Subacute ivermectin–induced affective dysregulation: Evidence for hippocampal microglial and astrocytic activation

Ivermectin (IVR) is a semi-synthetic macrocyclic lactone widely used against nematodes. Under physiological conditions, its central nervous system (CNS) penetration is limited by P-glycoprotein–mediated efflux at the blood–brain barrier (BBB). Nevertheless, supratherapeutic dosing, BBB-compromising pathologies, concomitant P-glycoprotein inhibitors, or MDR1 variants can enhance CNS entry and precipitate neurotoxicity. To evaluate behavioural and neuroinflammatory sequelae of subacute exposure, rats received IVR (1, 5, or 10 mg/kg; i.p.) once daily for 21 days. Animals were assessed for motor function (activity cage, Rota-rod), affective behaviour (elevated plus maze, modified forced swim test), and cognition (Morris water maze). Assay validation employed diazepam (1 and 3 mg/kg; i.p.), desipramine (30 mg/kg; i.p.), and piracetam (200 mg/kg; i.p.), administered according to their respective protocols. IVR did not alter motor performance or spatial learning and memory across doses. However, 5 and 10 mg/kg reduced the percentage of open-arm entries and increased immobility, consistent with anxiety- and depression-like phenotypes, respectively. At 10 mg/kg, hippocampal immunohistochemistry revealed increased Iba1 and GFAP immunoreactivity within CA1, indicating microglial and astrocytic activation. Quantitative counts demonstrated no significant change in CA1 neuronal number across treatment groups, implying that the observed glial activation occurred in the absence of detectable neuronal loss. Collectively, our data indicate that subacute, high-dose IVR provokes affective behavioural alterations coupled to hippocampal neuroinflammation, while sparing gross motor function and measurable cognitive performance under the present conditions. These findings underscore caution when administering IVR at elevated doses or in settings that compromise BBB integrity and warrant further mechanistic and time-resolved investigation.