Physiological Modulation of Intestinal Motility by Enteric Dopaminergic Neurons and the D2Receptor: Analysis of Dopamine Receptor Expression, Location, Development, and Function in Wild-Type and Knock-Out Mice
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abstract
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 D1–D5were analyzed by reverse transcription-PCR in stomach ≈ duodenum ≈ ileum ≈ proximal ≫ distal colon. Dissected muscle and myenteric plexus contained transcripts encoding D1–D3and D5, whereas mucosa contained D1and D3–D5. D1–D5expression 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 situhybridization revealed that subsets of submucosal and myenteric neurons contained mRNA encoding D2or D3. Immunoblots confirmed that D1, D2, and D5receptor proteins were present from stomach through distal colon. Subsets of submucosal and myenteric neurons were also D1, D2, or D3immunoreactive. When double labeled byin situhybridization, 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 D2plus D3. Both TGTT and CTT were decreased significantly (motility increased) in D2and D2plus D3, but not D3, knock-out animals. Mice lacking D2and D2plus D3but not D3were smaller than wild-type littermates, yet ate significantly more and had greater stool frequency, water content, and mass. Because motility is abnormal when D2is 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.
