Acetaminophen differentially enhances social behavior and cortical cannabinoid levels in inbred mice

Supratherapeutic doses of the analgesic acetaminophen (paracetomol) are reported to promote social behavior in Swiss mice. However, we hypothesized that it might not promote sociability in other strains due to cannabinoid CB₁ receptor-mediated inhibition of serotonin (5-HT) transmission in the frontal cortex. We examined the effects of acetaminophen on social and repetitive behaviors in comparison to a cannabinoid agonist, WIN 55,212-2, in two strains of socially-deficient mice, BTBR and 129S1/SvImJ (129S). Acetaminophen (100mg/kg) enhanced social interactions in BTBR, and social novelty preference and marble burying in 129S at serum levels of ≥70ng/ml. Following acetaminophen injection or sociability testing, anandamide (AEA) increased in BTBR frontal cortex, while behavior testing increased 2-arachidonyl glycerol (2-AG) levels in 129S frontal cortex. In contrast, WIN 55,212-2 (0.1mg/kg) did not enhance sociability. Further, we expected CB₁-deficient (+/-) mice to be less social than wild-type, but instead found similar sociability. Given strain differences in endocannabinoid response to acetaminophen, we compared cortical CB₁ and 5-HT_1A receptor density and function relative to sociable C57BL/6 mice. CB₁ receptor saturation binding (Bmax=958±117fmol/mg protein), and affinity for [³H] CP55,940 (K_D=3±0.8nM) was similar in frontal cortex among strains. CP55,940-stimulated [³⁵S] GTPγS binding in cingulate cortex was 136±12, 156±22, and 75±9% above basal in BTBR, 129S and C57BL/6 mice. The acetaminophen metabolite para-aminophenol (1μM) failed to stimulate [³⁵S] GTPγS binding. Hence, it appears that other indirect actions of acetaminophen, including 5-HT receptor agonism, may underlie its sociability promoting properties outweighing any CB₁ mediated suppression by locally-elevated endocannabinoids in these mice.