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

Abstract

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 (100 mg/kg) enhanced social interactions in BTBR, and social novelty preference and marble burying in 129S at serum levels ≥70 ng/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 (0.1 mg/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-HT1A receptor density and function relative to sociable C57BL/6 mice. CB1 receptor saturation binding (Bmax= 958±117 fmol/mg protein), and affinity for [3H]CP55,940 (KD= 3±0.8 nM) 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.

Elucidating cannabinoid biology in zebrafish (Danio rerio)

“…These results are consistent with previous findings that demonstrated anxiolytic effects of WIN55212-2 administration in the rodent elevated-plus maze paradigm (Naderi et al, 2008, Patel & Hillard, 2006). However, in contrast to the findings from the zebrafish visual-choice test, a 0.1 mg/kg dose of WIN55212-2 did not increase sociability in rodents (Gould et al, 2012). The cause of this incongruity remains to be seen and could be due to a host of the previously mentioned factors, or organismal differences.…”

AMPAKINE enhancement of social interaction in the BTBR mouse model of autism

“…We and others are employing BTBR and the control strain B6 to test interventions that may rescue autism-relevant phenotypes in BTBR, as a preclinical translational approach to discovering treatments for autism spectrum disorders (Gould et al, 2012; Silverman et al, 2010a; Silverman et al, 2012;). Although BTBR is an inbred strain rather than a targeted gene mutation with construct validity to a mutation identified in autism, the inbred strain approach may be more analogous to the large majority of cases of autism in which no genetic mutation has been identified, and useful for discovering therapeutic interventions that generalize across larger numbers of cases.…”

The BTBR mouse model of idiopathic autism – Current view on mechanisms

“…Administration of dietary tryptophan improved social approach, without affecting social novelty preference, reduction of excessive grooming or the number of marbles buried by the BTBR mice (Zhang et al 2015). Also, a commonly used painkiller, acetaminophen (paracetamol), acting as a 5HT agonist, increased social approach (but not social novelty preference) in the three-chambered apparatus (Gould et al 2012). Several psychostimulant drugs, acting at the dopaminergic circuitry, affect the behavior of BTBR mice.…”