regional glucose metabolism after dextrometorphane ... fileregional glucose metabolism after...
TRANSCRIPT
Regional Glucose metabolism after Dextrometorphane-Challenge in
Alcoholics and Controls
M. Soyka1, Rüther1, CG. Schütz1, K.Tatsch2, W.Koch2,
1Psychiatric Hospital2 Nuclear Medicine, LMU München
LMU
Glutamat Glutamat-Receptor
Alcohol
Normal
Alcohol
Withdrawal
InhibitionReceptor Upregulation
HyperexcitatbilityExzotoxicity
Postsynaptic Excitation
Effects of Alcohol on the glutamatergic Neurotransmission:
LMU
NR1NR2ANR2B
Ca2+ + Calmodulin CaM Kinase IV
CREB
Adenylat Zyklase
nNOSPI3 Kinase
PTK fyn
MAP-Kinase Signaltrans. cGMP-Kinase 2
mGluR V
Glutamat
Alcohol
PSD 95
inhibits
Glutamatergic signaltransductionIn alcohol dependence
LMU
NR1NR2ANR2B
Ca2+ + Calmodulin CaM Kinase IV
CREB
Adenylate Cyclase
nNOSPI3 Kinase
PTK fyn
MAP-kinase pathway cGMP-kinase 2
mGluR V
Glutamat
Alcohol
PSD 95
inhibits
Per-1
Systematic Analysis of Glutamatergic Signaltransductiongenes In alcohol dependence
Sequencing of 70 Alleles:- regulatory Domains- Exon- Exon-Intron Übergänge
Identification of- 204 SNPs- 29 SNPs coding Haplotypeblocks- 13 functional SNPs
LMU
Alcohol intake
AlcoholPreference
Sensitivity Tolerance Relapse
mGluR5 X X
PTK fyn X X
nNOS X XcGMP-Kinase 2 X X
Regulation of alcohol intake via Glutamatergic signaltransduction genes in animal model
Bäckström et al., in press; Miyakawa et al., 1997; Spanagel et al., in press; Werner et al., in press;
LMU
LMU
LMU
LMU
Breier et al. (1997)
Absolut: nur prefrontal (focal), no global increaseRelativ: n.a.
N= 17Ketamin0,65 mg/kg 1h
Vollenweideret al. (1999)
Absolut: ,v.a.frontal parietal,insula, temporalRelativ: frontolaterall.anteriores cingulum
N=10Ketamin 1,2mg/kg 1h
AuthorsMetabolismDesign
FDG- PET following Ketamine- Challenge
Vollenweider et al.
Vollenweider et al.
Vollenweider et al.
Dextromethorphane
(+)-3-Methoxy-N-methylmorphinanspecific, non-competitive NMDA antagonist(main metabolite Dextrorphan)
oxidative O-demethylisation (Cytocrom P4502D6) ,renal excretion
in 60 countries for 40 years over-the-counter
indication: antitussive treatment
fast absorption from gastrointestinal tract
LMU
Binding affinity at the ion channel of the NMDA receptor complexBinding affinity at the ion channel of the NMDA receptor complex
Compound Ki [nM]
MK- 801 15 PCP 42Dextrorphane 222Ketamine 420Memantine 540Dextromethorphane 3.500Amantadine 10.500
LMU
CYP
2E1
DextrorphanDextrorphan
100 ng/ml
CYP 2D6DextromethorphanDextromethorphan
102 ng/ml
Below the limit
of detection
33--MethoxymorphinanMethoxymorphinan 33--HydroxymorphinanHydroxymorphinan
101 ng/ml
Alcohol dependants Controls
DM -intake
CYP
3A
4
CYP
3A
4
Fig. 1
CYP 2D6
LMUCGS
Agent NR1 + NR2A
NR1 + NR2B
NR1 + NR2C
NR1 + NR2D
Alcohol + +++ + + D-Cycloserine + ++ +++ +++ Memantine ++ +++ +++ +++ Ketamine ++ ++ ++ ++ Dextrorphan ++ ++ +++ + Parsons et
al. 1998
Subtyp binding
LMU
LMU
LMU
Dextromethorphane-Challenge Visuelle Analogue Scale – Alcohol craving
0
4
8
12
16
20
0 30 60 90 120 150 180 210
Zeit [min]
VAS
[%]
(Alk
ohol
verla
ngen
)
Probanden Placebo Patienten PlaceboProbanden Verum Patienten Verum
LMU
Dextromethorphane-Challengesubjective alcohol-like effects
0
10
20
30
40
60 120 180 (min)
Dex
tror
phan
e-Se
rum
leve
ls (n
g/m
l) rs
p.. V
AS
(dru
nken
ness
)
VAS (drunkennes) PatientsVAS (dunkenness) controlsDextrorphane-level controls
Dextrorphane-level patients
LMU
Hypotheses
Alcohol effects only mediated by NMDA Antagonism
Metabolic Changes induced by Alcohol and Dextromethorphane are similar.
Chronic Alcohol consumption leads to Hypersensitivity of the NMDA System (Animal Model) Metabolic Changes more marked in alcoholics compared to controls.
LMU
Inclusion criteriacriteria:
Alcoholics Controls
1. Alcohol dependence 1. No alcohol dependence (DSM IV) or abuse
2. 14 to 26 days of 2. Irrelevantabstinence
3. Males only 3. Males only
4. Informed consent 4. Informed consent
LMU
Study design
Placebo-controlled, double blind, double dummy, randomized (S-Plus)
Probands:12 alcoholics (ICD 10) male, right-handed Patients, no psychiatric diagnosis- 14 - 26 days post inpatient withdrawal10 healthy, male, right-handed controls- age and sex matched [31-45]
Challenge substances:2mg/kg Dextromethorphane0,4g/kg Ethanol (n=8, controls only!)Placebo
LMU
Scanning
ECAT Exact HR + PET-Scanner
Transmissions-Scan (Ge-68-Quelle: Schwächungskorrektur)
120 MBq 18FDG i.v.
Emission scan over 60 min, aquisition in 3D
Arterialized bloodsamples (input-function) for absolute metabolic rates
Reconstruction with filtered back-projektion (Hann-filter)
LMU
Data analysis
BRASS software (sterotactic normalisation and analysis)
ROI 63 regions of interest using a 3 D template
LMU
Flow Chart
DX / Placebo
Alcohol / Placebo
30 min
Transmission FDG
30 min 30 min
Scan
30 min
BAK
DX
BAK
DX
BAK
DX
BAK
DX
BAK
DX
AlcoholPlacebo
Controls: Alcohol leads to a significant decrease in rCMRglc compared to pla-cebo condition. Data are shown as mean images of the respective conditions.
Controls: Influence of alcohol on rCMRglc
LMU
controls Placebo vs. Alkohol
-40
-30
-20
-10
0
front
al
parie
teal
tem
pora
l
occi
pita
l
thal
amus
stria
tum
cere
bellu
m
who
le B
r.
Controls: Influence of alcohol on rCMRglc
Frontal lobe
Parietal lobe
Temporal lobe
Occipital lobe
Thalamus
Striatum
Cerebellum
Whole brain
- 16% p < 0.05
- 17% p < 0.05
- 14% p < 0.05
- 17% p < 0.05
- 14% n.s.
- 12% n.s.
- 19% p < 0.05
- 16% p < 0.05
Controls: Dextromethorphane leads to a slight increase in rCMRglc compared to placebo condition.
Placebo Dextromethorphan
Controls: Influence of Dextromethorphan on rCMRglc
Patients: Dextromethorphan lead to a slight decrease in rCMRglc compared to placebo condition.
Placebo Dextromethorphan
Patients: Influence of Dextromethorphan on rCMRglc
LMU
Regional effects Placebo vs. Dextromethorphane
Frontal lobe
Parietal lobe
Temporal lobe
Occipital lobe
Thalamus
Striatum
Cerebellum
Whole brain
- 6% + 6% p < 0,05
- 6% + 5% p < 0,05
- 5% + 6% p < 0,05
- 5% + 5% p < 0,05
- 6% + 5% p < 0,05
- 4% + 6% p < 0,05
- 8% + 3% p < 0,05
- 6% + 5% p < 0,05
Patients Controls Sign.
-15,00
-12,00
-9,00
-6,00
-3,00
0,00
3,00
6,00
9,00
12,00
15,00
Patients
Controls
FL PL TL OL TH ST CB WB
FL PL TL OL TH ST CB WB
LMU
0,600,700,800,901,001,101,201,30
fronta
l
parie
taltem
poral
thalam
us
striat
um
occip
ital
cereb
ellum
*
*
* *
*
**
Controls: relative metabolic rates (hyperfrontality etc)
Placebo Dextromethorphan Alcohol
LMU
0,600,700,800,901,001,101,201,30
fronta
l pa
rietal
tempo
raltha
lamus
striatum
occip
ital
cereb
ellum
**
Patients: relative metabolic rates
Placebo Dextromethorphan Alcohol
FDG-PET after Alcohol
Global Reduction of CMRglc, v.a. occipital und cerebella
(Wang et al. 2002)
LMU
Summary:
No significant differences in rCMRglc between alcoholics and controls under placebo conditionAlcohol-like effects following dextromethorphan – challenge in controls and alcoholics(controls > alcoholics)
Acute effects of alcohol similar to findings in previous studies (Volkow et al. 1990, Wang 2000)
LMU
Summary:
While in controls dextromethorphan induces a slight increase in rCMRglc (similar to ketamine), in alcoholics rCMRglc decreases. Contrary to our hypothesis concerning sensitivity of the NMDA-System: Differences between alcoholics and controls were qualitativ not quantitativ. In healthy controls dextromethorphan shows a spezific pattern, similar to ketamine but not other drugs of abuse.
LMU
Ergebnisse: relative Werte Probanden
PL / DX PL / AL
Frontal: (re>li) ↑ ⇔
Temporal: (re) ↑ ⇔
Limb.S.: ⇔
Thalamus: ⇔
Brainstem: ↑ ⇔
parietal, occipital, cerebellar no significant differencies
CGS Bonn
LMU
Ziele
Untersuchung des rCMRglc beigesunden Probanden
Placebobedingungaktue Wirkung von Dextromethorphanakute Wirkung von Alkohol
alkoholabhängigen Patienten (2 Wochen nach stationärem Entzug)
Placebobedingungaktue Wirkung von Dextromethorphan
LMU
NMDA Subunit 2B in Alcohol Dependence
LMU
NMDA Subunit 2B in Alcohol Dependence
LMU
NMDA Subunit 2B in Alcohol Dependence
LMU
NMDA Subunit 2B in Alcohol Dependence