Dopamine D1 receptor agonist treatment alleviates morphine-exposure-induced learning and memory impairments

We investigated the mechanisms by which the dopamine D1 receptor alleviates morphine-exposure-induced cognitive impairments. Rats were intraperitoneally injected with morphine in a dose-escalating manner over 10 days, and 15 min before the morphine injection on days 1, 3, 5, 7, and 9, the rats were administered the D1 receptor agonist SKF81297 or the D1 receptor antagonist SCH38933 into the midbrain periaqueductal gray (PAG). The Morris water maze was used to examine learning- and memory-related behavioral changes. Midbrain PAG toll-like receptor 4 (TLR4) and protein kinase A (PKA) protein expression was examined using western blot analysis, and cellular expression and localization of TLR4 and PKA were investigated using immunohistochemistry. Chronic morphine exposure impaired spatial learning and memory ability, and resulted in longer latency to the platform, decreased number of platform crossings, and shortened time in the effective area and the target quadrant. Chronic morphine exposure also increased TLR4 and PKA expression in the PAG. However, D1 receptor agonist treatment improved learning and memory ability; in morphine-treated rats, administration of the D1 receptor agonist SKF81297 could shorten the latency to the platform, increase the number of platform crossings, and increase the time spent in the effective area and the target quadrant. In addition, TLR4 expression decreased and PKA expression significantly increased in the PAG in these animals. In summary, administration of the dopamine D1 receptor agonist SKF81297 into the PAG alleviated morphine-exposure-induced cognitive impairments.