Cross-talk between endocannabinoid and opioid systems in the modulation of social behavior in adolescent rats

Viviana Trezza, Louk J.M.J. Vanderschuren. Rudolf Magnus Institute of Neuroscience, Utrecht, Netherlands.

During adolescence, rats, as well as other mammalian species, display a characteristic form of social interaction termed social play behavior. This form of social behavior is highly rewarding and essential for social and cognitive development (Vanderschuren et al., 1997). However, despite its importance for behavioral development, the neural basis of this behavior is incompletely understood. The brain opioid system, which closely interacts with the endocannabinoid systems in the regulation of reward processes (Fattore et al., 2005; Manzanares et al., 1999), has been strongly implicated in the modulation of social play behavior (Vanderschuren et al., 1997). Cannabinoid neurotransmission may therefore influence social play in concert with the opioid system.

To study the role of endocannabinoid neurotransmission in the modulation of social play behavior, and its potential interaction with the opioid system, we used four-week old male Wistar rats that were briefly socially isolated before testing.

We found that directly stimulating cannabinoid receptors using the CB1 cannabinoid receptor agonist WIN55,212-2 reduced social play (Tukey’s post hoc test, p<0.01, n=8 per treatment group). However, URB597, which inhibits hydrolysis of the endogenous cannabinoid anandamide, enhanced social play (Tukey’s post hoc test, p<0.01, n=8 per treatment group). The effects of both WIN55,212-2 and URB597 were blocked by the CB1 cannabinoid receptor antagonist SR141716A. The opioid receptor antagonist naloxone did not affect the reduction in play behavior induced by WIN55,212-2 (Tukey’s post hoc test, p<0.01, n=8 per treatment group), whereas it reversed the effects induced by URB597 on social play. Furthermore, the well-known stimulatory effect of morphine on social play behavior was attenuated by SR141716A. The interaction between endocannabinoid and opioid systems in the modulation of social play was underscored by the observation that combined treatment with subeffective doses of URB597 and morphine enhanced social play (Tukey’s post hoc test, p<0.01, n=8 per treatment group).

Two main conclusions can be drawn from the present results. First, the reduction in play behavior induced by WIN55,212-2 suggests that stimulation of cannabinoid receptors throughout the brain, which occurs during cannabis use, inhibits sociability. In contrast, the effect of URB597 on social play suggests that on-demand release of endocannabinoids has facilitatory effects on social interaction. Second, the present results demonstrate that the neuronal mechanisms underlying cannabinoid-opioid interactions are already functional in adolescent animals. Furthermore, they extend the involvement of opioid-cannabinoid interactions in the modulation of drug-directed behavior (Fattore et al., 2005; Manzanares et al., 1999) and food-directed behavior (Solinas et al., 2005) to another natural reinforcer, i.e. social play behaviour.

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Manzanares, J. et al. (1999) Trends Pharmacol Sci 20, 287-94

Solinas, M. & Goldberg, S. R. (2005)Neuropsychopharmacology 30, 2035-45

Vanderschuren, L. J. et al. (1997) Neurosci Biobehav Rev 21, 309-26.