Effects of Age and Atomoxetine on Olfactory Perception and Learning and Underlying Plasticity Mechanisms in Rats

Abstract

The locus coeruleus (LC) plays a vital role in cognitive function through norepinephrine release. Impaired LC neuronal health and function is linked to cognitive decline during ageing and Alzheimer's disease. This study investigates age-related alterations in olfactory detection and discrimination learning, along with its reversal, in Long–Evans rats, and examines the effects of atomoxetine (ATM), a norepinephrine uptake inhibitor, on these processes. Adult (6–9 months) and aged (22–24 months) Long–Evans rats underwent odour detection threshold experiments with saline and two doses of ATM (0.3 and 1 mg/kg). Reward-based odour discrimination learning included simple, difficult and reversal learning tasks. LC neuron density, dopamine beta-hydroxylase and norepinephrine transporter expression in the piriform cortex (PC) and orbitofrontal cortex were measured. Reversal learning and olfactory threat extinction were used to measure behavioural flexibility. Immunohistochemistry and western blotting were used to analyse phosphorylated cAMP response element binding protein (pCREB) and cFos expression and ex vivo electrophysiology assessed long-term depression (LTD) in the PC. Whereas adult and aged cohorts showed similar odour detection and discrimination learning, fewer aged rats acquired reversal learning successfully. ATM improved reward-based odour discrimination in adults but hindered learning reversal. A delayed CREB phosphorylation in the posterior PC associated with atomoxetine administration possibly underlies learning enhancement. ATM resulted in less freezing behaviour in a threat conditioning and extinction paradigm at moderate, but not at higher doses. ATM administration ex vivo prevented PC LTD. These findings highlight the intricate effects of atomoxetine, influenced by target structures, and suggest potential interactions with other neurotransmitters. Our results contribute to understanding the impact of ageing and norepinephrine enhancers on cognitive processes.