John J. Grome

Quantitation of photochemically induced focal cerebral ischemia in the rat.

This study was carried out with a recently developed model of focal cerebral ischemia in the rat based on the photochemical induction of thrombotic stroke using the dye Rose Bengal. We examined the change in the volume of the lesion and brain water content, in separate groups of rats, at different times (1, 4, 24, 72, and 168 h) after the induction of the ischemic lesion. The volume of ischemic damage increased rapidly between 1 and 24 h after the ischemic insult and decreased between 24 and 168 h. The lesion at 168 h was significantly larger than that following 1 h of ischemia and similar to that obtained at 4 h, suggesting that the maximum extent of tissue damage (without the involvement of significant edema) was reached within the first 4 h in this model. The enlargement of the lesion after 4 h correlated closely with changes in brain water content.

The Effects of Serotonin on Local Cerebral Blood Flow

This study was undertaken to measure the effects of serotonin administration on local cerebral blood flow following blood–brain barrier (BBB) disruption with hypertonic urea. Rats were anesthetized with halothane in nitrous oxide and oxygen (70%:30%). In some animals urea (3.5 M) was infused retrogradely through an external carotid catheter, followed after 10 min by serotonin (50 ng kg−1 min−1) or physiological saline. Local cerebral blood flow was measured using the 14C-iodoantipyrine quantitative autoradiographic technique of Sakurada et al. (1978). The administration of saline or urea alone had only minimal effects on local cerebral blood flow. When the BBB was intact, serotonin produced a significant fall in regional blood flow only in the caudate nucleus. Following BBB disruption, however, serotonin produced a marked decrease in local perfusion in a number of discrete brain areas that are supplied by blood from the internal carotid artery. On the other hand, there were increases in local perfusion in areas not supplied by the internal carotid artery.

The effects of apomorphine upon local cerebral glucose utilization in conscious rats and in rats anesthetized with chloral hydrate.

Abstract: The effects of the dopaminergic agonist apomorphine (1 mg‐kg−1i.v.) upon local cerebral glucose utilization in 43 anatomically discrete regions of the CNS were examined in conscious, lightly restrained rats and in rats anesthetized with chloral hydrate by means of the quantitative autoradiographic [14C]2‐deoxyglucose technique. In animals anesthetized with chloral hydrate, glucose utilization was reduced throughout all regions of the CNS from the levels observed in conscious animals, although the magnitude of the reductions in glucose use displayed considerable regional heterogeneity. With chloral hydrate anesthesia, the proportionately most marked reductions in glucose use (by 40–60% from conscious levels) were noted in primary auditory nuclei, thalmaic relay nuclei and neocortex and the least pronounced reductions in glucose use (by 15–25% from conscious levels) were observed in limbic areas, some motor relay nuclei and white matter. In conscious, lightly restrained rats, the administration of apomorphine (1 mg‐kg−1) effected significant increases in glucose utilization in 15 regions of the CNS (e.g., subthalamic nucleus, ventral thalamic nucleus, rostral neocortex, substantia nigra, pars reticulata) and significant reductions in glucose utilization in two regions of the CNS (lateral habenular nucleus and anterior cingulate cortex). In rats anesthetized with chloral hydrate, the effects of apomorphine upon local glucose utilization were less widespread and less marked than in conscious animals. In only two of the regions (the globus pallidus and septal nucleus), which displayed increased glucose use following apomorphine in conscious rats, were significant increases in local glucose utilization observed with this agent in chloral hydrate‐anesthetized rats. In the pars compacta of the substantia nigra, in which apomorphine increased glucose utilization in conscious animals, significant reductions in glucose utilization were observed following apomorphine in rats anesthetized with chloral hydrate. The profound effects of chloral hydrate anesthesia upon local cerebral glucose use and the modification by this anesthetic regime of the local metabolic responses to apomorphine, emphasize the difficulties which exist in the extrapolation of data from anesthetized animals to the conditions which prevail in the conscious animal.

Local Cerebral Glucose Utilisation Following Indoleamine- and Piperazine-Containing 5-Hydroxytryptamine Agonists

Abstract: Substances with varying structural components have been shown to have 5‐hydroxytryptamine (5‐HT)‐like properties in the CNS. In this study, putative 5‐HT agonists with indoleamine moeities—lysergic acid diethylamide (LSD) and 5‐methoxy‐N,N‐dimethyltryptamine (5‐MeODMT)—and with piperazine moeities—quipazine (Quip) and 6‐chloro‐2‐(1‐piperazinyl)pyrazine (6‐CPP) were administered to rats. Local cerebral glucose utilisation was measured using the [14C]2‐deoxyglucose autoradiographic technique. It was found that in most cerebral structures, these substances produced dose‐dependent reductions in glucose utilisation. However, Quip and 6‐CPP increased glucose utilisation in specific areas of the diencephalon (e.g., nucleus reuniens) and produced a biphasic effect in some but not all extrapyramidal structures (e.g., ventromedial caudate nucleus). No such increases in local cerebral glucose utilisation were measured following LSD or 5‐MeODMT administration. These results indicate that although similarities exist between the effects of indoleamine‐ and piperazine‐containing 5‐HT agonists on local cerebral glucose utilisation there are also significant differences in the overall patterns of response produced.

The effects of chloral hydrate anesthesia on the metabolic response in the substantia nigra to apomorphine.

The effects of apomorphine (1 mg/kg) upon glucose utilization in the substantia nigra (pars compacta) have been examined with 2-deoxyglucose autoradiography in conscious rats and rats anesthetized with chloral hydrate. In conscious rats, apomorphine increased glucose use by 23%, whereas in the anesthetized rats, apomorphine decreased glucose use by 24%. These divergent responses to apomorphine highlight the difficulties associated with the use of chloral hydrate anesthesia in the study of nigro-striatal systems.

Functional consequences of unilateral lesion of the locus coeruleus: A quantitative [14C]2-deoxyglucose investigation

The functional consequences, as reflected in local rates of glucose utilization, of ablation of the locus coeruleus (the nucleus from which a major portion of the ascending noradrenergic fibres arise) have been examined in conscious rats with the quantitative autoradiographic [14C]2-deoxyglucose technique. Measurements of glucose utilization were made 72 h after histologically verified unilateral electrolytic lesions of the locus coeruleus. In the overwhelming majority of the 35 grey matter regions examined, the rate of glucose utilization was unaltered by lesions of the locus coeruleus, and in the limited number of CNS regions in which significant alterations were observed, the magnitude of the changes was invariably modest (less than 20% different from sham-operated control animals). Reductions in glucose use were observed in ipsilateral ventral (by 14%) and lateral thalamic nuclei (by 17%), and rates of glucose utilization in most regions of cerebral cortex were significantly lower (about 10%) in the ipsilateral hemisphere relative to the hemisphere contralateral to the lesion. In one region, the median raphe nucleus, glucose utilization was significantly elevated (by 19%) following lesions of the locus coeruleus. Attempts to accentuate the effects of locus coeruleus lesions by pharmacological manipulation of CNS adrenoreceptors by means of the systemic administration of phenoxybenzamine (30 mg/kg, 40 min prior to measurement of glucose use) in animals bearing unilateral locus coeruleus lesions were unsuccessful; the modest alterations in glucose utilization observed following locus coeruleus lesion alone were even less pronounced in lesioned animals receiving phenoxybenzamine. The alterations in local glucose utilization provoked by phenoxybenzamine were similar in sham-lesioned and locus coeruleus-lesioned animals. It would appear that the functional consequences, in terms of glucose utilization, are much less pronounced when a single neurotransmitter system (in the present studies, noradrenergic neurones) is lesioned than when a multiple neurotransmitter, functionally integrated pathway (such as the visual system) is disrupted.

Serotonin Depression of Local Cerebral Glucose Utilisation after Monoamine Oxidase Inhibition

The major catabolic enzyme for serotonin, monoamine oxidase (MAO), is present in the endothelium of cerebral vessels. We report the effects of the intracarotid administration of serotonin on local cerebral glucose utilisation in rats following MAO inhibition with the drug clorgyline. It was found that saline, clorgyline, or serotonin alone produced no significant changes in glucose utilisation. Following the infusion of clorgyline, the administration of serotonin produced significant decreases in glucose utilisation in cortical areas of between 12 and 33% and in the caudate nucleus of 16%.