This application will support basic and clinical research on the physiology and anatomy of neuronal cholecystokinin (CCK), a peptide neurotransmitter. The basic neuroscience research will examine the role of CCK in two regions of rat brain: CCK-containing neuronal cell bodies in the Edinger-Westphal (E.W.) complex and an area of CCK neuronal terminals in the lateral geniculate. We have extracellulary recorded from putative CCK-containing neurons in the E.W. complex. These neurons respond to noxious stimuli with an increase in firing rate and easily enter depolarization blockade. Morphine intravenously administered inhibits the firing of these cells, whereas morphine locally applied by microiontophoresis is largely without effect. This di9parity means that these CCK cells do not have functional opiate receptors and implies that they do not receive direct synaptic contact from enkephalin-containing terminals. Consistent with this hypothesis, electron microscopic immunohistochemical studies do not show direct contacts between enkephalin-containing terminals and CCK-containing dendrites. Proposed studies include the characterization of a full pharmacologic profile, definitive identification of these cells with in vivo intracellular marking, and detailed in vitro intracellular recording studies. The lateral geniculate body of the rat has a moderately dense cholecystokinin innervation. However, the transmitter (i.e., CCK) is concentrated in different regions from that of its receptor. Some of the CCK binding sites may be located on retinal ganglion cell axons, since these binding sites are located along the optic tract itself. The function of CCK in the lateral geniculate will be studied with electron microscopic immunohistochemistry of normal and enucleated animals, electrophysiology, and receptor autoradiography. This grant also involves two clinical research projects. Because CCK may be an endogenous safety signal, we are studying the efficacy of a CCK antagonist in patients with anorexia nervosa. Additionally, CCK has been co-localized with dopamine in mesolimbic dopamine neurons, which may be involved with the pathophysiology of schizophrenia. Thus, we are also investigating the usefulness of this same antagonist in the treatment of schizophrenic psychosis.
