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R F Ackermann

Publications and source records attributed to R F Ackermann.

At least 37 records · Page 2Linked to original sources
PubMed1990

Quantification of patterns of regional cardiac metabolism.

To quantitatively map and compare patterns of regional cardiac metabolism with greater spatial resolution than is possible with positron emission tomography (PET), the authors developed autoradiographic techniques for use with combinations of radiolabeled fluorodeoxyglucose (FDG), glucose (GLU), and acetate (ACE) and applied the techniques to normal rats. Kinetic models were developed to compare GLU-based oxidative glucose metabolism with FDG-based total glucose metabolism (oxidative plus anaerobic) and to compare ACE-based overall oxidative metabolism with FDG-based total glucose metabolism. GLU-based metabolism generally paralleled FDG-based metabolism, but divergence occurred in certain structures such as the papillary muscles, where FDG-based metabolism was much greater. ACE-based metabolism also generally paralleled FDG-based metabolism, but again, the papillary muscles had relatively greater FDG-based metabolism. These discrepancies between FDG-based metabolism and GLU- or ACE-based metabolism suggest the presence of high levels of anaerobic glycolysis. Thus, the study indicates that anaerobic glycolysis, in addition to occurring in ischemic or "stunned" myocardium (as has been shown in recent PET studies), occurs normally in specific cardiac regions, despite the presence of abundant oxygen.

Acetates↗
PubMed1989

Regional comparison of the lumped constants of deoxyglucose and fluorodeoxyglucose.

We determined the regional relationships of the lumped constants for deoxyglucose (DG) and fluorodeoxyglucose (FDG). Awake male rats were given simultaneous intravenous injections of [14C]DG and [18F]FDG, and sacrificed after 45 min. The brains were removed and small pieces of cortical tissue were sampled by dissection. The remainder of the brains were frozen and sliced into 20-microns-thick sections that were placed on coverslips and dried on a hot plate. Two sets of brain autoradiograms were prepared from the brain sections, one representing predominantly [14C] and the other [18F]. The autoradiograms were digitized, and after correcting for cross-contamination, tracer-concentration images of the DG and FDG were generated. Based on relative tracer concentrations in the tissue samples, the lumped constant of FDG was found to be 1.25 times that of DG, or 0.6. Using this value, images of glucose metabolism for the DG and FDG were generated from the tracer concentration images and compared. No significant regional differences were found, indicating that the relationship between the lumped constant of DG and that of FDG was stable throughout the normal brain.

Animals↗
PubMed1989

Restriction of enhanced [2-14C]deoxyglucose utilization to rhinencephalic structures in immature amygdala-kindled rats.

Sixteen-day-old albino rat pups were kindled to varying degrees of seizure severity with amygdala stimulations spaced 15 to 20 min apart. Subsequently, each rat pup was injected (ip) with 10 microCi of [2-14C]-deoxyglucose, and received several additional kindled seizures at regular intervals throughout the following 80 min, at which time it was killed and processed for deoxyglucose autoradiography. Increased seizure severity was associated with correspondingly increased deoxyglucose utilization in many rhinencephalic limbic structures. However, unlike adults, rat pups did not show discernibly increased neocortical, thalamic, or substantia nigra utilization. We postulate that the apparent confinement of seizure activity to limbic structures in pups is related to their relative lack of postictal seizure refractoriness, as well as to other indices of increased seizure susceptibility in immature animals.

Amygdala↗
PubMed1989

Glycolysis-induced discordance between glucose metabolic rates measured with radiolabeled fluorodeoxyglucose and glucose.

We have developed an autoradiographic method for estimating the oxidative and glycolytic components of local CMRglc (LCMRglc), using sequentially administered [18F]fluorodeoxyglucose (FDG) and [14C]-6-glucose (GLC). FDG-6-phosphate accumulation is proportional to the rate of glucose phosphorylation, which occurs before the divergence of glycolytic (GMg) and oxidative (GMo) glucose metabolism and is therefore related to total cerebral glucose metabolism GMt: GMg + GMo = GMt. With oxidative metabolism, the 14C label of GLC is temporarily retained in Krebs cycle-related substrate pools. We hypothesize that with glycolytic metabolism, however, a significant fraction of the 14C label is lost from the brain via lactate production and efflux from the brain. Thus, cerebral GLC metabolite concentration may be more closely related to GMo than to GMt. If true, the glycolytic metabolic rate will be related to the difference between FDG- and GLC-derived LCMRglc. Thus far, we have studied normal awake rats, rats with limbic activation induced by kainic acid (KA), and rats visually stimulated with 16-Hz flashes. In KA-treated rats, significant discordance between FDG and GLC accumulation, which we attribute to glycolysis, occurred only in activated limbic structures. In visually stimulated rats, significant discordance occurred only in the optic tectum.

Animals↗
PubMed1989

3-(2'-[18F]fluoroethyl)spiperone: in vivo biochemical and kinetic characterization in rodents, nonhuman primates, and humans.

3-(2'-[18F]fluoroethyl)spiperone (FESP), a recently developed dopamine D2-receptor binding radiopharmaceutical, was used for dynamic characterization of dopamine-receptor binding in Macaca nemestrina monkeys and humans with positron emission tomography (PET). FESP in vitro binding properties to the dopamine receptor (IC50 = 1.5 nM) are similar to those of spiperone. Serial PET scans in monkeys after intravenous bolus injection of FESP revealed specific radioactivity accumulation in striatum (rich in dopamine D2-receptors), whereas radioactivity concentration declined after 20 min in frontal cortex (serotonin receptors) and more rapidly in cerebellum (nonspecific binding). Specific dopamine D2-receptor binding was saturated with increasing concentrations of radioligand (specific activity range: 1-10,000 Ci/mmol), was stereospecifically blocked with (+)butaclamol (0.5 mg/kg), and showed only partial displacement with spiperone (200 micrograms/kg, i.v. administration 90 min after FESP injection). From PET experiments with FESP in humans, it is possible to visualize accumulation of radioactivity in striatum in a manner similar to that observed in monkeys and, ex vivo, in rodents (adult male Sprague-Dawley rats). Biochemical analyses in rat brain revealed that the activity (approximately 90%) in striatum was unmodified FESP up to 4 h after injection. On the other hand, FESP was metabolized peripherally (rat greater than monkey greater than human), with only 11% of plasma radioactivity remaining as intact FESP in rodents and 54% in humans after 2 h. Based on these interspecies scaling pharmacokinetic data, it is unequivocal that FESP peripheral metabolites do not significantly contribute to the accumulated radioactivity in striatal tissue. Therefore, it is concluded that FESP is suitable for the quantitative estimation of dopamine D2-receptor sites using PET.

Animals↗
PubMed1988

Functional [14C]2-deoxyglucose mapping of progressive states of status epilepticus induced by amygdala stimulation in rat.

Electrical stimulation of rat amygdala induced self-sustained steady-state seizures (status epilepticus (SE] within 60 min. These SE states varied in behavioral severity from mere alteration of motility to frank clonic convulsions. Four distinct behavioral states were observed: immobility, exploration, mastication and clonus. These SE states were associated with [14C]2-deoxyglucose (2-DG) autoradiography anatomic patterns that were correspondingly more extensive and complex. Four distinct 2-DG activation patterns were observed: a restricted pattern involving several discrete limbic nuclei, including amygdala; more extensive patterns involving numerous limbic areas, first unilaterally, then bilaterally; finally the most extensive pattern involving widespread areas of forebrain. These data imply a systematic progression of seizure activity: originating in the amygdala, then spreading to some direct amygdala projection areas, and from there to a restricted network of interconnected ipsilateral limbic nuclei. This restricted network then recruits most of the remaining limbic structures, first ipsilaterally, then contralaterally. Finally, most of the basal ganglia, thalamus and neocortex are recruited.

Amygdala↗
PubMed1988

In vivo [3H]spiperone binding: evidence for accumulation in corpus striatum by agonist-mediated receptor internalization.

The processes of receptor internalization and recycling have been well-documented for receptors for hormones, growth factors, lysosomal enzymes, and cellular substrates. Evidence also exists that these processes also occur for beta-adrenergic, muscarinic cholinergic, and delta-opiate receptors in frog erythrocytes or cultured nervous tissue. In this study, evidence is presented that agonist-mediated receptor internalization and recycling occurs at the dopamine receptor in rat corpus striatum. First, the in vivo binding of the dopamine antagonist [3H]spiperone was increased by both electrical stimulation and pharmacologically induced increases of dopamine release. Conversely, depletion of dopamine with reserpine decreased in vivo [3H]spiperone binding, but the same reserpine treatment did not alter its in vitro binding. Second, the rate of dissociation of [3H]spiperone from microsomal membranes prepared from rat striatum following in vivo binding was fivefold slower than its dissociation following in vitro equilibrium binding. Mild detergent treatment, employed to disrupt endocytic vesicle membranes, increased the rate of dissociation of in vivo bound [3H]spiperone from microsomal membranes to values not significantly different from its in vitro bound dissociation rate. Third, treatment of rats with chloroquine, a drug that prevents receptor recycling but not internalization, prior to [3H]spiperone injection resulted in a selective increase of in vivo [3H]spiperone binding in the light microsome membranes. The existence of mechanisms that rapidly alter the number of neurotransmitter receptors at synapses provides dynamic regulation of receptors in response to varied acute stimulation states.

Animals↗
PubMed1988

Comparison of cerebral glucose metabolic rates measured with fluorodeoxyglucose and glucose labeled in the 1, 2, 3-4, and 6 positions using double label quantitative digital autoradiography.

We compared local cerebral glucose metabolic rates (LCMRglu) that were determined with [18F]fluorodeoxyglucose (FDG) and [14C]glucose labeled in the 1, 2, 3-4, and 6 positions. Double label digital autoradiography was used with published kinetic models to determine LCMRglu for FDG and glucose in the same animals. Glucose showed metabolic rate dependent underestimation of LCMRglu compared to FDG, which worsened with increasing experimental times. The least underestimation occurred with glucose labeled in the 6 position at 6 min, reaching 10% in areas of high metabolism. Labeling in the 1 position, the 2 position and the 3-4 position caused progressively worse underestimation at all times. In addition, some structures showed differences not directly related to metabolic rate, indicating regional variations in relationships between individual kinetic constants of FDG and glucose.

Animals↗
PubMed1987

Increased susceptibility to hippocampal and amygdala kindling following intrahippocampal kainic acid.

The effects of unilateral intrahippocampal injection of kainic acid, a potent neuroexcitant and neurotoxin, on subsequent susceptibility to kindling of the contralateral hippocampus or contralateral amygdala were investigated in albino rats. At the chosen doses (0.20 to 1.25 micrograms dissolved in physiologic saline), the kainic acid-induced lesion was confined to the injected hippocampus and in two cases the ipsilateral entorhinal cortex; never were there contralateral lesions. Approximately 2 to 6 weeks post-injection, each animal received daily afterdischarge-producing electrical stimulations until stage 5 kindled limbic seizures occurred. Kindling in pretreated animals was significantly accelerated compared with controls; the hippocampal kindling rate decreased from 13.2 stimulations to 3.7, the amygdala kindling rate from 7.8 stimulations to 3.0. Many treated animals had first-stimulation stage 5 seizures, compared with none for controls. Importantly, this facilitation of kindling was not reversed by suppression of the acute, induced seizures with the anticonvulsants, diazepam and phenobarbital, which have repeatedly been demonstrated to effectively suppress limbic kindling. Such results, considered together with findings from the literature, suggest that partial kindling does not occur during kainic acid-induced seizures, and that the observed susceptibility to kindling and other epileptogenic agents subsequent to kainic acid treatment may in fact be related to neurophysiologic and neurochemical consequences of kainic acid-induced lesions.

Amygdala↗
PubMed1986

Identification of seizure-mediating brain structures with the deoxyglucose method: studies of human epilepsy with positron emission tomography, and animal seizure models with contact autoradiography.

This chapter describes tomographic and autoradiographic studies of human and animal seizure syndromes employing Sokoloff's deoxyglucose method. The method's rationale rests on two principal facts: that adult brains normally utilize glucose almost exclusively as their exogenous energy source, and that deoxyglucose, a glucose analog, accumulates in brain cells in proportion to their activity level. Thus, computed tomography or contact autoradiography allows visualization and indirect measurement of changes in the activity of different brain structures under specified conditions, such as between, during, or immediately following seizures. In humans, partial seizures have been the most extensively studied, with 18F-fluorodeoxyglucose and positron emission tomography. Interictally, the brains of patients with partial seizures are characterized by hypometabolism that is particularly severe in the vicinity of seizure foci. In many cases, these focal hypometabolic zones become hypermetabolic ictally. Other brain areas may also become hypermetabolic ictally, or they may instead become hypometabolic. Often the physical extent of interictal hypometabolic zones is substantially greater than the extent of overt pathology. This indicates that hypometabolism can result from subtle, presently undescribed, structural or functional derangements, as well as from frank neuronal loss. A variety of animal seizure "models" have also been studied, with 14C-2-deoxyglucose and contact autoradiography. Each model has produced a unique deoxyglucose and contact autoradiography. Each model has produced a unique deoxyglucose utilization pattern, but thus far none that closely resembles any of the human seizure patterns. This probably reflects true differences between the mechanisms mediating different types of animal seizures and those mediating human seizures. Although in widespread use for only a few years, the Sokoloff method has already demonstrated its ability to distinguish among a variety of seizure types in both humans and animals, and to correctly identify those structures most involved in focal seizures. Thus, the method can be of great aid in narrowing the search for seizure-mediating mechanisms.

Animals↗
PubMed1984

Opioid-induced epileptogenic phenomena: anatomical, behavioral, and electroencephalographic features.

Recent animal studies have indicated a possible role of opioids in epilepsy. Intraventricular opioid administration induces a prolonged nonconvulsive stuporous state characterized by epileptiform electroencephalographic patterns, and reversed by naloxone. In high doses, naloxone itself causes generalized clonic convulsions. We compared opioid-induced and naloxone-induced epileptogenic phenomena using quantitative 2-deoxyglucose autoradiography in order to define the anatomical structures involved in these two different seizure types. When opioid-induced seizures occurred, limbic structures were preferentially activated, but when naloxone-induced clonic convulsions occurred, pyramidal and extrapyramidal motor areas and some limbic structures were activated. Based on the present experiments and currently available evidence, we speculate that opioid-mediated epileptogenic phenomena are similar to those occurring during the postictal state of a fully kindled seizure, whereas naloxone-induced epileptogenic phenomena are similar to the ictal state. Therefore, simple pharmacological manipulation of endogenous opioid systems may allow selective study of ictal and postictal phenomena.

Animals↗
PubMed1984

Increased glucose metabolism during long-duration recurrent inhibition of hippocampal pyramidal cells.

The locally subnormal brain metabolism observed in some experiments utilizing the Sokoloff 2-deoxyglucose (2-DG) method has often been attributed to postsynaptic inhibition despite the fact that inhibitory postsynaptic potentials are themselves caused by energy-requiring mechanisms. To explore this issue, neurophysiologically confirmed long-duration recurrent inhibition of hippocampal pyramidal unit firing was induced by low frequency (2 to 4 Hz) stimulation of the fornix for 60 min following intravenous infusion of [14C]-2-DG. The resulting autoradiograms showed that long-duration suppression of pyramidal cell firing was accompanied by distinctly increased hippocampal 2-DG uptake, particularly in the stratum pyramidale, which contains a dense plexus of inhibitory interneuronal terminals upon pyramidal cells. Both the pyramidal inhibition and the increased 2-DG uptake were confined to the ipsilateral hippocampus in animals with previously severed fornices and hippocampal commissures. In a second series of rats, the excitatory entorhinohippocampal "perforant path" (PP) was stimulated at low frequency (2 to 9 Hz) following 2-DG administration. At 2 to 4 Hz, each PP stimulation resulted in a brief burst of pyramidal unit firing followed by short-duration firing suppression; this result was associated with paradoxically decreased 2-DG uptake in the ipsilateral stratum molecular. By contrast, 7 to 9 Hz entorhinal stimulation induced PP-mediated excitation immediately followed by powerful intrinsic hippocampal inhibition, evidenced by prolonged pyramidal unit suppression after each stimulation. This suppression was accompanied by increased 2-DG uptake in the dentate stratum molecular and hippocampal stratum pyramidale. Thus it appeared that even with entorhinal stimulation, hippocampal 2-DG uptake was more closely associated with long-duration recurrent inhibition than with transient pyramidal excitation. Therefore, although it still remains possible that regions of hypometabolism observed in some previous 2-DG studies may actually reflect mild inhibition, other mechanisms such as disfacilitation are more likely mechanisms for this metabolic pattern.

Animals↗
PubMed1983

Neuronal response of the hippocampal formation to injury: blood flow, glucose metabolism, and protein synthesis.

The reaction of the hippocampal formation to entorhinal lesions was studied from the viewpoints of cerebral blood flow ([123I]isopropyl-iodoamphetamine[IMP])-glucose utilization ([14C]2-deoxyglucose), and protein synthesis ([14C]leucine), using single- and double-label autoradiography. Our study showed (i) decreased glucose utilization in the inner part, and increased glucose utilization in the outer part of the molecular layer of the dentate gyrus, starting 3 days after the lesion; (ii) increased uptake of [123I]IMP around the lesion from 1 to 3 days postlesion; and (iii) starting 3 days after the lesion, marked decrease in [14C]leucine incorporation into proteins and cell loss in the dorsal CA1 and dorsal subiculum in about one-half of the rats. These changes were present only in animals with lesions which invaded the ventral hippocampal formation in which axons of CA1 cells travel. By contrast, transsection of the 3rd and 4th cranial nerves resulted, 3 to 9 days after injury, in a striking increase in protein synthesis in the oculomotor and trochlear nuclei. These results raise the possibility that in some neurons the failure of central regeneration may result from the cell's inability to increase its rate of protein synthesis in response to axonal injury.

Amino Acids↗
PubMed1983

Increased seizure susceptibility of the immature brain.

The ability of the CNS to generate seizures as a function of age was investigated utilizing the kindling model of epilepsy. Hourly electrical, low intensity stimulations of the amygdala induced kindling in adult rats, but stimulations delivered at 15 min intervals failed to or markedly retarded the development of kindled convulsions. In contrast, both types of stimulation induced consistent prolongation of the afterdischarges and repeated generalized seizures in suckling rat pups. The rate of development of the kindled convulsions in the pups was similar, irrespective of whether the stimulations were delivered at 15 or 60 min intervals, indicating that short (less than 15 min) seizure refractory periods exist in the immature brain. The data suggest that seizure susceptibility changes with age and is greater early in life.

Aging↗
PubMed1982

Behavioral and electrographic effects of opioids on kindled seizures in rats.

Our laboratory previously suggested that opioid peptides are released by an amygdaloid kindled seizure and may affect the elicitation of a subsequent seizure. The present study examined the effects of morphine, naloxone, enkephalin analogues, and conditions of morphine tolerance and withdrawal on the severity and duration of a series of amygdaloid kindled seizures. The results suggest two distinct opiate/opioid actions on seizures. The first is an anticonvulsant effect on the behavioral manifestations of seizures. This effect is seen following a high dose (50 mg/kg) of morphine or a low dose (6 mg/kg) of enkephalin analogue (LY146104), and is reversed by naloxone. The second is a naloxone-reversible prolonging effect of the high dose of morphine on the electrographic components of the seizures. Receptor affinities of these various opiate/opioid drugs suggest that these two actions are mediated by different receptors which appear not to include high affinity mu receptors.

Animals↗