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 Postnatal day (PND) 28 Arrival of animals Beginning of treatment End of treatment 2.5 mg/kg THC Twice a day 5 mg/kg THC Twice a day 10 mg/kg THC 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 exposure 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

COGNITION Classic Spatial Novel Object Recognition Test

Social Interaction Test Test phase (10 min) Habituation phase (10 min)EMOTIONALITY

Single session 15 minutes -Immobility -Climbing -Swimming EMOTIONALITY Forced Swim Test

a b Anhedonia through Fonzies intake Anhedonia through sucrose preference Anhedonia

PCP 2.5 mg/kg ONLY THC-TREATED RATS SHOW HYPERLOCOMOTION AND INCREASED STEREOTYPED BEHAVIORS IN RESPONSE TO A LOW DOSE OF PCP COMPARED TO CONTROL ANIMALS 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

ab cd e 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 BASAL GABA RELEASEGAD67 LEVELS

GluA2- containing GluA1- containing GluN2B- containing GluN2A- containing GluA2- containing GluA1- containing GluN2B- containing GluN2A- containing DEVELOPMENT Protein levels 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

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 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.