Modelli Malattie Neuro
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- Pages: 40
…from mouse genetics
to human psychiatric and neurological disorders...
Motor function
Sexual Behaviour
Motivated Behaviour
DOPAMINE Learning and Memory Sensorimotor gating
Parkinson disease
Drug of Abuse Schizophrenia
DAergic Nigrostriatal and Mesolimbic pathways
DOPAMINE RECEPTORS D1-LIKE FAMILY D1R D5R
D2-LIKE FAMILY D2R (D2L & D2S) D3R D4R
Basal Ganglia network
Some of the signal trasduction pathways of dopamine receptors
FIRING Pre-synaptic neuron
SYNTHESIS
TH
D3R
Ca2+ TH
D2R
Gi
ATP cAMP
P
Degradation
DA Tyrosine
MA O
L-DOPA
DA
D3R
DA
RELEASE
G
DA release
D A
AC
DAT
G
D2R
Synaptic cleft
DA D2R
D3R
Post-synaptic neuron
G i
D1R
AC
ATP
G s
cAMP
PKA
Numerous cellular processes regulation
Model of the dopaminergic synaptic transmission. .
D2R
Degradation
The controversy…
D2R ?
? D3R
Dopamine D2R exists as two different isoforms
Targeted disruption of dopamine D2 receptors
Microdialysis probe 2 mm long
FIRING Pre-synaptic neuron
SYNTHESIS
TH
D3R
Ca2+ TH
D2R
Gi
ATP cAMP
P
Degradation
DA Tyrosine
MA O
L-DOPA
DA
D3R
DA
RELEASE
G
DA release
D A
AC
DAT
G
D2R
Synaptic cleft
DA D2R
D3R
Post-synaptic neuron
G i
D1R
AC
ATP
G s
cAMP
PKA
Numerous cellular processes regulation
Model of the dopaminergic synaptic transmission. .
D2R
Degradation
DOPAMINE % OF BASELINE
The effects of haloperidol and quinpirole on DA release are suppressed in D2R null mice
400
D2RKO Halop. 0.5mg/kg
350
WT
Halop. 0.5mg/kg
WT
Quinp. 0.3mg/kg
D2RK0 Quinp. 0.3mg/kg
300 250 200
injection
150 100 50 0
40
20
0
20
40
60
TIME (min)
80 100
120
Alterata funzione di autoregolazione nei topi mutanti D2
Haloperidol effects on DA release are suppressed in striatum and Acb in D2R null mice
Selective targeted ablation of the D2L receptor
D2L null mice have normal D2 and D1 receptor binding sites
Parkinsonianlike locomotor impairment in mice lacking dopamine D2 receptors
D2L null mice have normal motor function
Drugs involved in the reward system of the brain
Cocaine Amphetamine Cannabinoids Alcohol Opioids Nicotine
Mesolimbic pathway Crucial role in Rewarding effects induced by natural events behavioural response to drugs of abuse
DOPAMINE AND DRUG ABUSE ANY ADDICTIVE DRUG INDUCES AN INCREASE OF DA RELEASE WHAT IS THE ROLE OF THE D2 RECEPTOR IN THE RESPONSE TO DRUGS OF ABUSE?
DAergic Mesolimbic pathways: cocaine effects
Cocaina e morphine: effetti nel cervello Microdialysis probe 2 mm long
Effetti comportamentali alterati della cocaina in topi D2 ko
Effetti di plasticità neuronale indotti dalla cocaina sono alterati nei topi D2 ko
Effetti di plasticità neuronale indotti dalla cocaina sono alterati nei topi D2 ko
Conditioned place preference Protocole :
Camera
•15’ pre-exposure (2 days) •15’ Pre-conditioning test
Informatic treatment of the data
•30’ Conditioning (8 days) Time
•15’ Post-conditioning test RESULTS
Compartment
Cocaina piacere e attivazione cerebrale nei topi D2 Ko
Mesolimbic pathways: morphine effects
Effetti motori indotti dalla morphina in topi mutanti per il recettore D2
Effetti motori indotti da trattamento cronico con morphine alterati nei mutanti
Espressione genica indotta da morphine
Conditioned place preference Protocole :
Camera
•15’ pre-exposure (2 days) •15’ Pre-conditioning test
Informatic treatment of the data
•30’ Conditioning (8 days) Time
•15’ Post-conditioning test RESULTS
Compartment
Piacere morphine e ruolo D2 receptor
Piacere morphine e ruolo D2L receptor
CONCLUSIONS Dopamine D2S isoform is a key element in regulating DA increase induced by drugs of abuse
We propose that functional D2Smediated presynaptic functions are pivotal in the rewarding mechanism underlying addiction.
DAergic Nigrostriatal and Mesolimbic pathways
Mutando geneticamente la TH………….
Induciamo un severo modello animale parkinsoniano
La terapia genetica come approccio al Parkinson
Microdialysis probe 2 mm long
to human psychiatric and neurological disorders...
Motor function
Sexual Behaviour
Motivated Behaviour
DOPAMINE Learning and Memory Sensorimotor gating
Parkinson disease
Drug of Abuse Schizophrenia
DAergic Nigrostriatal and Mesolimbic pathways
DOPAMINE RECEPTORS D1-LIKE FAMILY D1R D5R
D2-LIKE FAMILY D2R (D2L & D2S) D3R D4R
Basal Ganglia network
Some of the signal trasduction pathways of dopamine receptors
FIRING Pre-synaptic neuron
SYNTHESIS
TH
D3R
Ca2+ TH
D2R
Gi
ATP cAMP
P
Degradation
DA Tyrosine
MA O
L-DOPA
DA
D3R
DA
RELEASE
G
DA release
D A
AC
DAT
G
D2R
Synaptic cleft
DA D2R
D3R
Post-synaptic neuron
G i
D1R
AC
ATP
G s
cAMP
PKA
Numerous cellular processes regulation
Model of the dopaminergic synaptic transmission. .
D2R
Degradation
The controversy…
D2R ?
? D3R
Dopamine D2R exists as two different isoforms
Targeted disruption of dopamine D2 receptors
Microdialysis probe 2 mm long
FIRING Pre-synaptic neuron
SYNTHESIS
TH
D3R
Ca2+ TH
D2R
Gi
ATP cAMP
P
Degradation
DA Tyrosine
MA O
L-DOPA
DA
D3R
DA
RELEASE
G
DA release
D A
AC
DAT
G
D2R
Synaptic cleft
DA D2R
D3R
Post-synaptic neuron
G i
D1R
AC
ATP
G s
cAMP
PKA
Numerous cellular processes regulation
Model of the dopaminergic synaptic transmission. .
D2R
Degradation
DOPAMINE % OF BASELINE
The effects of haloperidol and quinpirole on DA release are suppressed in D2R null mice
400
D2RKO Halop. 0.5mg/kg
350
WT
Halop. 0.5mg/kg
WT
Quinp. 0.3mg/kg
D2RK0 Quinp. 0.3mg/kg
300 250 200
injection
150 100 50 0
40
20
0
20
40
60
TIME (min)
80 100
120
Alterata funzione di autoregolazione nei topi mutanti D2
Haloperidol effects on DA release are suppressed in striatum and Acb in D2R null mice
Selective targeted ablation of the D2L receptor
D2L null mice have normal D2 and D1 receptor binding sites
Parkinsonianlike locomotor impairment in mice lacking dopamine D2 receptors
D2L null mice have normal motor function
Drugs involved in the reward system of the brain
Cocaine Amphetamine Cannabinoids Alcohol Opioids Nicotine
Mesolimbic pathway Crucial role in Rewarding effects induced by natural events behavioural response to drugs of abuse
DOPAMINE AND DRUG ABUSE ANY ADDICTIVE DRUG INDUCES AN INCREASE OF DA RELEASE WHAT IS THE ROLE OF THE D2 RECEPTOR IN THE RESPONSE TO DRUGS OF ABUSE?
DAergic Mesolimbic pathways: cocaine effects
Cocaina e morphine: effetti nel cervello Microdialysis probe 2 mm long
Effetti comportamentali alterati della cocaina in topi D2 ko
Effetti di plasticità neuronale indotti dalla cocaina sono alterati nei topi D2 ko
Effetti di plasticità neuronale indotti dalla cocaina sono alterati nei topi D2 ko
Conditioned place preference Protocole :
Camera
•15’ pre-exposure (2 days) •15’ Pre-conditioning test
Informatic treatment of the data
•30’ Conditioning (8 days) Time
•15’ Post-conditioning test RESULTS
Compartment
Cocaina piacere e attivazione cerebrale nei topi D2 Ko
Mesolimbic pathways: morphine effects
Effetti motori indotti dalla morphina in topi mutanti per il recettore D2
Effetti motori indotti da trattamento cronico con morphine alterati nei mutanti
Espressione genica indotta da morphine
Conditioned place preference Protocole :
Camera
•15’ pre-exposure (2 days) •15’ Pre-conditioning test
Informatic treatment of the data
•30’ Conditioning (8 days) Time
•15’ Post-conditioning test RESULTS
Compartment
Piacere morphine e ruolo D2 receptor
Piacere morphine e ruolo D2L receptor
CONCLUSIONS Dopamine D2S isoform is a key element in regulating DA increase induced by drugs of abuse
We propose that functional D2Smediated presynaptic functions are pivotal in the rewarding mechanism underlying addiction.
DAergic Nigrostriatal and Mesolimbic pathways
Mutando geneticamente la TH………….
Induciamo un severo modello animale parkinsoniano
La terapia genetica come approccio al Parkinson
Microdialysis probe 2 mm long
