av beteenden som i förlängningen
ökar överlevnaden och befrämjar
släktets fortbestånd.
(Pappata et al Neuroimage 2002, 16:1015-1027)
Strömberoende råtta
FÖRVÄNTAN OM BELÖNING GER EN ”KICK” I LUSTCENTRUM
(Från B.Knutson et al. J.Neurosci. 2001,21:RC 159)
5
HJÄRNANS DOPAMIN BELÖNINGSSYSTEM
aktiveras av
alla beroendeframkallande droger såsom alkohol,
nikotin, heroin, kokain, amfetamin, cannabis och
kan betraktas som
surrogat till naturliga belöningar
Prefrontal
cortex
Nucleus
accumbens
Ventral tegmental
area
(Modefied from: Wickelgren. Science vol 278, 1997, 35-37)
Upprepat missbruk
leder till att de
beroendeframkallande
drogerna kidnappar
hjärnan.
Hippo
FC
C-P
PAG
DMT
CER
AC
LH
N.Acc
VP
VTA
SNr RN LC
ARC
AMG
Addictive behavior
Prefrontal
cortex
är tvångsmässiga beteenden som
kännetecknas av förlust av kontroll
och upprepade självdestruktiva
beteenden och som åtminstone i
början ger en “kick-känsla”.
Nucleus
accumbens
Definitionen av beroende riktas
alltmer mot beteendet.
Ventral tegmental
area
Pathological gambling
“ A reward is a
reward regardless of
whether it comes
from a chemical or
experience”.
Compulsive overeating
Compulsive buying disorder
Kleptomani
Compulsive sexual behavior
Internet addiction
6
FÖRKLARINGSMODELL TILL BEROENDEUTVECKLING
INSUFFICIENSHYPOTESEN
En förklaringsmodell för utveckling av beroende kan vara att dopamin-belöningssystemen
är mindre utvecklade hos en del alkoholister och andra beroende-problematiker. Det krävs
därför starkare stimuli än de naturliga förstärkningarna för att aktivera belöningssystemen
vilket gör dessa individer mera sårbara för att utveckla beroende.
Idag Tillgängliga
Farmakologiska Kryckor för Behandling
av
Alkoholproblematiker
•
Changes in Cortical Dopamine D1 Receptor Binding Associated with
Cognitive Training
•
Fiona McNab, Andrea Varrone, Lars Farde, Aurelija Jucaite, Paulina Bystritsky, Hans Forssberg, Torkel
Klingberg
SSRI
SEROTONIN
•
Working memory is a key function for human cognition, dependent on adequate dopamine neurotransmission. Here we show that the training
of working memory, which improves working memory capacity, is associated with changes in the density of cortical dopamine D1 receptors.
Fourteen hours of training over 5 weeks was associated with changes in both prefrontal and parietal D1 binding potential. This plasticity of
the dopamine D1 receptor system demonstrates a reciprocal interplay between mental activity and brain biochemistry in vivo.
BUSPIRON
SEROTONIN 1A +
•
Science 6 february 2009, vol 323, no 5915, pp 800-802
ACAMPROSATE
GLUTAMAT + ( GABA ??? )
NALTREXONE
OPIOIDER
BACLOFEN
GABA B
ONDANSETRON
DOPAMIN
SEROTONIN 3
TOPIRAMATE
GLUTAMAT +
GABA
”REWARD” PROFILE OF ALCOHOL
” För att inte känna tidens förfärliga ok
som krossar era skuldror och tynger er till
jorden
måste ni berusa er oavlåtligt.
Men med vad?
Med vin, med poesi eller med dygd,
allt efter behag.
Men berusa er. ”
Charles Baudelaire
CNS-stim. Euphoria ”Craving” Anxiolysis Sedation
DA
NA
Opioid.
Ach.
EAA.
DA
NA
Opioid.
5-HT
DA
Opioid.
GABA
EAA.
Musclerelax.
GABA
GABA
INDIVIDUAL
factors influencing sensitivity to alcohol
Genetic
Age Hormonal Environmental
( J.A. Engel, 1994 )
7
The Brain Symphony Orchestra
.
#
4/4
ALCOHOL THE CONDUCTOR
DRUMS
[ CNS - stim. ]
TRUMPETS
[ Euphoria ]
CLARINETS
[ Preference ]
HARP
VIOLIN
FLUTE
[ Anxiolysis ]
[ Sedation ] [ Musclerelax. ]
INDIVIDUAL FACTORS
influencing the sensation of the reward symphony
Genetic
Age
Hormonal Environmental
( J.A. Engel, 1994 )
8
