The Journal of Neuroscience, March 8, 2006, 26(10):2798-2807; doi:10.1523/JNEUROSCI.4720-05.2006
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Behavioral/Systems/Cognitive
Physiological Modulation of Intestinal Motility by Enteric Dopaminergic Neurons and the D2 Receptor: Analysis of Dopamine Receptor Expression, Location, Development, and Function in Wild-Type and Knock-Out Mice
Zhi Shan Li,1
Claudia Schmauss,2
Abigail Cuenca,1
Elyanne Ratcliffe,3 and
Michael D. Gershon1
1Department of Anatomy and Cell Biology, Columbia University College of Physicians and Surgeons, 2Department of Psychiatry, New York State Psychiatric Institute, and 3Department of Pediatrics, Columbia University, New York, New York 10032
Correspondence should be addressed to Dr. Zhi Shan Li, Department of Anatomy and Cell Biology, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032. Email: ZL64{at}columbia.edu
Dopaminergic neurons are present in both plexuses of the murine bowel and are upregulated after extrinsic denervation but play unknown roles in enteric nervous system (ENS) physiology. Transcripts encoding dopamine (DA) receptors D1D5 were analyzed by reverse transcription-PCR in stomach
duodenum
ileum
proximal >> distal colon. Dissected muscle and myenteric plexus contained transcripts encoding D1D3 and D5, whereas mucosa contained D1 and D3D5. D1D5 expression began in fetal gut [embryonic day 10 (E10)], before the appearance of neurons (E12), and was sustained without developmental regulation through postnatal day 1. In situ hybridization revealed that subsets of submucosal and myenteric neurons contained mRNA encoding D2 or D3. Immunoblots confirmed that D1, D2, and D5 receptor proteins were present from stomach through distal colon. Subsets of submucosal and myenteric neurons were also D1, D2, or D3 immunoreactive. When double labeled by in situ hybridization, these neurons contained mRNA encoding the respective receptors. Total gastrointestinal transit time (TGTT) and colonic transit time (CTT) were measured in mice lacking D2, D3, or D2 plus D3. Both TGTT and CTT were decreased significantly (motility increased) in D2 and D2 plus D3, but not D3, knock-out animals. Mice lacking D2 and D2 plus D3 but not D3 were smaller than wild-type littermates, yet ate significantly more and had greater stool frequency, water content, and mass. Because motility is abnormal when D2 is absent, the net inhibitory DA effect on motility is physiologically significant. The early expression of DA receptors is also consistent with the possibility that DA affects ENS development.
Key words: dopamine receptor; dopaminergic; colon motility; gastrointestinal transit time; enteric nervous system; development
Received Nov. 3, 2005;
revised Jan. 9, 2006;
accepted Feb. 3, 2006.
Correspondence should be addressed to Dr. Zhi Shan Li, Department of Anatomy and Cell Biology, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032. Email: ZL64{at}columbia.edu
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