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Título

Blockage of CB1 and CB2 receptors impairs sociability in intact rats but does not affect animals submitted to neonatal status epilepticus

Resumo

Introduction. The early life status epilepticus (SE) causes high anxiety and chronic socialization abnormalities, revealed by a low preference for social novelty and deficit in social discrimination. We previously demonstrated that the enhancement of endocannabinoid signaling reduced social motivation in intact rats but did not affect animals submitted to early-life seizures. Objective. Here, we investigated the effect of selective blockade of CB1 and CB2 receptors on sociability of intact rats and exposed to neonatal SE. Methods. Male Wistar rats at postnatal day 9 were subjected to pilocarpine-induced neonatal SE (380 mg/kg, i.p.) and controls received saline 0,9% (0,1 mL/ 10g). From P60 the groups received vehicle or selective CB1 antagonist Am281 (1,0 mg/ kg, i.p.) or selective Cb2 antagonist Am630 (1,0 mg/kg, i.p.) 30 min before behavioral tests. Results. In the social memory paradigm, as expected for vehicle-treated control rats, the investigation toward the same social stimulus decreased with the sequential exposition and increased toward a novel stimulus. In animals subjected to neonatal SE, regardless of the treatment, the social investigation, since the first exposition, was significantly reduced with no enhancement toward a novel stimulus. In contrast, treatment affected intact animals. Am281-treated controls did not discriminate between the social novelty and familiar animal as compared to vehicle-treated ones [treatment effect (F(1,21) = 8.063, p = 0.0098)]. The same was noticed with Am630 [treatment effect (F(1,20) = 5.204, p = 0.0336)]. However, it was noticed differences between treatment with Am281 and Am630 when we analyzed the motivation for the social encounter, measured by the time of overall investigation. Am281 decreased the time of overall interaction specifically in intact animals, being significantly lower in Am281-treated as compared to vehicle treated animals (t = 3.943, p = 0.0276). Differences in overall interaction were not noticed in Am630-treated intact animals. In the sociability test, only intact animals treated with vehicle exhibited social discrimination between the familiar animal and the social novelty. Animals submitted to SE and treated with vehicle did not exhibit social discrimination, measured by time spent in compartment with familiar animal and social novelty. In contrast, treatment affected social discrimination in intact animals, either with Am281 [stimuli × group × treatment interaction (F(1,21) = 11.75, p = 0.0025] or Am630 [stimuli × group × treatment interaction (F(1,20) = 10.10, p = 0.0047]. Analysis of direct social interaction, measured by total time of snout-snout contact, showed interaction of factors [stimuli x Am281 treatment x group (F(1,21)=15.32, p=0.0008)] [stimuli x Am630 treatment x group (F(1,20)=7.313, p=0.0137)]. Only intact animals treated with vehicle showed preference for investigating social novelty than familiar animal as compared to Am281-treated (t=9.232, p<0.0001) and Am630-treated (t=7.934, p<0.0001). Intact animals treated with vehicle also showed a higher time investigating social novelty stimuli as compared to experimental animals, Am281-treated controls (t=6.568, p<0.0001) and to Am630-treated controls (t=4.204, p=0.004). For locomotion, no significant differences were observed between groups or treatments. Conclusion: The blockade of CB1 and CB2 receptors did not modify the sociability of animal subjected to neonatal seizures. In intact animals, social recognition memory was impaired for both antagonists, but social motivation for social novelty was only affected by CB1 receptor antagonist, suggesting that both CB1 and CB2 receptors have a role in social recognition memory, but CB1 has an additional role on social motivation.
Keywords. Neonatal status epilepticus, endocannabinoid system, social behavior.