Background: Recent evidence suggests that 2-week treatment with the nonpsychotomimetic cannabinoid cannabidivarin (CBDV) could be beneficial towards neurological and social deficits in early symptomatic Mecp2 mutant mice, a model of Rett syndrome (RTT). Aim: To provide further insights into the efficacy of CBDV in Mecp2-null mice we used a lifelong treatment schedule (from 4 to 9 weeks of age) and evaluated its effect on recognition memory and neurological defects in both early and advanced stages of the phenotype progression. Methods: CBDV 0.2, 2, 20, 200 mg/kg/day was administered to Mecp2-null mice from 4 to 9 weeks of age. Cognitive and neurological defects were monitored during the whole treatment schedule. Biochemical analyses were carried out in brain lysates from 9-week-old wildtype and knockout mice to evaluate brainderived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1) levels as well as components of the endocannabinoid system. Results: CBDV rescues recognition memory deficits in Mecp2 mutant mice and delays the appearance of neurological defects. At the biochemical level, it normalizes BDNF/IGF1 levels and the defective PI3K/AKT/mTOR pathway in Mecp2 mutant mice at an advanced stage of the disease. Mecp2 deletion 3 upregulates CB1 and CB2 receptor levels in the brain and these changes are restored after CBDV treatment. Conclusions: CBDV administration exerts an enduring rescue of memory deficits in Mecp2 mutant mice, an effect that is associated with the normalization of BDNF, IGF-1 and rpS6 phosphorylation levels as well as CB1 and CB2 receptor expression. CBDV delays neurological defects but this effect is only transient.

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IntroductionAim of studyto investigate the consequences of chronic psychosocial stress on behavior, endocannabinoids and CBR expression in prefrontal cortex (PFC) and striatum of mice.Materials and MethodsPsychosocial stress was induced in adult C57Bl/6 mice by resident-intruder paradigm (Brzózka et al. 2011). After 3 weeks daily exposure to psychosocial stress for 1 hour, animals were studied during the rodent active phase (night) by behavioral tests such as Functional Observational Battery (FOB), Rota-Rod (R-R), Open Field (OF), Prepulse Inhibition test (PPI). After behavioral testing, mice were sacrificed. 4 mice brains (prefrontal cortex, dorsal striatum) were studied by LC-MS to estimate the concentration of anandamide (AEA), 2- arachidonoylglycerol (2-AG), N-oleoylethanolamine (OEA), palmitoylethanolamide (PEA) (coll. di Marzo). In Situ Hybridization (ISH)and Immunohistochemistry (IHCH) against CB1 receptor were performed on free floating brain coronal sections fixed by 4% paraformaldehyde (coll del Río).Results1. After psychosocial stress, mice displayed lower body weight (p<0.01), higher scratching and miccions activity compared to controls (p<0.05), decreased number of falls (p<0.01) and increased latency (p<0.05) in Rotarod. No effects in PPI were found. 2. In the same mice psychosocial stress reduced AEA levels in dorsal striatum and PFC (p<0.05). Endocannabinoids significantly showed an inverse relationship in PFC compared to striatum in control mice (AEA, p<0.001; 2-AG, p<0.001; OEA, p<0.001) and in psychosocially stressed mice (PEA, p<0.001; OEA, p<0.001). 3. Psychosocial stress increased the protein CBR1 expression in striatum (p<0.05) but not in prefrontal cortex.ConclusionChronic psychosocial stress significantly changes behavior, endocannabinoids, CB receptor function and the striatal-cortical connectivity. These changes may contribute to vulnerability for psychosis and addiction.

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