Abstract
The serotonin 4 receptor, 5-HT4R, represents one of seven different serotonin receptor families and is implicated in a variety of physiological functions and their pathophysiological variants, such as mood and depression or anxiety, food intake and obesity or anorexia, or memory and memory loss in Alzheimer’s disease. Its central nervous system expression pattern in the forebrain, in particular in caudate putamen, the hippocampus and to lesser extent in the cortex, predispose it for a role in executive function and reward-related actions. In rodents, regional overexpression or knockdown in the prefrontal cortex or the nucleus accumbens of 5-HT4R was shown to impact mood and depression-like phenotypes, food intake and hypophagia; however, whether expression changes are causally involved in the etiology of such disorders is not clear. In this context, more data are emerging, especially based on PET technology and the use of ligand tracers that demonstrate altered 5-HT4R expression in brain disorders in humans, confirming data stemming from post-mortem tissue and preclinical animal models. In this review, we would like to present the current knowledge of 5-HT4R expression in brain regions relevant to mood/depression, reward and executive function with a focus on 5-HT4R expression changes in brain disorders or caused by drug treatment, at both the transcript and protein levels.
Highlights
5-HT receptors are composed of 7 families (5-HT1–7 receptors), comprising 14 structurally and pharmacologically distinct 5-HT receptor subtypes [1]
Expression in the brain is greatest in the basal ganglia, the hippocampal formation and the cortex, as shown in human and rat brain [10,11]. 5-HT4R is widely distributed in the body
In Hek293 cells, it was shown that GRK2 phosphorylates and desensitizes 5-HT4R resulting in downregulation of the cAMP/PKA pathway, while GRK5-mediated 5-HT4R phosphorylation resulted in reduced inhibition of ERK phosphorylation [19,78]
Summary
5-HT receptors are composed of 7 families (5-HT1–7 receptors), comprising 14 structurally and pharmacologically distinct 5-HT receptor subtypes [1]. The 5-HT4 antagonist GR125487 significantly reduced the nigrostriatal haloperidol-induced but not basal DA outflow without affecting the mesoaccumbal DA release, indicating that 5-HT4R exerts facilitatory control under activated conditions [41] This finding is important in the context of Parkinson’s disease where the substantia nigra is selectively vulnerable to degeneration compared to the VTA, leading to a depletion in striatal dopamine. It was described in rodents that subchronic (3 days) treatment with 5-HT4R agonist yields behavioral as well as biochemical responses in the hippocampus (CREB phosphorylation, neurogenesis) that are comparable to responses to treatment with SSRIs over 3 weeks [48], possibly through its action in the above mentioned PFC-DRN feedback loop [44,45,46] These findings clearly indicate that 5-HT4R is a major regulator of the homeostasis of several neurotransmitter systems, implying a role in brain disorders such as Alzheimer’s, Huntington’s, Parkinson’s diseases or Major Depressive Disorder. We want to present knowledge on cell-type specific expression, which has not yet been studied extensively, partly due to the lack of immunohistochemistry-competent antibodies as well as resolution limits of binding experiments in brain slices with radioactive antagonists
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