The effects of atomoxetine on odor detection, associative valence learning and reversal in rats

Abstract

The locus coeruleus (LC) is a pivotal structure in supporting cognitive functions by releasing norepinephrine (NE). Neuronal deterioration closely correlates with decreased cognition during Alzheimer’s disease (AD). Given this, there is a growing interest in exploring interventions that enhance norepinephrine at synaptic levels. Atomoxetine (ATM) is a norepinephrine uptake inhibitor and a potential candidate for AD interventions. Understanding the potential therapeutic effects of NE-enhancing drugs in healthy subjects begins with characterizing their function. Olfactory impairment has been identified as one of the earliest symptoms of preclinical AD. In this study, we investigated the effects of aging on olfactory detection and discrimination learning, as well as the influence of ATM on olfactory associative learning and its potential cellular effects in both male and female Long-Evans rats. Results showed that aged (22-24 months old) rats exhibited comparable odor detection and discrimination learning abilities to adult (6-9 months old) rats. However, aged rats demonstrated impaired performance in olfactory reversal learning tasks. Interestingly, ATM administration at two different doses enhanced odor discrimination learning but hindered olfactory reversal learning and threat extinction in a dose-dependent manner in adult rats. Further analysis revealed that the learning enhancement induced by ATM is accompanied by a delayed phosphorylation of cyclic AMP-responsive element binding protein (CREB) in the posterior piriform cortex. In conclusion, the study reveals that the complex effects of ATM are influenced by target structures and suggest potential interactions with other neurotransmitters, revealing the complex mechanisms underlying its therapeutic potential in cognitive function.