Regional Glucose metabolism after Dextrometorphane ... fileRegional Glucose metabolism after Dextrometorphane-Challenge in Alcoholics and Controls M. Soyka 1, Rüther , CG.Schütz1,

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

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Glutamat Glutamat-Receptor

Alcohol

Normal

Alcohol

Withdrawal

InhibitionReceptor Upregulation

HyperexcitatbilityExzotoxicity

Postsynaptic Excitation

Effects of Alcohol on the glutamatergic Neurotransmission:

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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

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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

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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;

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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

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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

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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

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Agent NR1 + NR2A

NR1 + NR2B

NR1 + NR2C

NR1 + NR2D

Alcohol + +++ + + D-Cycloserine + ++ +++ +++ Memantine ++ +++ +++ +++ Ketamine ++ ++ ++ ++ Dextrorphan ++ ++ +++ + Parsons et

al. 1998

Subtyp binding

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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

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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

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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.

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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

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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

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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)

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Data analysis

BRASS software (sterotactic normalisation and analysis)

ROI 63 regions of interest using a 3 D template

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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

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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

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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

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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

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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)

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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)

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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.

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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

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Ziele

Untersuchung des rCMRglc beigesunden Probanden

Placebobedingungaktue Wirkung von Dextromethorphanakute Wirkung von Alkohol

alkoholabhängigen Patienten (2 Wochen nach stationärem Entzug)

Placebobedingungaktue Wirkung von Dextromethorphan

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NMDA Subunit 2B in Alcohol Dependence

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NMDA Subunit 2B in Alcohol Dependence

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NMDA Subunit 2B in Alcohol Dependence

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NMDA Subunit 2B in Alcohol Dependence