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NEUROREGULATION AND MOTILITY

5-HT₄ receptor activation facilitates recovery from synaptic rundown and increases transmitter release from single varicosities of myenteric neurons

¹Neuroscience Program and ²Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan

Submitted 15 February 2008 ; accepted in final form 18 April 2008

5-HT₄ receptor agonists facilitate synaptic transmission in the enteric nervous system, and these drugs are used to treat constipation. In the present study, we investigated the effects of the 5-HT₄ receptor agonist, renzapride, on rundown and recovery of fast excitatory postsynaptic potentials (fEPSPs) during and after trains of stimulation and on transmitter release from individual myenteric neuronal varicosities. Intracellular electrophysiological methods were used to record fEPSPs from neurons in longitudinal muscle myenteric plexus preparations of guinea pig ileum in vitro. During trains of supramaximal electrical stimulation (10 Hz, 2 s), fEPSP amplitude declined (time constant = 0.6 ± 0.1 s) from 17 ± 2 mV to 0.7 ± 0.3 mV. Renzapride (0.1 µM) did not change the time constant for fEPSP rundown, but it decreased the time constant for recovery of fEPSP amplitude after the stimulus train from 7 ± 2 s to 1.6 ± 0.2 s (P < 0.05). 5-HT (0.1 µM) also increased fEPSPs and facilitated recovery from rundown. The adenylate cyclase activator, forskolin (1 µM), mimicked the actions of renzapride and 5-HT, whereas H-89, a protein kinase A (PKA) inhibitor, blocked the effects of renzapride. We used nicotinic acetylcholine receptor containing outside-out patches obtained from myenteric neurons maintained in primary culture to detect acetylcholine release from single varicosities. Renzapride (0.1 µM) increased release probability twofold. We conclude that 5-HT₄ receptors activate the adenylyl cyclase-PKA pathway to increase acetylcholine release from single varicosities and to accelerate recovery from synaptic rundown. These responses may contribute to the prokinetic actions of 5-HT₄ receptor agonists.

fast synaptic transmission; enteric nervous system; electrophysiology; renzapride; single nicotinic acetylcholine receptor channels