Considerable work in the Laboratory of Behavioral and Neurological Toxicology has focused on the role of enkephalin and dynorphine in seizure activity and related sequelae. Among other things, this work has implicated enkephalin as playing a major role in the elucidation of a phenomenon in rats known as """"""""wet dog shakes"""""""" (WDS). This work, as well as other sources, has also implicated the dentate granule cells (DGCs) as being necessary for the elicitation of WDS, at least with respect to indution by kainic acid or by stimulation of the perforant path (PP). Our first objective of this project is to develop a method for electrical stimulation of the PP which will elicit WDS consistently and repeatedly in the absence of an overt seizure. To date we have succeeded in eliciting WDS in the absence of overt seizures but cannot do so after the animals have received several stimulations. We have reached a stage where we can elicit enough WDS in the absence of overt seizures to effectively determine whether or not changes in hippocampal enkephalin content, but not dynorphin, are correlated with the number of WDS. During this year we also plan to determine whether or not opioid delta receptor antagonists will block the occurrence of WDS and whether they are specific among the opioid receptors in so doing. In addition, preliminary experiments suggest that dexamethazone increases the number of WDS following PP stimulation. Thus a possible interaction between glucocorticoids and enkephalin is suggested and will be pursued. Other studies in progess concern whether or not there is a loss of recurrent inhibition on the DGC before WDS can be elicited. If such is the case we will determine whether or not delta receptor antagonists can restore this recurrent inhibition. The effect of enkephalin on dentate granule cells and basket cells (inhibitory internuncial neurons) will be examined in hippocampal slices and in hippocampal cells grown in tissue culture in order to characterize the mechanism by which enkephalin affects these cells.
