Impact of the developing endocannabinoid system in rats on the modulatory influence of stress on adolescent ethanol intake
Final Report Abstract
With the present project we were able to shed light on the impact of the eCB system, and in particular CB1 receptor activity, on ethanol intake and its modulation by stress-experiences during adolescence. Adolescence is a critical neurodevelopmental period and many neuropsychiatric disorders, including drug abuse, have their onset specifically during this phase. In a translational approach we could demonstrate in rats and humans that specifically the pubertal period represents a highly vulnerable time window during adolescence for the initiation of ethanol use with respect to long-term consequences, such as problematic ethanol abuse in late life. This was an important finding for drug prevention programs and evoked high public interest and media coverage. The finding might be related to the behavioral characteristics of puberty, such as high novelty-seeking, risk taking behavior and low cognitive control. One further important factor contributing to the high vulnerability towards ethanol use during puberty and its consequences is also the increased reward processing for natural and drug rewards in a pubertal brain. We could further demonstrate that CB1 receptor signaling is transiently increased during the pubertal period and also serves as an important factor in various reward related behaviors including hedonic reward processing. Additionally, aside from reward processing, enhanced CB1 receptor signaling appears also to be involved in further behavioral characteristics of the pubertal period (e.g. risk taking) which was shown by behavioral characterization of a genetic animal model for increased CB1 receptor activity. These findings were highlighted in Neuronline – a publication platform for teaching and learning purposes of the Society of Neuroscience. In line with these findings on increased reward processing during puberty and the impact of eCB signaling, chronic treatment with a CB1 receptor agonist during puberty was found to stimulate ethanol intake simultaneously and also persistently in later life. With respect to the impact of stress-experiences in adolescence - the importance of the choice of the stressor became apparent. We therefore focused on the establishment of a psychosocial stress-model, where animals were specifically deprived for adequate playful interactions, but not normal social contact, during the adolescent period. This peer-rejection model was found to induce persistent behavioral changes as well as alterations in the eCB system. In particular CB1 receptor signaling in the amygdala was found to be increased on the long-term after such subtle social manipulations in adolescence. Furthermore, we could demonstrate that rejection experiences in adolescence enhanced simultaneous as well as later voluntary ethanol intake, implicating altogether a strong modulatory effects of stressexperiences and eCB signaling during adolescence on ethanol use.
Publications
- Behavioral differences in three wistar rat lines for emotional reactivity, cognitive processing and ethanol intake. Physiol. Behav. 110:102–108 (2013)
Goepfrich A, Gluch C, Friemel C, Schneider M
(See online at https://doi.org/10.1016/j.physbeh.2012.12.019) - Impact of pubertal stage at first drink on adult drinking behavior. ACER 37(10):1804-11 (2013)
Blomeyer D, Friemel C, Buchmann A, Banaschewski T, Laucht M, Schneider M
(See online at https://doi.org/10.1111/acer.12154) - Adolescent peer-rejection persistently alters pain perception and CB1 receptor expression in female rats. Eur. Neuropsychopharm. 24: 290-301. (2014)
Schneider P, Hanusch C, Schmahl C, Bohus M, Spanagel R, Schneider M
(See online at https://doi.org/10.1016/j.euroneuro.2013.04.004) - The CB1 receptor as an important mediator of hedonic reward processing. Neuropsychopharmacology 39(10):2387-96 (2014)
Friemel C, Zimmer A, Schneider M
(See online at https://doi.org/10.1038/npp.2014.86) - Enhanced functional activity of the cannabinoid receptor 1 drives adolescent behavior, J Neurosci 35(41):13975-88. (2015)
Schneider M, Kasanetz F, Lynch D, Friemel C, Lassalle O, Hurst DP, Steindel F, Monory K, Schäfer C, Miederer I, Leweke FM, Schreckenberger M, Lutz B, Reggio PH, Manzoni OJ, Spanagel R
(See online at https://doi.org/10.1523/JNEUROSCI.1937-15.2015)
