ABSTRACT
Title
Effects of the indirect cannabinoid agonist URB597 in the modulation of social behavior in rats
Authors
A. Manduca1, P. Campolongo2, M.C. Bedetta2, M. Palmery2, V. Trezza1, V. Cuomo2
1 Dept. of Biology, University of Roma Tre, Rome, Italy
2 Dept. of Physiology and Pharmacology, Sapienza University of Rome, Italy
1 Dept. of Biology, University of Roma Tre, Rome, Italy
2 Dept. of Physiology and Pharmacology, Sapienza University of Rome, Italy
Abstract
The endocannabinoid system is a unique neuromodulatory system in mammalian physiology, which plays an important role in the regulation of emotional and cognitive processes.
The indirect cannabinoid agonist URB597, a potent and selective inhibitor of the enzyme fatty-acid amide hydrolase (FAAH), which catalyzes the intracellular hydrolysis of the endocannabinoid anandamide, exerts antidepressant- (Gobbi et al., 2005) and anxiolityc-like effects (Kathuria et al., 2003) in different animal models of mood and anxiety disorders. Interestingly, it has recently been suggested that the behavioral effects induced by URB597 are strongly dependent on environmental factors, both in adolescent (Trezza et al., 2008) and adult (Haller et al.,2009) rats. For instance, previous studies performed by our group (Trezza et al., 2008) reported a context-dependent effect of URB597 in the modulation of social play behavior in rats: thus, the increase in social play induced by URB597 depended on the level of social activity exhibited by the social partner. The aim of the present study was to provide more insights into the role of the endocannabinoid system in the modulation of emotional reactivity, by focusing on endocannabinoid modulation of social behavior in adolescent and adult rats. To this aim, we tested the effects of URB597 in social play behavior, the most characteristic social activity in adolescent rats, and measured the rate of ultrasonic vocalizations emitted by adolescent rats during the social encounter. Furthermore, we tested the effects of URB597 in the social interaction test in adult rats, a task sensitive to environmental and physiological factors that can affect emotionality in rodents.
To study the effects of URB597 in the modulation of social play behavior in adolescent rats, we used four-week old male Wistar rats, briefly socially isolated before testing; to study the effects of URB597 in social behavior at adulthood, we used eight-eleven week-old male Wistar rats, isolated 24 hours before testing and either habituated or non-habituated to the test cage prior to testing.
We found that URB597 enhanced social play in adolescence rats without affecting ultrasonic vocalizations, confirming that on-demand release of endocannabinoids has facilitatory effects on social behavior during adolescence and that endocannabinoids are released in brain areas mediating social play. Furthermore, we found that URB597 increased social interaction in adult rats that were not habituated to the test cage prior to testing, but not in rats habituated to the experimental apparatus. These data confirm previous findings (Haller et al., 2009) by showing that, in adult rats, FAAH inhibition affects emotional reactivity under high stressful circumstances. Our findings suggest that selective indirect cannabinoid agonists could represent a potential target to treat social dysfunctions in neurodevelopmental diseases and could protect against the anxiogenic effects of stressful stimuli at adulthood.
Gobbi et al. (2005). Proc Natl Acad Sci U S A. 102(51):18620-5.
Kathuria et al. (2003). Nat Med. 9(1):76-81.
Trezza et al. (2008). Eur Neuropsychopharmacol. 18(7):519-30.
Haller et al. (2009). Psychopharmacology (Berl). 204(4):607-16.
The indirect cannabinoid agonist URB597, a potent and selective inhibitor of the enzyme fatty-acid amide hydrolase (FAAH), which catalyzes the intracellular hydrolysis of the endocannabinoid anandamide, exerts antidepressant- (Gobbi et al., 2005) and anxiolityc-like effects (Kathuria et al., 2003) in different animal models of mood and anxiety disorders. Interestingly, it has recently been suggested that the behavioral effects induced by URB597 are strongly dependent on environmental factors, both in adolescent (Trezza et al., 2008) and adult (Haller et al.,2009) rats. For instance, previous studies performed by our group (Trezza et al., 2008) reported a context-dependent effect of URB597 in the modulation of social play behavior in rats: thus, the increase in social play induced by URB597 depended on the level of social activity exhibited by the social partner. The aim of the present study was to provide more insights into the role of the endocannabinoid system in the modulation of emotional reactivity, by focusing on endocannabinoid modulation of social behavior in adolescent and adult rats. To this aim, we tested the effects of URB597 in social play behavior, the most characteristic social activity in adolescent rats, and measured the rate of ultrasonic vocalizations emitted by adolescent rats during the social encounter. Furthermore, we tested the effects of URB597 in the social interaction test in adult rats, a task sensitive to environmental and physiological factors that can affect emotionality in rodents.
To study the effects of URB597 in the modulation of social play behavior in adolescent rats, we used four-week old male Wistar rats, briefly socially isolated before testing; to study the effects of URB597 in social behavior at adulthood, we used eight-eleven week-old male Wistar rats, isolated 24 hours before testing and either habituated or non-habituated to the test cage prior to testing.
We found that URB597 enhanced social play in adolescence rats without affecting ultrasonic vocalizations, confirming that on-demand release of endocannabinoids has facilitatory effects on social behavior during adolescence and that endocannabinoids are released in brain areas mediating social play. Furthermore, we found that URB597 increased social interaction in adult rats that were not habituated to the test cage prior to testing, but not in rats habituated to the experimental apparatus. These data confirm previous findings (Haller et al., 2009) by showing that, in adult rats, FAAH inhibition affects emotional reactivity under high stressful circumstances. Our findings suggest that selective indirect cannabinoid agonists could represent a potential target to treat social dysfunctions in neurodevelopmental diseases and could protect against the anxiogenic effects of stressful stimuli at adulthood.
Gobbi et al. (2005). Proc Natl Acad Sci U S A. 102(51):18620-5.
Kathuria et al. (2003). Nat Med. 9(1):76-81.
Trezza et al. (2008). Eur Neuropsychopharmacol. 18(7):519-30.
Haller et al. (2009). Psychopharmacology (Berl). 204(4):607-16.