PHARMACOLOGICAL MODIFICATION OF ISCHEMIA-INDUCED BEHAVIORAL AND NEUROCHEMICAL CHANGES IN GERBILS (LOCOMOTOR ACTIVITY, MONOAMINE NEUROTRANSMITTERS, CALCIUM ANTAGONISTS, CEREBRAL, ADENYLATE CYCLASE)

The molecular mechanisms responsible for ischemic damage are still controversial. A significant portion of the neurologic deficit caused by cerebral ischemia may occur during reperfusion. A surgical procedure has been developed as part of this study to permit assessment of postischemic changes, and the effects of drugs on these changes, in unanesthetized gerbils.; Functional changes following transient carotid artery occlusion were demonstrated by the occurrence of spontaneous locomotor activity alterations that were related to degree of ischemia and length of reperfusion. Brain monoamine disposition and adenylate cyclase activity were selected as potentially appropriate biochemical correlates to assessment of postischemic locomotor activity. In contrast to the observed behavioral changes, basal and stimulated adenylate cyclase activities were not altered greatly after five minutes of carotid occlusion. Increases in frontal cortex concentrations of the neurotransmitter metabolites, homovanillic acid and 5-hydroxyindole acetic acid, were correlated with degree of ischemia but were not correlated with changes in motor behavior.; An anesthetic dose of pentobarbital administered before five minutes of carotid occlusion resulted in complete protection against the locomotor activity changes and partial protection against the alterations in monoamine disposition.; Increases in locomotor activity observed after five minutes of ischemia were attenuated by pretreatment with the calcium antagonists flunarizine, bepridil and cetiedil; diltiazem had no effect. The protective effect of bepridil on postischemic hyperactivity was not associated with prevention of the characteristic neurochemical changes.; These data indicate there may not be a functional relationship between the changes in locomotor activity and the neurochemical changes observed after transient cerebral ischemia. Spontaneous locomotor activity was sensitive to very short periods of carotid occlusion; this postischemic behavioral change was modified by drug pretreatment. Insights into the molecular mechanisms of ischemic damage may be gained by assessing the molecular mechanisms of various drugs and their effects on postischemic locomotor activity. The results obtained in this dissertation support the hypothesis that changes in calcium homeostasis are involved in ischemic damage.