Serotonin and neuroprotection in functional bowel disorders

Abstract

The 5-HT(4) partial agonist tegaserod is effective in the treatment of chronic constipation and constipation predominant irritable bowel syndrome. 5-HT(4) receptors are located on presynaptic terminals in the enteric nervous system. Stimulation of 5-HT(4) receptors enhances the release of acetylcholine and calcitonin gene related peptide from stimulated nerve terminals. This action strengthens neurotransmission in prokinetic pathways, enhancing gastrointestinal motility. The knockout of 5-HT(4) receptors in mice not only slows gastrointestinal activity but also, after 1 month of age, increases the age-related loss of enteric neurons and decreases the size of neurons that survive. 5-HT(4) receptor agonists, tegaserod and RS67506, increase numbers of enteric neurons developing from precursor cells and/or surviving in culture; they also increase neurite outgrowth and decrease apoptosis. The 5-HT(4) receptor antagonist, GR113808, blocks all of these effects, which are thus specific and 5-HT(4)-mediated. 5-HT(4) receptor agonists, therefore, are neuroprotective and neurotrophic for enteric neurons. Because the age-related decline in numbers of enteric neurons may contribute to the dysmotilities of the elderly, the possibility that the neuroprotective actions of 5-HT agonists can be utilized to prevent the occurrence or worsening of these conditions should be investigated.

Figure 1

An electron micrograph of an axo-dendritic synapse in the myenteric plexus of a mouse. 5-HT₄ receptors were demonstrated by electron microscopic immuncytochemistry using an antibody to the 5-HT_4a receptor (the most abundant isoform in the ENS). Postembedding immunostaining was used with colloidal gold. A cluster of gold particles (arrow) in the presynaptic membrane shows the location of the receptors. Bar = 100 nm.

Figure 2

Whole cell patch clamp recordings were obtained from a guinea pig myenteric neuron that has been cultured overnight. A series of three fast excitatory postsynaptic currents (EPSCs) are shown. These responses are cholinergic. Tegaserod reversibly increases the amplitude of the EPSCs, indicating that it enhances the synaptic release of acetylcholine.

Figure 3

A minimal enteric nervous system circuit, leading to a peristaltic reflex is diagrammed. Pressure or chemical stimuli release 5-HT from an EC cell. 5-HT activates an intrinsic primary afferent neuron in the submucosal plexus (IPAN). This neuron activates other submucosal neurons, but also projects to interneurons in the myenteric plexus. Ascending interneurons activate excitatory motor neurons, which in turn secrete acetylcholine to cause oral contraction of the smooth muscle. Descending interneurons activate inhibitory motor neurons, which in turn secrete nitric oxide, VIP and/or ATP to cause anal relaxation of the smooth muscle. Presynaptic 5-HT₄ receptors (arrows) increase the strength of neurotransmission in prokinetic pathways. These events occur between IPANs and follower neurons, interneurons within the myenteric plexus, and at the cholinergic (muscarinic) excitatory neuromuscular junction.