risk for psychiatric diseases following cannabis abuse in adolescence :an experimental study daniela...
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Risk for psychiatric diseases following cannabis abuse in adolescence :an
experimental study
Daniela ParolaroUniv of Insubria
Characterization of the phenotype present in adult rats pre-exposed to THC in adolescence
Postnatal day (PND)
28
Arrival ofanimals
35 36 37 38 39 40 41 42 43 44 45
Beginning of treatment
End of treatment
2.5 mg/kgTHC
Twice a day
5 mg/kgTHC
Twice a day
10 mg/kgTHC
Twice a day
Beginning of behavioral tests
75
DRUG-FREE
No alteration in anxiety behaviour
No presence of behavioural despair
Rubino et al., Neuropsychopharmacol 2008; Hippocampus 2009
changes in dendritic morphology and spine density in dentate granule cells of the hippocampus
Spatial working memory impairments in the radial maze
Adolescent THC exposureAdolescent THC exposure induced…induced…
reduced markers of neuronal plasticity in the hippocampus
Adult THC exposure did not induce
cognitive impairment in the radial maze
alteration in markers of neural plasticity in the hippocampus
COGNITIONCOGNITION
Classic Spatial
Novel Object Recognition Test
-50
-25
0
25
50
*
*
Dis
crim
inat
ion
in
dex
-50
-25
0
25
50
****
vehicle+vehicleTHC+vehiclevehicle+PCP
Dis
crim
inat
ion
In
dex
Social Interaction Test
Test phase (10 min)Habituation phase (10 min)
EMOTIONALITYEMOTIONALITY
Active social behaviors
veh+veh THC+veh veh+PCP0
10
20
30
40
50
60
70
80
90
******
tim
e (s
)
Aggressive behaviors
veh+veh THC+veh veh+PCP0
2
4
6
nu
mb
er o
f ep
iso
des
Single session15 minutes
-Immobility-Climbing
-Swimming
EMOTIONALITYEMOTIONALITYForced Swim Test
Immobility
veh+veh THC+veh veh+PCP0
50
100
150
200
250
300
350 ** **
tim
e(s)
Swimming
veh+veh THC+veh veh+PCP0
100
200
300
400
500
600
700
tim
e (s
)
Climbing
veh+veh THC+veh veh+PCP0
20
40
60
80
100
tim
e (s
)
a b
1 2 3 40.0
0.2
0.4
0.6
0.8 vehicleTHC
Days
Pal
atab
le f
oo
d (
g)
Anhedonia through Fonzies intake
0 1 2 360
70
80
90
100
* *
Day
% s
ucro
se p
refe
renc
e
Anhedonia through sucrose preference
Anhedonia
PCP 2.5 mg/kgPCP 2.5 mg/kg
10 20 30 40 500
1000
2000
3000
4000
***°°°^̂ ^
***°°°^̂ ^
***°°°^̂ ^
Time (min)
n.
of
ph
oto
cell
bea
m b
reak
s
ONLY THC-TREATED RATS SHOW HYPERLOCOMOTION AND INCREASED STEREOTYPED BEHAVIORS IN RESPONSE TO A LOW DOSE OF PCP COMPARED TO CONTROL ANIMALS
10 20 30 40 500
50
100
150
200
250
*°^
***
***^̂ ^
^̂ ^°°° ***
***^̂ ^
^̂ ^°°°
***
***^̂ ^
^̂ ^°°°
****^̂ ^°°
^
vehTHCPCPTHC+PCP
Time (min)
Tim
e (
sec)
Locomotor activity
Stereotypies
Adolescent THC exposure in female rats induces cognitive deficit, social withdrawal, avolition, anhedonia and sensitizes to PCP
The hypersensitivity to PCP seems to be due to increased neuronal activation in the caudate putamen and nucleus
accumbens as confirmed by enhanced glutamate release in the dorsal striatum
1 2 360
70
80
90
100
VehicleTHC
Days
% s
ucro
se p
refe
renc
e
a b
c d e
swimming climbing immobility
0
75
150
225vehicleTHC
*
Tim
e (s
)
Adult female rats exposed to THC did not show altered phenotype
Realini et al 2010
Adolescent THC exposure led to decreased GAD 67 levels in adulthood paralleled by decreased basal GABA release in the prefrontal cortex
46 PND 60 PND 75 PND0.0
0.5
1.0
1.5
2.0
2.5controlTHC
***
***
Arb
itrary
Units
(GA
D67/
act
)
***
BASAL GABA RELEASEGAD67 LEVELS
0
2
4
6
8
10
controlTHC
Bas
al e
xtra
cellu
lar
GA
BA
leve
ls(n
M)
GluA2-containing
GluA1-containing
GluN2B-containing
GluN2A-containing
GluA2-containing
GluA1-containing
GluN2B-containing
GluN2A-containing
DEVELOPMENT
Pro
tein
leve
ls
ADOLESCENT THC EXPOSURE ALTERS THE REARRANGEMENT OF NMDA AND AMPA RECEPTOR SUBUNITS, RESULTING IN THE PRESENCE OF
IMMATURE, MORE EXCITABLE, GLUTAMATERGIC SYNAPSES IN THE ADULT PFC
THC
DISTAL DENDRITES
46 PND 60 PND 75 PND0
2
4
6
8
10
*
*** ***
spin
es/1
0m
Adolescent THC exposure decreased spine density at the distal portion of basilar dendrites
the brain continues to develop throughout adolescence
At cellular level, changes in gray matter volumes appear to be associated with pruning in later adolescence
important structural and functional changes in synaptic plasticity and neural connectivity
Endocannabinoids as retrograde messengersEndocannabinoids as retrograde messengers
THC
lasting changes in brain and behavior?
ECS
Adolescent brain
The endocannabinoid system undergoes maturational events during adolescence that are impaired by chronic
THC exposure
correct neuronal refinement peculiar of the adolescent brain
altered brain functionality and behavior at adulthood
The possible problems associated with marijuana consumption in adolescence suggest that the adolescence developmental phase represents a vulnerable time period for persistent effects on synaptic plasticity that could underline adverse actions of cannabinoids in adulthood.These effects are sex-dependent.