Abstract
Animal experimental studies suggest that 5-HT4 receptor activation holds promise as a novel target for the treatment of depression and cognitive impairment. 5-HT4 receptors are post-synaptic receptors that are located in striatal and limbic areas known to be involved in cognition and mood. Consistent with this, 5-HT4 receptor agonists produce rapid antidepressant effects in a number of animal models of depression, and pro-cognitive effects in tasks of learning and memory. These effects are accompanied by molecular changes, such as the increased expression of neuroplasticity-related proteins that are typical of clinically useful antidepressant drugs. Intriguingly, these antidepressant-like effects have a fast onset of their action, raising the possibility that 5-HT4 receptor agonists may be a particularly useful augmentation strategy in the early stages of SSRI treatment. Until recently, the translation of these effects to humans has been challenging. Here, we review the evidence from animal studies that the 5-HT4 receptor is a promising target for the treatment of depression and cognitive disorders, and outline a potential pathway for the efficient and cost-effective translation of these effects into humans and, ultimately, to the clinic.
Highlights
The potentiation of monoamine activity, and in particular serotonergic neurotransmission, has been the dominant target of antidepressant treatments since the serendipitous discovery of the antidepressant effects of monoamine oxidase inhibitor and tricyclics in the 1950s
Studies in rodents have demonstrated that 5-HT4 receptor agonists exert antidepressant-like effects on behavioural paradigms that mirror those seen with conventional selective serotonin reuptake inhibitors (SSRIs), but with a more rapid onset of action (Lucas et al, 2007; Mendez-David et al, 2014; Pascual-Brazo et al, 2012)
The 5-HT4 receptor agonist RS67333 has been shown to restore emotional memory performance in a passive avoidance test in the Flinders sensitive line rat model of depression (Eriksson et al, 2012). Together these findings suggest that 5-HT4 receptor agonists may be a potential target for the improvement of the cognitive and emotional processing deficits associated with depression
Summary
The potentiation of monoamine activity, and in particular serotonergic neurotransmission, has been the dominant target of antidepressant treatments since the serendipitous discovery of the antidepressant effects of monoamine oxidase inhibitor and tricyclics in the 1950s. 5-HT4 receptor agonists produce pro-cognitive effects in tasks of learning and memory in rodents, highlighting a potential role in targeting cognitive deficits associated with depression, which are not well addressed by current antidepressant medications (Shilyansky et al, 2016).
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