DESCRIPTION: The enteric nervous system (ENS) is the only region of the peripheral nervous system (PNS) that is intrinsically capable of mediating reflect activity. This activity is made possible by the presence within the bowel of microcircuits that contain the necessary primary afferent neurons and interneurons, as well as the excitatory and inhibitory motor neurons that innervate gastrointestinal smooth muscle and glands. The complexity of the functions controlled by the ENS is reflected in an equally complex organization that resembles that of the CNS more than the remainder of the PNS. The ENS also innervates other organs, including the pancreas. Pancreatic ganglia are similar to enteric ganglia, and are the primary target of the enteric innervation. Many different classes of neurotransmitter have been found in the ENS, including most of those known also to be present in the CNS. It is thus surprising that glutamate, which is the major excitatory transmitter of the brain, has not previously been found to be a transmitter in the ENS. The PI recently obtained the first evidence: (1) that the ENS and pancreas contain glutamate-immunoreactive neurons and that these cells express the same plasma membrane glutamate transporter that is found in central glutamatergic neurons, (2) that glutamate depolarizes enteric and pancreatic neurons via N-methyl-D-aspartate (NMDA) and non-NMDA receptors, (3) that glutamate antagonists block some enteric and pancreatic fast and slow excitatory postsynaptic potentials (EPSPs), (4) that glutamate (and NMDA) raises [Ca2+]i in enteric neurons, (5) that pancreatic glutamate receptors mediate long germ potentiation (LTP), and (6) that glutamate-mediated excitotoxicity occurs in the ENS. The specific aims of this project are: (1) to establish that glutamate is an excitatory neurotransmitter in the gut and pancreas, (2) to determine if glutamate is a transmitter of enteric sensory neurons, and (3) to determine which physiological processes are mediated by enteric and pancreatic glutamate receptors. The abundance of enteric and pancreatic neurons that express glutamate receptors suggests that drugs designed to interact with these receptors may exert unanticipated visceral actions. These drugs may also affect insulin secretion since insulin-immunoreactive islet cells express glutamate receptors.