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…from mouse genetics

to human psychiatric and neurological disorders...
Motor function Motivated Behaviour

DOPAMINE 
Sexual Behaviour Learning and Memory

Sensorimotor gating

Parkinson disease
Drug of Abuse

Schizophrenia
DAergic Nigrostriatal and Mesolimbic pathways
DOPAMINE RECEPTORS
 D1-LIKE FAMILY  D2-LIKE FAMILY
 D1R  D2R (D2L & D2S)
 D5R  D3R
 D4R
Basal Ganglia network
Some of the signal trasduction 
pathways of dopamine receptors
FIRING

Pre-synaptic neuron

Degradation

SYNTHESIS TH DA
P
Tyrosine
MA
D3R Ca2+ D3R
O
L-DOPA

RELEASE
TH G
DA
ATP cAMP release
D2R Gi DA DA G
D2R
D
AC
A
DAT
Synaptic cleft
DA Degradation
D2R D1R
G i AC G s
D2R

D3R Numerous
ATP cAMP
cellular
processes
Post-synaptic neuron PKA
regulation

Model of the dopaminergic synaptic 
transmission.
.
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

Degradation

SYNTHESIS TH DA
P
Tyrosine
MA
D3R Ca2+ D3R
O
L-DOPA

RELEASE
TH G
DA
ATP cAMP release
D2R Gi DA DA G
D2R
D
AC
A
DAT
Synaptic cleft
DA Degradation
D2R D1R
G i AC G s
D2R

D3R Numerous
ATP cAMP
cellular
processes
Post-synaptic neuron PKA
regulation

Model of the dopaminergic synaptic 
transmission.
.
The effects of haloperidol and quinpirole on DA
release are suppressed in D2R null mice

D2RKO Halop. 0.5mg/kg


DOPAMINE % OF BASELINE 400
D2RK0 Quinp. 0.3mg/kg
350 WT Halop. 0.5mg/kg
WT Quinp. 0.3mg/kg
300

250

200
injection
150

100

50

0
­40 ­20 0 20 40 60 80 100 120

TIME (min)
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

Camera Protocole :

•15’ pre-exposure (2 days)

•15’ Pre-conditioning test

•30’ Conditioning (8 days)


Informatic Time
treatment of
the data
•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

Camera Protocole :

•15’ pre-exposure (2 days)

•15’ Pre-conditioning test

•30’ Conditioning (8 days)


Informatic Time
treatment of
the data
•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

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