Β₂-ADRENOCEPTOR AGONIST FORMOTEROL ATTENUATES DEFICITS IN DELAYED NON-MATCH TO POSITION TASK FOLLOWING SYSTEMIC LPS CHALLENGE AND BILATERAL LPS DELIVERY INTO THE LOCUS COERULEUS IN RATS

The delayed non-match to position (DNMTP) task is an instrumental learning paradigm used to assess attention, learning, and working memory in rodents. How inflammatory challenge affects DNMTP performance is largely unreported. The locus coeruleus (LC)–noradrenergic system plays a critical role in attention and cognition; therefore, inducing LC inflammation would be expected to impair task performance. Given the anti-inflammatory actions of noradrenaline mediated via β2-adrenoceptors, we examined whether the β2-adrenoceptor agonist formoterol modulates inflammation-induced effects on performance. In this study, the effect of a systemic inflammatory challenge [lipopolysaccharide (LPS), 0.25 mg/kg, i.p.] on DNMTP performance was assessed in Wistar rats. Sex differences were observed in mnemonic responses to LPS 24 hours post-administration, with females outperforming males at higher working memory loads. Co-administration of formoterol (0.5 mg/kg, s.c.) attenuated LPS-driven impairments in males only. A subsequent study in males found that bilateral injection of LPS into the LC did not affect pre-conditioned DNMTP performance but impaired task acquisition. Daily formoterol administration (0.1 mg/kg, i.p.) for one week following LPS injection rescued this effect. Following a paradigm shift, LC-LPS animals adopted a new rule more rapidly than vehicle-treated controls. Post-mortem immunohistochemistry showed that formoterol attenuated LPS-induced increases in LC microglia number and partially rescued reductions in TH+ cell counts. These findings support utility of the DNMTP task in detecting LPS-associated cognitive impairment and highlight the noradrenergic system as a target to counteract neuroinflammation-associated cognitive deficits. Given the early vulnerability of the LC in Alzheimer’s disease, these results have important translational implications.