β-caryophyllene, a CB2-selective phytocannabinoid, differentially modulates attention and inhibitory control in low- and high-performing young and aged mice.

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.