Abstract
Cognitive deficits commonly accompany psychiatric disorders but are often underrecognised, and difficult to treat. The 5-HT4 receptor is a promising potential treatment target for cognitive impairment because in animal studies 5-HT4 receptor agonists enhance hippocampal-dependent memory processes. To date, there has been little work translating these effects to humans. We tested whether short-term administration of the 5-HT4 partial agonist, prucalopride, modified behavioural and neural (fMRI) memory processing in 44 healthy human volunteers using an experimental medicine model. We found that participants who had received six days of prucalopride treatment were significantly better at recalling previously seen neutral images and distinguishing them from new images. At a neural level, prucalopride bilaterally increased hippocampal activity and activity in the right angular gyrus compared with placebo. Taken together, these findings demonstrate the potential of 5-HT4-receptor activation for cognitive enhancement in humans, and support the potential of this receptor as a treatment target for cognitive impairment.
Highlights
Impairments in cognitive function are present across the spectrum of psychiatric disorders, including affective, psychotic, and neurodevelopmental conditions [1, 2]
Given the significant impact such impairments can have on quality of life, there is a critical need for the development of treatments that can ameliorate the cognitive deficits associated with psychiatric disorder
Following 5-HT4-receptor agonist administration, rodents demonstrate improved performance during learning and memory tasks [8, 9], with effects obvious after only a few doses [10, 11]. This is apparent in tasks tapping hippocampal-dependent learning and memory [9], which likely relates to various downstream effects of 5-HT4-receptor activation including increased hippocampal cell proliferation and promotion of learning-induced spine growth [10, 12, 13], induction of long-term potentiation (LTP) in the hippocampus [14], increased release of neurotransmitters such as acetylcholine in the hippocampus and frontal cortex [9, 15], and increased expression of neuroplasticity proteins such as brain-derived neurotrophic factor (BDNF) [9, 10, 12]
Summary
Impairments in cognitive function are present across the spectrum of psychiatric disorders, including affective, psychotic, and neurodevelopmental conditions [1, 2]. Following 5-HT4-receptor agonist administration, rodents demonstrate improved performance during learning and memory tasks [8, 9], with effects obvious after only a few doses [10, 11] This is apparent in tasks tapping hippocampal-dependent learning and memory [9], which likely relates to various downstream effects of 5-HT4-receptor activation including increased hippocampal cell proliferation and promotion of learning-induced spine growth [10, 12, 13], induction of long-term potentiation (LTP) in the hippocampus [14], increased release of neurotransmitters such as acetylcholine in the hippocampus and frontal cortex [9, 15], and increased expression of neuroplasticity proteins such as brain-derived neurotrophic factor (BDNF) [9, 10, 12]. Anticholinergic-induced cognitive impairments can be reversed by the administration of 5-HT4receptor agonists [20, 22,23,24,25]
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