ABSTRACT
Title
Chronic THC exposure during adolescence modifies the physiological development of the endocannabinoid system and neural refinement in specific brain areas
Authors
T. Rubino1, P. Prini1, F. Piscitelli2, E. Zamberletti1, S. Speziali1, A. Ligresti2, D. Parolaro1
1DBSF and Neuroscience Center, University of Insubria, Busto Arsizio (VA), Italy
2Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli (NA), Italy
1DBSF and Neuroscience Center, University of Insubria, Busto Arsizio (VA), Italy
2Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli (NA), Italy
Abstract
We recently demonstrated that adolescent exposure to THC in female rats induces long-lasting behavioural and cellular modifications leading to the development of a complex depressive-like phenotype at adulthood. Adolescence represents a vulnerable time window for the deleterious effects of THC on mood, in fact adult exposure to THC did not induce the depressive phenotype observed after the adolescent treatment.
Adolescence is increasingly viewed as an important developmental window, where ongoing neuroplastic modifications occur in the central nervous system. These include changes in dendritic spine density, synaptic rearrangements, myelinization of nerve fibers, changes in neurotransmitter concentrations and their receptor levels. Since the endocannabinoid system plays an important role during the different stages of brain development, exposure to cannabinoids during adolescence may conceivably alter the physiology of the endocannabinoid system as well as the processes involved in brain maturation and neural refinement specific of this developmental phase.
On these bases, the first aim of the present work was to study the maturation of the endocannabinoid system from adolescence into adulthood, in term of receptors and endogenous ligands, in the brain areas more involved in the modulation of emotional behaviour (i.e. the prefrontal cortex, nucleus accumbens, amygdala and hippocampus) and how adolescent exposure to THC may affect it. To this aim, CB1 receptor binding studies and evaluation of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) levels were performed at 46 post natal day (PND), 60 PND and 75 PND, representing the middle and late adolescence, and adulthood, respectively. The same study was then performed on the brains from animals exposed to THC during adolescence (35-45 PND). Our results indicate that both CB1 receptor and AEA increase during adolescence and then decrease with different intensity when animals reach adult age. On the contrary, 2-AG levels decreased through adolescence and then increased at adulthood. Adolescent THC treatment altered this course, with lower CB1 receptor levels during adolescence and, in some brain regions, also at adulthood; lower AEA levels in the prefrontal cortex and nucleus accumbens and increased 2-AG in the hippocampus and amygdala.
The second step of this work was to investigate the occurrence of neuronal refinement in this specific time window and the impact of adolescent THC treatment on it. To this aim we monitored synaptophysin and PSD95 levels at 46, 60 and 75 PND in control and THC-treated rats. PSD95 progression appears to be the most affected by adolescent exposure to THC. In fact, while control animals exhibited a decrease in this protein levels at 60 PND and then an increase at 75 PND, this trend was flattened in the nucleus accumbens and significantly altered in the other brain areas.
Taken together these results suggest that adolescent THC treatment disrupts the physiological course of the endocannabinoid system maturation into adulthood and the processes of synaptic remodelling proper of the adolescent period.
Adolescence is increasingly viewed as an important developmental window, where ongoing neuroplastic modifications occur in the central nervous system. These include changes in dendritic spine density, synaptic rearrangements, myelinization of nerve fibers, changes in neurotransmitter concentrations and their receptor levels. Since the endocannabinoid system plays an important role during the different stages of brain development, exposure to cannabinoids during adolescence may conceivably alter the physiology of the endocannabinoid system as well as the processes involved in brain maturation and neural refinement specific of this developmental phase.
On these bases, the first aim of the present work was to study the maturation of the endocannabinoid system from adolescence into adulthood, in term of receptors and endogenous ligands, in the brain areas more involved in the modulation of emotional behaviour (i.e. the prefrontal cortex, nucleus accumbens, amygdala and hippocampus) and how adolescent exposure to THC may affect it. To this aim, CB1 receptor binding studies and evaluation of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) levels were performed at 46 post natal day (PND), 60 PND and 75 PND, representing the middle and late adolescence, and adulthood, respectively. The same study was then performed on the brains from animals exposed to THC during adolescence (35-45 PND). Our results indicate that both CB1 receptor and AEA increase during adolescence and then decrease with different intensity when animals reach adult age. On the contrary, 2-AG levels decreased through adolescence and then increased at adulthood. Adolescent THC treatment altered this course, with lower CB1 receptor levels during adolescence and, in some brain regions, also at adulthood; lower AEA levels in the prefrontal cortex and nucleus accumbens and increased 2-AG in the hippocampus and amygdala.
The second step of this work was to investigate the occurrence of neuronal refinement in this specific time window and the impact of adolescent THC treatment on it. To this aim we monitored synaptophysin and PSD95 levels at 46, 60 and 75 PND in control and THC-treated rats. PSD95 progression appears to be the most affected by adolescent exposure to THC. In fact, while control animals exhibited a decrease in this protein levels at 60 PND and then an increase at 75 PND, this trend was flattened in the nucleus accumbens and significantly altered in the other brain areas.
Taken together these results suggest that adolescent THC treatment disrupts the physiological course of the endocannabinoid system maturation into adulthood and the processes of synaptic remodelling proper of the adolescent period.