Cannabidiol attenuates behavioral impairments and deficits in parvalbumin interneurons and their perineuronal nets induced by adolescent stress in adult mice.

Lima T.; Verza F.; Godoy L.; Guimarães F.; Gomes F. · Progress in neuro-psychopharmacology & biological psychiatry · 2026

**Background & Methods** Male C57BL/6J mice were exposed to footshock stress during adolescence (postnatal days 31-40), then treated with cannabidiol (CBD) or vehicle for 10 days. After a 15-day drug-free period, animals underwent behavioral testing in adulthood, followed by histological analysis of parvalbumin-containing interneurons (PV+) and perineuronal nets (PNNs) in the medial prefrontal cortex and ventral hippocampus. **Key Findings** • Adolescent stress impaired social discrimination and novel object recognition memory in adulthood; CBD (30 mg/kg) significantly attenuated these cognitive deficits, while anxiety-like behavior and sociability remained unaffected by stress or treatment. • Stressed animals exhibited reduced PV+ cells, PNN+ cells, and co-localized PV+/PNN+ cells in both the mPFC and vHip, with less pronounced reductions in somatostatin-expressing (SST+) interneurons in the vHip; CBD treatment restored these stress-induced cellular alterations across brain regions. • The study demonstrates CBD's potential neuroprotective effects specifically targeting GABAergic interneuron dysfunction and their extracellular matrix components as a mechanism underlying stress-induced cognitive impairments. **Dosage & Administration** CBD 30 mg/kg administered intraperitoneally (i.p.) for 10 consecutive days (postnatal days 41-50), initiated 24 hours after adolescent stress exposure cessation. **Safety & Adverse Effects** Not reported. **Evidence Quality** This is a preclinical rodent study with significant translational relevance but limited direct applicability to humans. Strengths include the use of a well-characterized stress model during a critical developmental period, comprehensive behavioral assessment across multiple domains, and integrated neurobiological analysis. Limitations include the exclusive use of male mice (limiting generalizability to females), reliance on a single CBD dose without dose-response analysis, and the 15-day drug-free period before testing, which does not address long-term CBD effects. The study is classified as basic research with moderate-to-good internal validity but requires further investigation to establish clinical relevance, particularly regarding optimal dosing regimens, sex differences, and potential mechanisms of action. Replication in independent laboratories and extension to other stress models would strengthen the evidence base.

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