Risk for psychiatric diseases following
cannabis abuse in adolescence :an
experimental study
Daniela Parolaro
Univ of Insubria
Characterization of the phenotype present in
adult rats pre-exposed to THC in adolescence
Arrival of
animals
Postnatal day
(PND)
28
Beginning
of treatment
End
of treatment
35 36 37 38 39 40 41 42
2.5 mg/kg
5 mg/kg
THC
THC
Twice a day Twice a day
43 44
10 mg/kg
THC
Twice a day
Beginning of
behavioral tests
75
45
DRUG-FREE
Adolescent THC exposure induced…
No alteration in anxiety behaviour
No presence of behavioural despair
Spatial working memory impairments in the radial maze
reduced markers of
neuronal plasticity in the
hippocampus
changes in dendritic morphology
and spine density in dentate granule
cells of the hippocampus
Rubino et al., Neuropsychopharmacol 2008; Hippocampus 2009
Adult THC exposure did not induce
cognitive impairment in the radial maze
alteration in markers of neural plasticity
in the hippocampus
COGNITION
Novel Object Recognition Test
Classic
Spatial
50
50
vehicle+vehicle
THC+vehicle
vehicle+PCP
*
0
*
-25
Discrimination Index
Discrimination index
25
25
0
-25
**
-50
-50
**
EMOTIONALITY
Social Interaction Test
Habituation phase (10 min)
Test phase (10 min)
90
80
70
60
50
40
30
20
10
0
Aggressive behaviors
6
***
***
veh+veh
THC+veh
veh+PCP
number of episodes
time (s)
Active social behaviors
4
2
0
veh+veh
THC+veh
veh+PCP
EMOTIONALITY
Forced Swim Test
Single session
15 minutes
- Immobility
- Climbing
- Swimming
Immobility
**
350
**
300
Swimming
Climbing
700
200
100
600
150
80
100
50
time (s)
500
time (s)
time(s)
250
400
300
60
40
200
20
100
0
veh+veh
THC+veh
veh+PCP
0
0
veh+veh
THC+veh
veh+PCP
veh+veh
THC+veh
veh+PCP
Anhedonia
a
b
100
vehicle
THC
% sucrose preference
Palatable food (g)
0.8
0.6
0.4
0.2
90
80
*
*
2
3
70
0.0
1
2
3
4
Days
60
0
1
Day
Anhedonia through Fonzies intake
Anhedonia through sucrose
preference
n. of photocell beam breaks
PCP 2.5 mg/kg
4000
Locomotor activity
^^^
°°°
***
^^^
°°°
***
3000
^^^
°°°
***
2000
1000
0
10
20
30
40
50
Time (min)
250
Stereotypies
Time (sec)
°°°
^^^
***
°°°
^^^
***
200
150
^^^
***
100
°°°
^^^
***
^^^
***
^^^
***
^
°
*
50
veh
THC
PCP
THC+PCP
^
*
°°
^^^
***
0
10
20
30
40
50
Time (min)
ONLY THC-TREATED RATS SHOW HYPERLOCOMOTION AND INCREASED STEREOTYPED
BEHAVIORS IN RESPONSE TO A LOW DOSE OF PCP COMPARED TO CONTROL ANIMALS
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
Adult female rats exposed to THC did not show
altered phenotype
a
b
100
Time (s)
vehicle
THC
150
*
75
c
d
% sucrose preference
225
90
80
70
e
Vehicle
THC
60
1
0
swimming
climbing
2
Days
immobility
Realini et al 2010
3
Adolescent THC exposure led to decreased GAD 67 levels
in adulthood paralleled by decreased basal GABA release
in the prefrontal cortex
GAD67 LEVELS
***
control
THC
***
2.0
***
1.5
1.0
0.5
Basal extracellular GABA levels
(nM)
10
2.5
Arbitrary Units
(GAD67/ act)
BASAL GABA RELEASE
8
6
4
2
0.0
46 PND
60 PND
75 PND
0
control
THC
Protein levels
THC
GluN2B- GluA1containing containing
GluN2A- GluA2containing containing
GluN2A- GluA2containing containing
GluN2B- GluA1containing containing
DEVELOPMENT
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
Adolescent THC exposure decreased spine density at the
distal portion of basilar dendrites
DISTAL DENDRITES
10


spines/10m
8
6
*
4
***
***
60 PND
75 PND
2
0
46 PND
the brain continues to develop throughout adolescence
important structural and functional changes in synaptic plasticity
and neural connectivity
At cellular level, changes in gray matter volumes appear to be
associated with pruning in later adolescence
Endocannabinoids as retrograde messengers
THC
ECS
Adolescent brain
lasting changes in brain
and behavior?
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.
Daniela.parolaro@uninsubria.it