Given the sex differences evident in the prevalence of autism, there is an increased awareness of the importance of including females in autism research to determine sexual dimorphism and sex-specific treatments. Cannabinoids and endocannabinoid modulators have been proposed as potential novel treatments for autism-related symptoms; however, few studies to date have examined if these pharmacological agents elicit sex-specific effects. The aim of the present study was to use the valproic acid (VPA) model of autism to compare the behavioural responses of male and female rats and examine the effects of increasing endocannabinoid tone on the behavioural responses of VPA-exposed female rats. These data revealed that VPA-exposed male, but not female, rats exhibit reduced social responding in the three-chamber and olfactory habituation/dishabituation (OHD) test during adolescence. In comparison, VPA-exposed female, but not male, adolescent rats exhibited anxiety-like behaviour in the elevated plus maze (EPM) and open field test (OFT). In VPA-exposed female rats, increasing 2-AG levels augmented anxiety-like behaviour in the EPM and OFT, while increasing AEA levels reduced stress coping behaviour in the swim stress test. These data highlight sexual dimorphic behaviours in the VPA model and indicate that enhancing endocannabinoid levels may exacerbate negative affective behaviour in VPA-exposed females. Thus, considerations should be paid to the possible sex-specific effects of cannabinoids for the treatment of symptoms associated with autism.

The influence of parental support on child pain experiences is well recognised. Accordingly, animal studies have revealed both short- and long-term effects of early life stress on nociceptive responding and neural substrates such as endocannabinoids. The endocannabinoid system plays an important role in mediating and modulating stress, social interaction, and nociception. This study examined the effects of maternal support or acute isolation on nociceptive responding of female rats to a range of stimuli during the juvenile pre-adolescent period and accompanying changes in the endocannabinoid system. The data revealed that juvenile female Sprague Dawley rats (PND21−24) isolated from the dam for 1 h prior to nociceptive testing exhibited increased latency to withdraw in the hot plate test and increased mechanical withdrawal threshold in the Von Frey test, compared to rats tested in the presence of the dam. Furthermore, isolated rats exhibited reduced latency to respond in the acetone drop test and enhanced nociceptive responding in the formalin test when compared to dam-paired counterparts. Anandamide, but not 2-AG, levels were reduced in the prefrontal cortex of dam-paired, but not isolated, juvenile rats following nociceptive testing. There was no change in the expression of CB₁, FAAH or MAGL; however, CB₂ receptor expression was reduced in both dam-paired and isolated rats following nociceptive testing. Taken together the data demonstrate that brief social isolation or the presence of the dam modulates nociceptive responding of juvenile rat pups in a modality specific manner, and suggest a possible role for the endocannabinoid system in the prefrontal cortex in sociobehavioural pain responses during early life.