Louis Sokoloff

Localization of functional activity in the central nervous system by measurement of glucose utilization with radioactive deoxyglucose.

Sokoloff provided a review of his labs deoxyglucose work so far: the theory and properties of the [14C] deoxyglucose and its derivative [18F] fluorodeoxyglucose methods, and their applications to many physiological, pharmacological, and pathological conditions.

Effects of d- and l-amphetamine on local cerebral glucose utilization in the conscious rat.

Amphetamine, a potent sympathomimetic amine, has powerful stimulant actions in the central nervous system. These actions are believed to be related to the influence of amphetamine on release and uptake of catecholamine neurotransmitters. The [14C]deoxyglucose method makes it possible to study changes in cerebral metabolic rate in different areas of gray and white matter. Because of the close relationship between metabolic rate and functional activity, this method may be used to identify specific structures in the brain in which functional activity is altered. The [14C]deoxyglucose method was used to explore for changes in metabolic rate produced by d‐and l‐amphetamine (5 mg/kg) in forty gray and four white matter structures in normal conscious rats. d‐Amphetamine produced increases in local cerebral glucose utilization in a number of components of the extrapyramidal motor system, as well as in some other structures known to contain dopamine‐producing and/or dopaminoceptive cells. The largest increases after d‐amphetamine administration occurred in the subthalamic nucleus and the zona reticulata of the substantia nigra. l‐Amphetamine produced increases in some but not all of these same structures, and these were generally smaller than those observed with d‐amphetamine. Decreases in local cerebral glucose utilization after either d‐ or l‐amphetamine administration were found in the habenula and the suprachiasmatic nuclei of the hypothalamus. The effects in the suprachiasmatic nuclei may reflect their normal diurnal rhythm in metabolic rate. These results indicate that amphetamines may influence behavior through effects on specific regions of the brain. Only some of these regions have previously been studied as possible sites of action of amphetamine.

Measurement of Free Glucose Turnover in Brain

A method has been developed for the measurement of the turnover rate constant or the half‐life of the free glucose content of brain. It is based on an equation derived by the mathematical analysis of a kinetic model of the equilibration of the specific activity of the free glucose in brain with that of the plasma during an infusion of radioactive glucose. The method requires the measurement of the time course of the specific activity of glucose in the arterial plasma during an intravenous infusion of radioactive glucose for a period of 1 to 4 min and the specific activity of the free glucose in brain at the termination of the infusion. The turnover rate constant, or the half‐life, is then calculated from these data by means of the operational equation of the method. The technique has been applied to conscious and anesthetized rats. In conscious rats the half‐life of the free glucose content of brain was found to be 1.6 ± 0.5 min (mean ±s.d.) when the animals were killed by decapitation and 1.2 ± 0.2 min (mean ±s.d.) when they were killed by microwave irradiation; this difference is not statistically significant. In anesthetized rats, the half‐life was found to be 2.6 ± 0.8 min (mean ±s.d.) in those killed by decapitation and 1.8 ± 0.3 min (mean ±s.d.) in those killed by microwave irradiation; this difference is statistically significant. The half‐life of the glucose content of brain was found to be significantly prolonged during anesthesia and to be significantly and positively correlated with the plasma glucose concentration (r= 0.78; p < 0.001).

Correlation of dose-dependent effects of acute amphetamine administration on behavior and local cerebral metabolism in rats

Rates of local cerebral glucose utilization were measured by means of the quantitative autoradiographic 2-[14C]deoxyglucose technique in conscious rats following the acute administration of D-amphetamine (0.2-5.0 mg/kg, i.v.). Changes in locomotor and stereotypic behavior in similarly treated rats were examined as well. Administration of low doses (0.2 and 0.5 mg/kg) of amphetamine resulted in increased locomotor activity, accompanied by elevations in glucose utilization limited mainly to the nucleus accumbens. A moderate dose of D-amphetamine (1.0 mg/kg) produced locomotion and stereotypic sniffing. Metabolic activity at this dose was increased in the nucleus accumbens, throughout neocortical areas, and in components of the extrapyramidal system. A high dose of amphetamine (5.0 mg/kg) produced stereotypic gnawing and licking and was associated with significant increases in glucose utilization in the extrapyramidal system, most prominently in the subthalamic nucleus. These data demonstrate that the acute administration of D-amphetamine produces effects on local cerebral glucose utilization and on behavior that differ with dose. The results also show a strong coupling between locomotion and the level of metabolic activity in the nucleus accumbens and demonstrate that the different forms of stereotypic behavior elicited by high and moderate doses of amphetamine are correlated with distinct patterns of distribution of local cerebral glucose utilization, indicating mediation by different neuronal circuits.

The extraneural distribution of gamma-hydroxybutyrate.

Abstract— γ‐Hydroxybutyrate has been found to be widely distributed in both neural and extraneural tissues in the rat. The kidney and brown fat have more than 10 times higher concentrations of y‐hydroxybutyrate than does the brain. This observation suggests that γ‐hydroxybutyrate may participate in the metabolism of many organs, and that GABA may not be the precursor in extraneural tissues.

CHANGES IN BLOOD FLOW IN THE COMPONENT STRUCTURES OF THE DOG BRAIN DURING POSTNATAL MATURATION

Abstract— Blood flow was measured quantitatively in 35 structures of the brains of dogs of various ages from birth to maturity. In general, values were low at birth and rose to maximal levels between 3 and 7 weeks of postnatal age; declines from the peak levels then followed until values characteristic of maturity were attained by 13 weeks of postnatal age. From relatively uniform perfusion rates throughout the brain at birth there gradually emerged a marked heterogeneity, in parallel with the structural and functional maturation and differentiation known to occur in the brain during this period of life. Our observations may reflect the summation of the changes in energy demands associated on the one hand with biosynthetic processes essential for growth and development and with the support for progressively increasing functional activities on the other.

The distribution of alterations in energy metabolism in the rat brain produced by apomorphine

The effects of the putative dopaminergic agonist, apomorphine (0.15-5 mg/kg, i.v.), on glucose utilization in 43 anatomically discrete regions of the rat brain have been examined by the quantitative autoradiographic 2-deoxyglucose technique. Apomorphine failed to alter the rates of glucose utilization in 25 of these regions (for example, primary auditory areas, regions of white matter, hippocampal areas, nucleus accumbens and caudal regions of the neocortex). Dose-dependent alterations in glucose utilization were observed following apomorphine administration in a number of regions known to contain dopaminergic receptors (viz: caudate nucleus, substantia nigra, amygdala, subthalamic nucleus and anterior cingulate cortex). Moreover, dose-dependent alterations in glucose utilization were produced by apomorphine in a number of regions thought to contain few specific dopaminergic receptors (e.g., cerebellar hemisphere and vermis, lamina VI of rostral neocortical areas, and ventral nucleus of the thalamus). The distribution of alterations in glucose utilization following apomorphine administration are considered to reflect the functional involvement of the region in the overall response to apomorphine, and not simply the topography of dopaminergic receptor mechanisms.

The lumped constant of the deoxyglucose method in hypoglycemia : effects of moderate hypoglycemia on local cerebral glucose utilization in the rat

The applicability of the [14C]deoxyglucose method for measuring local cerebral glucose utilization (lCMRglc) has been extended for use in hypoglycemia by determination of the values of the lumped constant to be used in rats with plasma glucose concentrations ranging from approximately 2 to 6 mM. Lumped constant values were higher in hypoglycemia and declined from a value of 1.2 at the lowest arterial plasma glucose level (1.9 mM) to about 0.48 in normoglycemia. The distribution of glucose, and therefore also of the lumped constant, was found to remain relatively uniform throughout the brain at the lowest plasma glucose levels studied. lCMRglc in moderate, insulin-induced hypoglycemia (mean arterial plasma glucose concentration ± SD of 2.4 ± 0.3 mM) was determined with the appropriate lumped constant corresponding to the animals plasma glucose concentration and compared with the results obtained in six normoglycemic rats. The weighted average rate of glucose utilization for the brain as a whole was significantly depressed by 14% in the hypoglycemic animals, i.e., 61 μmol/100 g/min in hypoglycemia compared to 71 μmol/100 g/min in the normoglycemic controls (p < 0.05). lCMRglc was lower in 47 of 49 structures examined but statistically significantly below the rate in normoglycemic rats in only six structures (p < 0.05) by multiple comparison statistics. Regions within the brainstem were most prominently affected. The greatest reductions, statistically significant or not, occurred in structures in which glucose utilization is normally high, suggesting that glucose delivery and transport to the tissue became rate-limiting first in those structures with the greatest metabolic demands for glucose.

Distribution of effects of haloperidol on energy metabolism in the rat brain.

The effects of the putative dopaminergic antagonist, haloperidol (0.01-10 mg/kg, i.v.), on cerebral glucose utilization in 43 anatomically discrete regions of the rat brain have been examined by the quantitative autoradiographic 2-deoxyglucose technique. Dose-dependent reductions in glucose utilization were observed in 10 regions of the CNS (e.g. hippocampus, ventral thalamus and almost the entire neocortex, with the notable exception of anterior cingulate cortex). Two regions of the CNS (nucleus accumbens and pars compacta of the substantia nigra) displayed dose-related increases in glucose utilization following haloperidol administration. In addition to these specific alterations, the largest doses of haloperidol produced widespread, moderate (about 25%) reductions in glucose utilization throughout the CNS. The prior administration of haloperidol (0.1 mg/kg) prevented the effects on glucose utilization of the administration of apomorphine (1.5 mg/kg) in all regions of the CNS examined. The distribution of alterations in glucose utilization following haloperidol administration are considered in relation to the overall functional consequences of dopaminergic receptor blockade.

Enzymes catalysing ethanol metabolism in neural and somatic tissues of the rat.

Abstract— The enzymes catalysing ethanol metabolism, alcohol dehydrogenase (EC 1.l.1.1) and aldehyde dehydrogenase (EC 1.2.1.3), were assayed in a variety of neural and somatic tissues of the rat, the human counterparts of which are known to be vulnerable to excessive ethanol. The activity of alcohol dehydrogenase was assayed by the coupled oxidation of ethanol and reduction of lactaldehyde, a method which we have recently found to be sufficiently sensitive and specific to measure the relatively low levels of activity in whole brain. Detectable activities of these enzymes were found in peripheral nerve, skeletal muscle, retina, optic nerve and various regions of brain, as well as in a variety of non‐neural tissues. The levels of the enzymic activities in all tissues were markedly lower than those of liver, but probably sufficient to perform a local function in the metabolism of ethanol or other endogenous substrates. The activity of alcohol dehydrogenase in the various tissues, like that of liver, was confined to the cytosol and exhibited kinetic properties and responses to inhibitors almost identical to those of the liver enzyme. We consider the results to be consistent with the hypothesis that the pathological effects of alcohol may be related, at least in part, to local mechanisms for the metabolism of alcohol.