Control of dopamine ascending pathways Control of dopamine ascending pathways by central 5-HT system: by central 5-HT system: implications for treatment of implications for treatment of Parkinson’s disease Parkinson’s disease Bordeaux 2 University – INSERM U862 Bordeaux - France July, 7 -13, 2007, Catania, Italy Umberto Spampinato Summer School of Neuroscience (5)
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Control of dopamine ascending pathways by central 5-HT system: implications for treatment of Parkinsons disease Bordeaux 2 University – INSERM U862 Bordeaux.
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Control of dopamine ascending pathways Control of dopamine ascending pathways
by central 5-HT system: by central 5-HT system:
implications for treatment of Parkinson’s implications for treatment of Parkinson’s
diseasedisease
Control of dopamine ascending pathways Control of dopamine ascending pathways
by central 5-HT system: by central 5-HT system:
implications for treatment of Parkinson’s implications for treatment of Parkinson’s
target for improved treatment of DA related diseases
5-HT/DA interaction and neuropsychiatric 5-HT/DA interaction and neuropsychiatric
disordersdisorders
5-HT/DA interaction and neuropsychiatric 5-HT/DA interaction and neuropsychiatric
disordersdisorders
5-HT5-HT systemsystem and Parkinson’s diseaseand Parkinson’s disease5-HT5-HT systemsystem and Parkinson’s diseaseand Parkinson’s disease
• Preclinical data (rat):
central 5-HT transmission Catalepsy
central 5-HT transmission (SSRI) Catalepsy
SSRI:
recent preclinical (MPTP monkey) and clinical studies:
pas Δ L-dopa-induced dyskinesia / park symptoms
• Clinical data:
Park symptoms dyskinesiacentral 5-HT transmission (SSRI)
DAVTA / SN DR
5-HTDA
Frontal cortex
n. Accumbens
striatumDA
DA
5-HT
5-HT5-HT3
Na+/K+ channel
5-HT1A
5-HT1BAMPc
5-HT4
5-HT6
5-HT7
AMPc
5-HT2A
5-HT2C
IP3/DAG
5-HT
Schizophrenia
Depression
Drug Addiction
Parkinson’s disease
5-HT/DA interaction and neuropsychiatric 5-HT/DA interaction and neuropsychiatric
disordersdisorders
5-HT/DA interaction and neuropsychiatric 5-HT/DA interaction and neuropsychiatric
disordersdisorders
selective action on 5-HT receptor subtypes
MPTP monkey
5-HT5-HT1 1 receptorsreceptors and Parkinson’s diseaseand Parkinson’s disease5-HT5-HT1 1 receptorsreceptors and Parkinson’s diseaseand Parkinson’s disease
• 5-HT1AR agonists
LID
Park patients
8-OH-DPAT
sarizotan (low doses)
↑ duration of L-dopa action
• 5-HT1BR agonists
MDMA (ecstasy): 5-HT1A/ 1B stim ( )
buspirone
5-HT5-HT2 2 receptors and Parkinson’s disease receptors and Parkinson’s disease 5-HT5-HT2 2 receptors and Parkinson’s disease receptors and Parkinson’s disease
• 5-HT2C antagonism is effective in animal models of Parkinson’s disease
• 5-HT2A/2C antagonism catalepsy
anti-parkinsonian action DA agonists
L-dopa induced dyskinesia (MPTP primates)
• 5-HT2C receptor binding is increased in the SN ret of parkinsonian patients
- atypical antipsychotic (clozapine)
- antidepressant mirtazapine
L-dopa-induced psychosis, LID / tremor
tremor - LID
• 5-HT2A/2C antagonism may participate to the therapeutic benefit of:
composite responses involving different populations
of 5-HT2C receptors in multiple brain nuclei
and/or DA transmission
5-HT5-HT2C2C Rs control DA release and/or transmission Rs control DA release and/or transmission5-HT5-HT2C2C Rs control DA release and/or transmission Rs control DA release and/or transmission
I.I. 5-HT 5-HT2C2C receptors and basal DA receptors and basal DA releaserelease
I.I. 5-HT 5-HT2C2C receptors and basal DA receptors and basal DA releaserelease
Mesulergine, a non selective 5-HT2C antagonist
Tonic and inhibitory control on DA neuron activity
Cumulative i.v. doses of mesulergine (MES) on basal DA neuron firing rate in the VTA
Prisco et al., 1994 Time (min)
-30 0 30 60 90
DA
(%
of
bas
elin
e)
100
120
140
160
180
200
0.5 mg/kg0.2 mg/kg0.1 mg/kgcontrols
Dose-response of mesulergine (0.1/0.2/0.5 mg/kg) on DA release at terminals (NAC/Striatum)
Spampinato et al., 1997
SNc
Striatum
VTA
NAC
selective
5-HT2C agents
Tonic and inhibitory control
I. 5-HTI. 5-HT2C2C receptors and basal DA release receptors and basal DA release I. 5-HTI. 5-HT2C2C receptors and basal DA release receptors and basal DA release
SB 206553 5-HT2C/2B antagonist
SB 242084 5-HT2C antagonist
SB 243213 5-HT2C antagonist
Ro 60-0175 5-HT2C agonist
SNc
Striatum
VTA
NAC
5-HT2C agents
5-HT5-HT2C2C receptors and basal DA release receptors and basal DA release5-HT5-HT2C2C receptors and basal DA release receptors and basal DA release
Tonic and inhibitory control
preferential control
of the
mesoaccumbens DA pathway ?
Sensitivity / magnitude
n. accumbensstriatum
Willins & Meltzer, 1998
Di Giovanni et al., 2000
Di Giovanni et al., 2000
Di Matteo et al., 1999
Gobert et al., 2000
-10 -20 -30 -40-30 -20-40 -10 0
5-HT2C agonists
0
n.d.
mCPP
MK-212
Ro60-0175
1
1
5
1
2.5
+60 +40+80 +20 0
5-HT2C antagonists
n.d.
0 +20 +40 +60 +80
SB 206553
SB 242084
n.d.
n.d.
1
2.5
10
5
2.5
10
5
Porras et al., 2002
Di Matteo et al., 1998
Di Matteo et al., 1998
Di Matteo et al., 1999
Di Matteo et al., 1999
DA release (%)
Gobert et al., 2000
Di Giovanni et al., 2000
10 Gobert et al., 2000
mg/kg
mg/kg
Effect of 5-HT2C agents on DA release assessed by in vivo microdialysis
Do 5-HT2C receptors exert a preferential
control of the mesoaccumbens DA pathway ?
SNc
Striatum
VTA
NAC
Dose-response studies
Simultaneous monitoring of DA release in both regions
5-HT2C agents
5-HT5-HT2C2C receptors and basal DA release receptors and basal DA release
Haloperidol and SB 243213 Haloperidol and SB 243213 Haloperidol and SB 243213 Haloperidol and SB 243213
blockade of 5-HT2C receptors : no effect on haloperidol-induced DA release
Δ haloperidol effect : related to the constitutive activity of 5-HT2C receptors
Time (min)
nM range inverse agonist
5-HT2C
5-HT5-HT2C 2C receptors and antipsychotic drugsreceptors and antipsychotic drugs 5-HT5-HT2C 2C receptors and antipsychotic drugsreceptors and antipsychotic drugs
VTA and NAc 5-HTVTA and NAc 5-HT2C2C receptors receptorsVTA and NAc 5-HTVTA and NAc 5-HT2C2C receptors receptors
experimental procedure
Injection canula
1 - Ro 60-0175-induced DA release 1 - Ro 60-0175-induced DA release
Intra-VTAIntra-VTA injection of 5-HT injection of 5-HT2C2C antagonists antagonists
1 - Ro 60-0175-induced DA release 1 - Ro 60-0175-induced DA release
Intra-VTAIntra-VTA injection of 5-HT injection of 5-HT2C2C antagonists antagonists
SB 242084SB 242084
Time ( min )
SB 242084SB 242084 prevents the inhibitory effect of Ro 60-0175
***p<0.001 vs veh, ++p<0.01, +++p<0.001
vs Ro 60-0175 , PLSD test
0.5µg/0.2µl
-30 0 30 60 90 12060
80
100
120
++
+***
veh / veh
SB 242084 / veh
veh / Ro 60-0175
SB 242084 / Ro 60-0175
NA
c D
A
(% o
f b
asel
ine)
0.1µg/0.2µl
***+
+60
80
100
120
-30 0 30 60 90 120
veh / veh
SB 243213 / veh
veh / Ro 60-0175
SB 243213 / Ro 60-0175
-60 -30 0 30 60 90 120
***+
++
NA
c D
A
(% o
f b
asel
ine)
60
80
100
120
0.1µg/0.2µl
Time ( min )
1 - Ro 60-0175-induced DA release 1 - Ro 60-0175-induced DA release
Intra-VTAIntra-VTA injection of 5-HT injection of 5-HT2C2C antagonists antagonists
1 - Ro 60-0175-induced DA release 1 - Ro 60-0175-induced DA release
Intra-VTAIntra-VTA injection of 5-HT injection of 5-HT2C2C antagonists antagonists
SB 243213
***p<0.001 vs controls; +++p<0.001 vs RO 60-0175, PLSD test
-60 -30 0 30 60 90 120
++
+***
60
80
100
120
0.5µg/0.2µl
VTA 5-HT2C Rs participate in the
phasic inhibitory control of DA release
SB 243213 prevents the inhibitory effect of Ro 60-0175
2 - SB 206553-induced DA release 2 - SB 206553-induced DA release
Intra-VTAIntra-VTA injection of 5-HT injection of 5-HT2C2C antagonists antagonists
2 - SB 206553-induced DA release 2 - SB 206553-induced DA release
Intra-VTAIntra-VTA injection of 5-HT injection of 5-HT2C2C antagonists antagonists
SB 242084SB 242084
NA
c D
A (
% o
f b
asel
ine)
time (min)
-30 0 30 60 90 12080
100
120
140
160
180
0.1 µg/0,2µl
***
v eh / veh
SB 242084 / veh
veh / SB 206553
SB 242084 / SB 206553
***p<0.001 vs veh PLSD test
-30 0 30 60 90 120
0.5 µg/0,2µl
***
80
100
120
140
160
180
SB 242084SB 242084 has no influence on SB 206553-induced DA release
VTA 5-HT2C Rs do not participate in the tonic inhibition
of DA release related to the CA of 5-HT2C Rs
VTAVTA
DADANAc NAc
5-HT5-HT2C2C
(-)DADA
5-HT5-HT2C2C
DA release
VTA and NAc 5-HTVTA and NAc 5-HT2C2C receptors receptorsVTA and NAc 5-HTVTA and NAc 5-HT2C2C receptors receptors
Nucleus Accumbens
5-HT2C receptors
SB 242084SB 242084
1 - Ro 60-0175-induced DA release 1 - Ro 60-0175-induced DA release
Intra-NAcIntra-NAc perfusion of 5-HT perfusion of 5-HT2C2C antagonist antagonist
1 - Ro 60-0175-induced DA release 1 - Ro 60-0175-induced DA release
Intra-NAcIntra-NAc perfusion of 5-HT perfusion of 5-HT2C2C antagonist antagonist
SB 242084SB 242084 prevents the inhibitory effect of Ro 60-0175
NAc 5-HT2C Rs participate in the phasic inhibitory
control of DA release
**p<0.01, ***p<0.001 vs veh; ++p<0.01; +++p<0.001 vs RO 60-0175 group PLSD test
Time (min)
NA
c D
A (
% o
f b
asel
ine)
-30 0 30 60 90 12060
80
100
120
**+
+
0.1 µM
-30 0 30 60 90 12060
80
100
120
***+
++
1 µM
veh / veh
SB 242084 / veh
veh / Ro 60-0175
SB 242084 / Ro 60-0175
2 - SB 206553-induced DA release 2 - SB 206553-induced DA release
Intra-NAcIntra-NAc perfusion of 5-HT perfusion of 5-HT2C2C antagonists antagonists
2 - SB 206553-induced DA release 2 - SB 206553-induced DA release
Intra-NAcIntra-NAc perfusion of 5-HT perfusion of 5-HT2C2C antagonists antagonists
SB 242084SB 242084 v eh / veh
SB 242084 / veh
veh / SB 206553
SB 242084 / SB 206553
time (min)
-30 0 30 60 90 120
100
120
140
160
***+
++
NA
c D
A (
% o
f b
asel
ine)
-30 0 30 60 90 120
100
120
140
160
***+
++
***p<0.001 vs veh; +++p<0.001 vs SB 206553 PLSD test
SB 242084SB 242084 prevents the excitatory effect of SB 206553
1µM0.1µM
NAc 5-HT2C Rs participate in the tonic inhibitory control
exerted by the CA of 5-HT2C Rs
Basal DA releaseBasal DA release
intra-VTA and intra-NAc administrationintra-VTA and intra-NAc administration
Basal DA releaseBasal DA release
intra-VTA and intra-NAc administrationintra-VTA and intra-NAc administration
vehSB 206553
**p<0.01 vs veh test PLSD
NA
c D
A (
% o
f b
asel
ine
)
time (min)
-30 0 30 60 90 120
100
120 **
1µM
110
130
-30 0 30 60 90 120
100
120
time (min)
0.5 µg/0.2 µl
110
130
SB 206553SB 206553
Intra-NAc application of the 5-HT2C inverse agonist SB 206553
increases basal DA release in the NAc
VTAVTA
DADANAc NAc
5-HT5-HT2C2C
DADA
5-HT5-HT2C2C
• VTA and NAc 5-HT2C Rs both participate in the
overall inhibitory control of NAc DA release
• The NAc may represent a primary site of action for
the effects of the CA of 5-HT2C Rs
VTA and NAc 5-HTVTA and NAc 5-HT2C2C receptors receptorsVTA and NAc 5-HTVTA and NAc 5-HT2C2C receptors receptors
DA release
≠ ≠ levels of 5-HTlevels of 5-HT2C 2C R CA in the NAc and VTA related to R CA in the NAc and VTA related to RNA editingRNA editing
lowers the CA and modulates the desensitization state of 5-HTlowers the CA and modulates the desensitization state of 5-HT2C2C Rs Rs
generatesgenerates tissue-specific expression of 5-HT tissue-specific expression of 5-HT2C2C R isoforms with R isoforms with
distinct biological propertiesdistinct biological properties (Niswender et al., 1999; Marion et al., 2004(Niswender et al., 1999; Marion et al., 2004)
phasic & tonic
phasic
DADA
NAC / StriatumNAC / Striatum
DADA
VTAVTASNSN
5-HT5-HT2C2C receptor control of DA ascending pathways in receptor control of DA ascending pathways in
vivovivo
ConclusionsConclusions
5-HT5-HT2C2C receptor control of DA ascending pathways in receptor control of DA ascending pathways in
vivovivo
ConclusionsConclusions
• inhibitory tonic / phasic control
• involvement of constitutive activity in vivo
- clozapine: inverse agonist in vivo
- DAergic effects of antipsychotic drugs
• region-dependent control by constitutive activity
- NAc → primary site of action
- Role of mRNA editing ( ↓ constitutively active isoforms)
in the control of DA neuron excitability
5-HT2C receptor
“fine tuning”
DA pathways
DADA
NAC / StriatumNAC / Striatum
DADA
VTAVTASNSN
need for studies
assessing the functional significance
and the therapeutic potential
of inverse agonism in vivo
5-HT5-HT2C2C receptor control of DA ascending pathways in receptor control of DA ascending pathways in
vivovivo
ConclusionsConclusions
5-HT5-HT2C2C receptor control of DA ascending pathways in receptor control of DA ascending pathways in
vivovivo
ConclusionsConclusions
Long term studies ……
studies in animal models of Parkinson’s disease….
5-HT2C receptor
“fine tuning”
DA pathways
VTAVTA
NAcNAc
5-HT5-HT2C2C
DADA
5-HT5-HT2C2C
DADA
Sylvia Navailles
Delphine Moison
Dimitri Ryczko
« Neuropharmacologie et Neurochimie « Neuropharmacologie et Neurochimie
Fonctionnelle »Fonctionnelle »
Université Bordeaux 2
INSERM U 862
France
Pr William Clarke & Dr Kelly Berg
Department of Pharmacology, University of TexasHealth Science Center, San Antonio, USA
Philippe De
Deurwaerdère
Guillaume Lucas
Grégory Porras
Umberto Spampinato
Striatum
SNc
DADA
n. Accumbens
VTA
5-HT2A
DA synthesis DA synthesis
DA transmission
5-HT tone
DA cell firing DA cell firing5-HT3
state-dependent facilitatory controltonic inhibitory control
5-HT2C DA cell firing
5-HT receptors and in vivo DA release: conditional 5-HT receptors and in vivo DA release: conditional
involvementinvolvement5-HT receptors and in vivo DA release: conditional 5-HT receptors and in vivo DA release: conditional
involvementinvolvement
Selective modulation of one DA pathway depending
on the state of DA neuron activity
Rational basis for therapeutics
DA transmission
DA cell firing5-HT4
Factors ?
• Preclinical data (rat):
5-HT5-HT and Parkinson’s diseaseand Parkinson’s disease5-HT5-HT and Parkinson’s diseaseand Parkinson’s disease
• Clinical data:
central 5-HT transmission5-HT2C antagonism
Catalepsy
central 5-HT transmission (SSRI)5-HT4 agonists
Catalepsy
5-HT2C antagonism motor response (L-dopa, DA agonists)
5-HT4 agonist (cisapride)
central 5-HT transmission (SSRI)
5-HT1A agonism (buspiron)
5-HT2A/2C - 5-HT3 antagonists
atypical antipsychotic (clozapine)
5-HT2/3 + α2 antagonism (mirtazapine)
Park (tremor)
Park symptoms dyskinesia
dyskinesia
(mianserin, ondansetron) Dopa-induced psychosis(no change motor score)
Dopa-induced psychosis, tremor
tremor- dyskinesia
5-HT5-HT2C2C receptors: receptors:
DA release & cocaine-induced effectsDA release & cocaine-induced effects
5-HT5-HT2C2C receptors: receptors:
DA release & cocaine-induced effectsDA release & cocaine-induced effects
control / contributioninvolvementVTA 5-HT2C R NAc 5-HT2C R
Inhibitory effect on DA release
Phasic inhibitory control of DA release
yes
Basal DA release
yes
no
Cocaine-induced DA release
Cocaine-induced behaviors
yes (ago)
yes (ago)
Involvement in the systemic effect of 5-HT2C agents
Behaviors
DA releaseno
no
yes
yes
no
yes (ago/antag)
no (ago/antag)
yes (antag)
yes (antag)
5-HT5-HT2C2C receptors: receptors:
DA release & cocaine-induced behaviorsDA release & cocaine-induced behaviors
5-HT5-HT2C2C receptors: receptors:
DA release & cocaine-induced behaviorsDA release & cocaine-induced behaviors
ip. Intra-VTA Intra-NAc
5-HT2C agents administration
Ro-induced DA antagonist
agonist
antagonistBasal DA release 0
000
0agonist
antagonistbasal behaviors 0
00 0
0
agonist
antagonistCocaine- behaviors
0
agonist
antagonistCocaine- DA
00
5-HT5-HT2C2C receptors and DA neuron firing rate receptors and DA neuron firing rate 5-HT5-HT2C2C receptors and DA neuron firing rate receptors and DA neuron firing rate
Tonic and phasic inhibitory control on DA neuron activity
composite responses involving different populations
of 5-HT2C receptors in multiple brain nuclei
and/or DA transmission
(-)
(-)
releaserelease
5-HT5-HT2C2C Rs control DA release and/or transmission Rs control DA release and/or transmission5-HT5-HT2C2C Rs control DA release and/or transmission Rs control DA release and/or transmission
DA releaseDA release
DAVTAVTA
DA transmission
firing
regulation of DA exocytosis
via DA neuron firing
modulation of DA transmission may occur
independently from changes of DA release
biochemical
electrophysiological
behavioral
studies
Fr Cortex / NAc Fr Cortex / NAc
“DARP-32”Svenningsson et al., Pnas, 2001
5-HT2C
5-HT5-HT2C2C
5-HT5-HT2C2C
5-HT5-HT2C2C receptors and basal DA release receptors and basal DA release5-HT5-HT2C2C receptors and basal DA release receptors and basal DA release
SB 206553 - SB 242084
Frontal Cortex
Gobert et al., 2000
TIME (MIN)
PE
RC
EN
T O
F C
ON
TR
OL
* p<0.05 ANOVA
SB 206553 SB 242084
5-HT5-HT2C2C receptors and basal DA release receptors and basal DA release5-HT5-HT2C2C receptors and basal DA release receptors and basal DA release
Ro 60-0175Frontal Cortex
TIME (MIN)
PE
RC
EN
T O
F C
ON
TR
OL
Gobert et al., 2000
* p<0.05 ANOVA
Clozapine: 5-HTClozapine: 5-HT2C2C inverse agonist inverse agonist in vivoin vivo ? ?Clozapine: 5-HTClozapine: 5-HT2C2C inverse agonist inverse agonist in vivoin vivo ? ?
NACStriatum
SB 243213 (1 mg/kg, ip.) 30 min before clozapine (1 mg/kg, sc.)