Acute and long-term effects of haloperidol on surgery-induced neuroinflammation and cognitive deficits in aged rats

Neuroinflammation may contribute to the pathogenesis of the cognitive symptoms of postoperative delirium (POD) and its subsequent long-term cognitive impairment. Haloperidol (HAL), a dopamine receptor antagonist, is widely used to treat POD, whereas the effects of HAL on postoperative neuroinflammation and related cognitive deficits have been underdetermined.

Aged rats underwent sham or abdominal surgery and were subcutaneously treated with either vehicle, low-dose (0.5 mg/kg bolus, then 0.5 mg/kg/day infusion), or high-dose (2.0 mg/kg bolus, then 2.0 mg/kg/day infusion) HAL. All treatments were initiated immediately after surgery and continued for 48 h. On either postoperative day 2 (early) or 7 (late), all rats were tested for trace and context fear memory retention after acquisition of trace fear conditioning. Following the cognitive testing, the levels of pro-inflammatory cytokines, as well as dopamine and its metabolite, in hippocampus and medial prefrontal cortex (mPFC) were measured.

In the early postoperative period, surgery induced acute neuroinflammation along with related trace and context memory dysfunction. Dopamine turnover was increased in both hippocampus and mPFC, whereas no relationship with memory functions was observed. However, HAL even at high-dose failed to restore the surgery-induced neuroinflammation and related cognitive deficits. In the late postoperative period, chronic neuroinflammation was detected only in hippocampus, which was associated with context, but not trace memory dysfunction. Neither low- nor high-dose HAL could prevent the development of these late-phase neurocognitive deficits.

Our findings indicate that perioperative administration with HAL may have no effects on postoperative neuroinflammation and related cognitive impairment.