Attention-deficit/hyperactivity disorder (ADHD) is linked to heightened risk-taking tendencies. Core symptoms and traits, such as impulsivity, hyperactivity, and risk-taking, stem from dysfunctions in frontostriatal circuitry. The endocannabinoid system (ECS) modulates frontostriatal dynamics and monoaminergic signaling. The pair of strains, spontaneously hypertensive rats (SHRs) and Wistar Kyoto (WKY) rats, is an established model for ADHD. The endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) impact defensive behaviors by fine-tuning neural circuits involved in threat detection and response. This study explores how enhancing 2-AG and AEA levels shapes defensive behavior in approach–avoidance paradigms using the open field and elevated plus maze tasks. We also investigated strain- and sex-related differences in CB1R, CB2R, FAAH, and MAGL protein content in brain regions implicated in executive function, including the prefrontal cortex (PFC), striatum (STR), and hippocampus (HP). A MAGL inhibitor enhanced risk assessment in WKY rats. Female rats exhibited reduced stretch-attend posture (SAP) when endocannabinoid ligand levels were elevated. Specifically, in the SHR strain, males showed increased head dipping (HD) with a FAAH inhibitor, whereas females exhibited the opposite pattern. SHR females exhibited increased HD following administration of an AEA transport inhibitor. Basal protein content analysis showed that in the STR, female SHRs had higher FAAH and MAGL levels than female WKY rats, while male SHRs had lower CB2R levels. In the HP, CB2R content was elevated in female SHRs compared to WKYs. Both WKY and SHR females showed reduced PFC CB1R content relative to their male counterparts. In SHRs, females exhibited higher FAAH levels in the STR and HP, and lower CB2R in the HP, compared to males. These findings indicate that increasing 2-AG and AEA by inhibiting their degradation pathways modulates defensive behavior in a strain- and sex-dependent manner. Differences in protein expression within the PFC, STR, and HP align with behavioral outcomes, providing molecular insight into strain- and sex-specific patterns of defensive behavior. • Spontaneously hypertensive rats display impairment in defensive repertoire. • Inhibition of MAGL and FAAH produces strain- and sex-dependent defensive effects. • The ADHD model shows sex and strain differences in CB1R, CB2R, FAAH and MAGL levels.
Penna et al. (Tue,) studied this question.