RATIONALE: Evidence suggests that modulation of cannabinoid signaling via CB2 receptors regulates neuroinflammation and confers neuroprotection, positioning these receptors as promising targets for age-related cognitive decline. However, there are limited studies that have directly explored the effects of acute CB2 receptor activation on cognitive domains impacted in aging. OBJECTIVE: This study examined the impact of β-caryophyllene (BCP), a sesquiterpene with putative CB2 receptor agonist properties, on executive function and recognition memory in young and aged mice. METHODS: Young (2 mo) and aged (15 mo) male and female C57BL/6J mice were trained in an operant go/no-go (GNG) visual discrimination task. Animals trained to criterion were injected with BCP (0, 25, 50, or 100 mg/kg; i.p.) using a within-subjects design. BCP effects were also tested in novel object recognition (NOR) and object location recognition (OLR) paradigms. RESULTS: Aged mice required more sessions than young mice to acquire GNG contingencies but performed equivalently post-acquisition. Acute BCP induced dose-dependent impairments in attentional control, with moderate-to-high doses (50 and 100 mg/kg) reducing go trial performance independent of age or sex, while inhibitory control (no-go trial performance) remained unaffected. In contrast, low-dose BCP (25 mg/kg) selectively enhanced inhibitory control in aged low-performing mice but not in young or high-performing aged mice. Low-dose BCP improved NOR but not OLR performance. CONCLUSIONS: Acute BCP produces domain- and dose-specific cognitive effects, with low doses enhancing inhibitory control in cognitively vulnerable aged mice. These rapid effects likely arise from neuromodulatory rather than delayed anti-inflammatory mechanisms, warranting further validation of CB2 receptor dependence.
M.N. et al. (Mon,) studied this question.