This research proposal is concerned with studies on the behavioral, analeptic and gastrointestinal (GI) effects of centrally administered TRH. In barbiturate narcotized rats and rabbits TRH produces an analeptic effect, antagonism of hypothermia and a shaking behavior. The analeptic effect is blocked by atropine, indicating a central cholinergic mechanism. Our recent microinjection studies indicate that the medial septum is the most sensitive brain area to TRH in producing the analeptic effect. Because the medial septum is closely associated with the hippocampus via the septo-hippocampal cholinergic pathway, and from various other supporting evidence, we are postulating that these brain structures are involved in the TRH analeptic response. Much lesioning techniques will be employed to determine whether the septum and the septohippocampal pathway are required for the response. We shall also carry out several neurochemical procedures (ACh turnover and TRH receptor binding assays) to attempt to complete the picture of TRH acting via septal receptors and activating, via the septohippocampal cholinergic pathway, the hippocampal arousal system. The GI tract exhibits marked increases in motility (as measured by strain gauge) and propulsive activity (as measured by 51Cr or charcoal movement) after icv, but not iv, administration of TRH. Bilateral vagotomy abolishes these effects, but atropine blocked only the motility effect. Very recently we found that two antiserotonin compounds blocked only the propulsive effect of TRH. From these preliminary data we are postulating that vagally released serotonin is responsible for the atropine-resistant propulsive effect. Part of the proposal is aimed at confirming this hypothesis. We shall measure portal blood serotonin levels before and after TRH and in control and vagotomized animals. If these experiments are positive, we shall attempt to clarify how vagally stimulated release of serotonin takes place. Other studies will attempt to localize brain site at which TRH exerts its GI effects. These studies will be done with stereotaxic microinjections of TRH into different regions of the rabbit brain.
