Decrease In Local Cerebral Glucose Utilization Research Articles

Differential effects of ibogaine on local cerebral glucose utilization in drug-naive and morphine-dependent rats

Ibogaine, a hallucinogenic indole alkaloid, has been proposed as a treatment for addiction to opioids and other drugs of abuse. The mechanism for its putative anti-addictive effects is unknown. In this study, the effects of ibogaine on local cerebral glucose utilization (LCGU) were determined in freely moving, drug-naive, or morphine-dependent adult, male, Sprague–Dawley rats using the [ 14C]2-deoxyglucose (2-DG) method. Morphine-dependent rats were treated with increasing doses of morphine (5–25 mg/kg, s.c., b.i.d.) and then maintained at 25 mg/kg (bid) for 4–7 days. For the 2-DG procedure, rats were injected with saline or ibogaine (40 mg/kg, i.p.). 2-DG was administered 1 h after administration of ibogaine. The rate of LCGU was determined by quantitative autoradiography in 46 brain regions. In drug-naive animals, ibogaine produced significant increases in LCGU in the parietal, cingulate, and occipital cortices and cerebellum compared to controls consistent with its activity as a hallucinogen and a tremorogen. Morphine-dependent rats had only minor alterations in LCGU at the time assessed in this experiment. However, in morphine-dependent animals, ibogaine produced a global decrease in LCGU that was greatest in brain regions such as the lateral and medial preoptic areas, nucleus of the diagonal band, nucleus accumbens shell, inferior colliculus, locus coeruleus, and flocculus compared to morphine-dependent animals treated with saline. These findings indicate that ibogaine produces distinctly different effects on LCGU in drug-naive and morphine-dependent rats. This suggests that different mechanisms may underlie ibogaine's hallucinogenic and anti-addictive effects.

RF加温後のラット正常脳における局所グルコース代謝の変化

The responsible mechanisms for hyperthermia-induced injury in the brain are not fully understood. The changes in glucose metabolism may play an important role in hyperthermia-induced injury. To elucidate these mechanisms, the changes in local cerebral glucose utilization (LCGU) was measured following the induction of localized interstitial hyperthermia using the [14C] -2-deoxy-D-glucose autoradiographic technique. The induction of hyperthermia was achieved by using 8MHz radiofrequency (RF) in rats. The range of hyperthermia is from 37 to 45°C for 30min. We found that (1) LCGU was significantly decreased in the lesions heated to 45°C ; (2) it was increased in the lesions heated to 43°C ; and (3) it was increased in the contralateral thalamus and hippocampus of a hyperthermia group. In conclusion, severe hyperthermia at 45°C caused irreversible cell damage as shown by a marked decrease in LCGU. Hyperthermia at 43°C caused neuronal shrinkage and an increase in LCGU. In comparison with our previous cerebral blood flow (CBF) study, increased LCGU occurred prior to the oneset of decreased CBF. These findings suggest that the increased LCGU around severely damaged lesions caused by hyperthermia may be manifested as cellular injury and the threshold temperature may be 43°C for 30min.

The Role of the Perirhinal Cortex for Secondary Generalization in Kainic Acid–Induced Seizures

Purpose: We previously reported that a lesion in the perirhinal cortex (PRC) made by the microinjection of ibotenic acid resulted in the suppression of secondary generalization in kainic acid (KA‐induced limbic status epilepticus (LSE) in rats (Epilepsia 1996;37:95–6). We again studied the effects of PRC lesions made by electrocoagulation on KA‐induced LSE and also examined the differences in glucose metabolism between the PRC‐lesioned and the control rats by using the [14C]2‐deoxyglucose method. Methods: Fourteen male Wistar rats, weighing 250–300 g, were used for this study: eight for the behavioral and electroencephalographic (EEG) study, and six for the metabolic study. Under pentobarbital (PTB) anesthesia, the electrocoagulation probe was stereotaxically inserted into the PRC and the lesion (80°C, 1 m 30 s) was made. For EEG recordings, bipolar twisted electrodes were placed into the left sensorimotor cortex (LCx), the left hasolateral nucleus of the amygdala (LA), and the left dorsal hippocampus (LH). A cannula was implanted obliquely into the LA for KA injection. In the control group, an electrocoagulation probe was inserted into the PRC, but the lesion was not made. After a 7‐day recovery period, 1 μg of KA (0.5 μ1) was injected into the LA. All rats were observed for clinical and EEG changes for 6 h and were perfused under deep PTB anesthesia for the histopathologic examination (n = 8). We also studied the glucose metabolism in rats with a PRC lesion and the controls (n = 6). The rats were anesthetized with 1.5% halothane, and the femoral vein was cannulated. After recovery from the anesthesia, KA was injected into the LA. One and half hours after the KA injection, when all rats were exhibiting LSE, a bolus of [14C]2‐deoxyglucose (100 μCi/kg) was injected intravenously. Thirty minutes later, the rats were decapitated, the brains carefully removed and frozen in liquid freon‐12 (‐40°C). Consecutive coronal sections 20 pm thick were prepared in a cryostat, mounted on glass coverslips and dried at 60°C. Autoradiograms were made by exposing a Kodak SB5 film to the dried sections in a roentogenogram cassette for 7 days. The pattern of the local cerebral glucose utilization (LCGU) was compared between the rats with a PRC lesion and the controls. Results: In rats with a PRC lesion, the seizures were less frequent and severe compared with the controls. Interestingly, electrographic propagation of the epileptic discharges to the LCx was suppressed during the observation period. Clinically, motor manifestations were less frequently observed. In the histopathologic examination, hippocampal neuronal damage, especially in the CA3 and CA4 fields, was present in the control rats: however, only slight neuronal damage was seen in the hippocampus in the PRC‐lesioned rats. In the glucose metabolic study, a decrease in LCGU was confined to the LCx compared with the controls. Conclusions: In the PRC kindling model, McIntyre et al. demonstrated that the PRC has strong excitability, and the latency to onset of convulsive seizures is very short. Furthermore, Holmes et al. reported that the NMDA receptors located in the PRC play a major role in the modulation of after discharge activity elicited from the endopiriform nucleus or prepiriform cortex. Our study also suggests that the PRC is one of the important pathways for the secondary generalization of the seizure discharges from the limbic system to the sensorimotor cortex.

Autoradiographic determination of local cerebral blood flow and local cerebral glucose utilization during chemical stimulation of the nucleus tractus solitarii of anesthetized rats

This study was conducted to determine whether the decrease in cerebral blood flow (CBF) observed during chemical stimulation of the nucleus tractus solitarius (NTS) can be explained by a decrease in cerebral metabolism. In anesthetized (urethane and chloralose), paralyzed and artificially ventilated rats, neurons in the NTS were chemically stimulated by microinjection of l-glutamate. Local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCGU) were quantified in 43 brain structures by quantitative autoradiographic techniques using [ 14 C] iodoantipyrine and 2- [ 14 C] deoxyglucose, respectively. During chemical stimulation of the NTS ( n=6), LCBF decreased significantly in 32 of the 43 structures investigated when compared to either a control group with artificial cerebrospinal fluid injection ( n=6), or a controlled hemorrhage group ( n=5). In the controlled hemorrhage group, blood pressure was decreased to a degree comparable to that induced by microinjection of l-glutamate into the NTS. Mean blood flow of all structures investigated was significantly ( P<0.01) lower in the stimulation group than that in the control group and in the hemorrhage group. No significant differences in LCGU were observed between the three investigated groups in all structures examined except for an increase in LCGU in the chemically stimulated NTS site. It is concluded that the decrease in LCBF measured in most brain structures during chemical stimulation of the NTS is not caused by a decrease in LCGU in these structures and may therefore be explained by neurogenic influences on brain vessels.

The importance of baroreceptor afferents for the decrease in brain glucose utilization during stimulation of the rostroventrolateral medulla of the rat

The rostroventrolateral medulla (RVLM) is the main integration center for the regulation of the sympathetic outflow. The present study had the aim of investigating the effects of stimulation of the RVLM on the glucose utilization of the brain. Local cerebral glucose utilization (LCGU) can be regarded as an indicator of the brain functional activity. In anesthetized (chloralose-urethan), paralyzed (pancuronium) and ventilated rats, the medulla was exposed by a ventral craniotomy. The RVLM was stimulated by microinjection of 100 nl of 0.5 M sodium glutamate ( n = 6). The effective stimulation was verified by the increase in arterial blood pressure. In a control group ( n = 7), an identical volume of saline was injected into the RVLM. Local cerebral glucose utilization was measured in both groups using the 2-[ 14C]deoxyglucose method. The results showed a significant decrease in LCGU in the stimulated group in 33 of 39 brain structures examined. In order to investigate whether the decrease in brain glucose utilization is secondary to the stimulation of baroreceptor afferents by the increase in arterial blood pressure the carotid sinus nerves and both vagal nerves were cut. In this denervated group ( n = 5) the decrease in LCGU was abolished in all brain structures although blood pressure was increased to a degree comparable to the innervated group. It is concluded that cerebral glucose metabolism is decreased during stimulation of the RVLM and that this decrease is secondary to the activation of baroreceptor afferents by the increase in blood pressure.

Cocaine depresses cerebral glucose utilization in fetal sheep

To assess if cocaine alters cerebral glucose metabolism in the fetus, we infused cocaine 0.6 mg/min intravenously to 6 of 13 fetal sheep for the 55 min prior to measurement of glucose utilization by an autoradiographic method. Overall, local cerebral glucose utilization (LCGU) was lower in cocaine-exposed fetuses than in 7 controls ( P = 0.058). In the cocaine-exposed fetuses, 33 of 34 structures had lower mean LCGU than in the comparable structures of control fetuses. In addition, the autoradiographs in 4 of 6 cocaine-exposed fetuses revealed thin, dark lines of increased glucose utilization within the central white matter of some frontal gyri which were not seen in any of the 7 control fetuses. These lines were distributed similarly to ones seen earlier in severely hypoxic newborn lambs. In fetal lambs, cocaine resulted in a generalized decrease in LCGU and a specific increase in glucose utilization in parts of cortical white matter of the frontal gyri, possibly secondary to local ischemia.

Ethanol dependence and withdrawal selectively alter localized cerebral glucose utilization

The 2-deoxyglucose technique was used to determine local cerebral glucose utilization (LCGU) in over 50 brain regions of rats physically dependent upon ethanol and compared to those of acutely intoxicated and those undergoing an overt ethanol-withdrawal syndrome. Dependent-intoxicated rats (average 3lood ethanol concentration 64 mM) had decreased LCGU in 13/54 regions, including those associated with the limbic system, cerebellum, and motor system. The ethanol withdrawal syndrome was associated with 17/50 gray regions showing an increase, including regions involved with motor function, auditory system, and mammillary bodies-anterior thalamus-cingulate cortex pathway. The most pronounced differences between these groups occurred in regions associated with motor function, cerebellar function, anterior thalamus, and median raphe. Comparisons between dependent-intoxicated and acutely intoxicated rats (average blood ethanol concentration 66 mM) revealed that acute intoxication was associated with a relatively greater reduction in LCGU in regions involved with sensory-related functions, mammillary bodies, and median raphe. With the development of dependence, adaptation occurred in these regions except for inferior colliculus and median raphe. Dependence was also associated with a relative decrease in LCGU in white matter, limbic system, and extrapyramidal motor system.

The Effect of α-Adrenergic Receptor Blockers Prazosin and Yohimbine on Cerebral Metabolism and Biogenic Amine Content of Traumatized Brain

Widespread decrease in local cerebral glucose utilization (LCGU) previously shown to occur 3 days after a local freezing lesion was interpreted as reflecting a depression of functional activity in the affected areas. In parallel experiments, cortical norepinephrine (NE) content of traumatized brain was found to be decreased. The effects of prazosin (PZ), an alpha 1-adrenergic receptor blocker, and yohimbine (YOH), an alpha 2-blocker, on glucose use and biogenic amine content of lesioned rat brain were studied to determine if the changes in the noradrenergic system associated with injury are of functional importance, to identify the receptors that may be involved in mediating the action of NE in injured brain, and to look for evidence of interaction between the noradrenergic and the serotonergic systems in traumatized brain. PZ (1 mg/kg) given 30 min before the lesion ameliorated the subsequent metabolic cortical depression seen in untreated animals. PZ given for 3 days starting before the lesion (3 mg/kg/day) was also effective in normalizing LCGU in areas where it was depressed by lesioning, despite the fact that this regimen induced significant global decrease in LCGU in normal animals. Once cortical metabolic depression had developed 3 days after the lesion, it could not be modified by PZ. YOH was less effective than PZ and was so only when given for 3 days (22.5 mg/kg/day in three divided doses). PZ (3 mg/kg/day in three divided doses) slightly but significantly decreased the accumulation of the serotonin (5-HT) metabolite 5-hydroxyindoleacetic acid in the traumatized hemisphere. These results provide evidence that blockage of alpha 1-adrenergic receptors prevents the development of cortical dysfunction associated with brain trauma. This implies that the noradrenergic system plays a role in the functional consequences of injury and that this effect is, at least in part, mediated by alpha 1-adrenergic receptors. Furthermore, alpha 1-adrenergic receptor blockage appears to modulate cortical turnover of 5-HT, previously also implicated in functional consequences of brain injury. The data are compatible with inhibitory effects of NE in the cortex and suggest a potential of alpha 1-adrenergic blockage in development of novel therapeutic approaches to brain injury.

Effects of Ginkgolide B and Ginkgo biloba extract on local cerebral glucose utilization in the awake adult rat

The effects of the extract of the leaves of Ginkgo biloba and of one of its major components, Ginkgolide B, on local cerebral glucose utilization (LCGU) have been studied in the awake adult rat. Ginkgolide B (10 mg/kg i.p.) had no significant effect on LCGU in 38 brain regions studied. In contrast, the Ginkgo biloba extract (150 mg/kg i.p. in 3 divided doses) produced significant and widespread decreases in LCGU in 21 brain regions (range 3–26% reduction). These results demonstrate that Ginkgo biloba is able to reduce brain glucose utilization, but that the substance responsible for this effect may not be Ginkgolide B.

Morphine-induced alterations of local cerebral glucose utilization in the basal ganglia of rats

The actions of various doses of morphine on the local cerebral glucose utilization (LCGU) were studied by means of the autoradiographic [ 14C]2-deoxyglucose technique. Morphine (1–15 mg/kg i.p.) decreased LCGU in most areas of the basal ganglia (caudate nucleus, globus pallidus, nucleus accumbens), but not in the substantia nigra pars compacta. LCGU was also decreased in limbic nuclei, such as septum, hippocampus and amygdala, and in most thalamic areas. In most cortical regions, a decrease was found as well. Findings in some efferent nuclei seemed of particular interest, namely in the substantia nigra pars reticulata, anteroventral and lateral nucleus of the thalamus and the subthalamic nucleus, where decrease in LCGU were found after administration of 7.5 mg/kg or sometimes lower doses, but not after 15 mg/kg of morphine. The decreases seem to reflect a general depressory effect of morphine on neuronal activity which is known from electrophysiological studies. Part of these effects might be, in addition, due to an activation of dopaminergic neurons, since dopamine mainly acts as an inhibitory neurotransmitter. This dopaminergic activation leads to characteristic behavioral effects after lower doses of morphine. The largest dose used (15 mg/kg) produces muscular rigidity, probably by a direct action on the striatum. This effect antagonizes and masks the dopaminomimetic effects. The results suggest that it also antagonizes the functional alterations in some efferent nuclei of the basal ganglia manifest after lower doses of morphine. Local injections of morphine (15 μg) led to decreases of LCGU in the various parts of the striatum, but to increases in lateral and anteroventral thalamus. These increases in LCGU in two thalamic areas seem to support the above hypothesis that the rigidity is accompanied, at least in part of the efferent nuclei of the basal ganglia, by increases in LCGU antagonizing the inhibitory effects described above.

Uncoupling of cerebral blood flow and glucose utilization by dihydroergocristine in the conscious rat.

Dose-dependent effects of the dihydrogenated ergot alkaloid dihydroergocristine on physiological variables, local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCGU) were evaluated in the conscious rat after intravenous injection. Heart rate was reduced with 2.5 mg/kg and 20 mg/kg dihydroergocristine. LCBF and LCGU were determined autoradiographically by employing the 14C-iodoantipyrine or 14C-2-deoxyglucose technique, respectively. At a dose of 0.5 mg/kg, dihydroergocristine neither changed LCGU nor LCBF, while at 2.5 mg/kg a slight decrease in LCGU was measured, which was more pronounced at 20 mg/kg. LCBF was significantly increased in several structures at 2.5 mg/kg, but it was markedly reduced at 20 mg/kg. The divergent effects on LCBF and LCGU at a dose of 2.5 mg/kg suggest a potential capacity of dihydroergocristine to uncouple the close interrelation of cerebral blood flow and cerebral energy metabolism.

Stimulatory effect of the D2 antagonist sulpiride on glucose utilization in dopaminergic regions of rat brain.

Local cerebral glucose utilization (LCGU) was measured, using the quantitative autoradiographic [14C]2-deoxy-D-glucose method, in 56 brain regions of 3-month-old, awake Fischer-344 rats, after intraperitoneal administration of sulpiride (SULP) 100 mg/kg. SULP, an "atypical" neuroleptic, is a selective antagonist of D2 dopamine receptors. LCGU was reduced in a few nondopaminergic regions at 1 h after drug administration. Thereafter, SULP progressively elevated LCGU in many other regions. At 3 h, LCGU was elevated in 23% of the regions examined, most of which are related to the CNS dopaminergic system (caudate-putamen, nucleus accumbens, olfactory tubercle, lateral habenula, median eminence, paraventricular hypothalamic nucleus). Increases of LCGU were observed also in the suprachiasmatic nucleus, lateral geniculate, and inferior olive. These effects of SULP on LCGU differ from the effects of the "typical" neuroleptic haloperidol, which produces widespread decreases in LCGU in the rat brain. Selective actions on different subpopulations of dopamine receptors may explain the different effects of the two neuroleptics on brain metabolism, which correspond to their different clinical and behavioral actions.

Altered local cerebral glucose utilization by unilateral frontal cortical ablations in rats

Alterations in local cerebral glucose utilization (LCGU) following ablations of the unilateral frontal cortex in rats were studied to elucidate the effect of the lesion on the functional activity in the related cerebral structures. Frontal cortical ablations (areas 2, 4, 6 and 10) were made by aspiration on the left side, and LCGU was evaluated at 7 days after the operation, using the [ 14C]deoxyglucose method. Significant decreases in LCGU in rats with unilateral frontal cortical ablations, were observed in the ipsilateral thalamic nuclei (ventroanterior-ventrolateral (VAL), ventrobasal (VB), reticular), red nucleus and pontine nucleus. The ipsilateral globus pallidus showed a significant LCGU increase. The contralateral cerebellar cortex showed a tendency toward a decrease in LCGU. The striatum, which receives direct projections from the frontal cortex, showed no LCGU change. These results indicated that ablations of unilateral frontal cortex in rats produced LCGU changes in the cerebral structures which have direct or indirect neuronal connections with the ablated area. These LCGU changes were, for the most part, brought about by alteration in the neuronal activity. Particularly, the LCGU increase in the globus pallidus which receives transsynaptic neuronal input from the frontal cortex, without changes in the striatum, which receives direct projection, was attributed to the functional alteration of the globus pallidus produced by the cortical ablation. Destructive lesion of a cerebral structure, therefore, does not necessarily cause functional depressions in the pertinent structures, but it may enhance the function of some structures, depending on the functional characteristics of each neuronal connection and functional organization of those structures.

Bilateral cerebral metabolic alterations following lesion of the ventromedial thalamic nucleus: mapping by the 14C-deoxyglucose method in conscious rats.

The functional role of the ventromedial thalamic nucleus (VM) was investigated by means of the quantitative autoradiographic 14C-deoxyglucose method. Local cerebral glucose utilization (LCGU) was measured bilaterally in 53 discrete brain areas of conscious rats 1 week and 1 month following electrolytic lesion of the VM. There was no difference observed in the LCGU values between the two groups of lesioned animals. In the VM-lesioned rats glucose consumption was decreased in several ipsilateral (pre-frontal, frontal, cingulate, sensorimotor, visual) and in some contralateral (cingulate, sensorimotor, visual) cortical areas. Furthermore, LCGU values were depressed bilaterally in the striatum, hippocampus, dentate gyrus, substantia nigra compacta, superficial layers of the superior colliculus, oculomotor complex, and cerebellar dentate nuclei. Glucose utilization was diminished also in the deep layers of the superior colliculus and in the fastigial nucleus ipsilateral to the lesion. Within the thalamus, glucose metabolism was decreased in several nuclei either bilaterally (reticular, intralaminar, paralamellar mediodorsal) or ipsilaterally (lateroposterior, ventrobasal, ventrolateral, ventroanterior, and medioventral) to the lesion. A significant correlation between the percentage of injured VM and the regional metabolic depression was demonstrated in the areas displaying the most pronounced decrease in LCGU. These results support a widespread influence of the VM on brain function extending beyond the limits of purely motor systems and reveal the consequences of a unilateral lesion of the thalamus on metabolic activity in several contralateral structures.

Altered local cerebral glucose utilization by unilateral frontal cortical ablations in rats

Alterations in local cerebral glucose utilization (LCGU) following ablations of the unilateral frontal cortex in rats were studied to elucidate the effect of the lesion on the functional activity in the related cerebral structures. Frontal cortical ablations (areas 2, 4, 6 and 10) were made by aspiration on the left side, and LCGU was evaluated at 7 days after the operation, using the [14C]deoxyglucose method. Significant decreases in LCGU in rats with unilateral frontal cortical ablations, were observed in the ipsilateral thalamic nuclei (ventroanterior-ventrolateral (VAL), ventrobasal (VB), reticular), red nucleus and pontine nucleus. The ipsilateral globus pallidus showed a significant LCGU increase. The contralateral cerebellar cortex showed a tendency toward a decrease in LCGU. The striatum, which receives direct projections from the frontal cortex, showed no LCGU change. These results indicated that ablations of unilateral frontal cortex in rats produced LCGU changes in the cerebral structures which have direct or indirect neuronal connections with the ablated area. These LCGU changes were, for the most part, brought about by alteration in the neuronal activity. Particularly, the LCGU increase in the globus pallidus which receives transsynaptic neuronal input from the frontal cortex, without changes in the striatum, which receives direct projection, was attributed to the functional alteration of the globus pallidus produced by the cortical ablation. Destructive lesion of a cerebral structure, therefore, does not necessarily cause functional depressions in the pertinent structures, but it may enhance the function of some structures, depending on the functional characteristics of each neuronal connection and functional organization of those structures.

Effect of Middle Cerebral Artery Occlusion on Catecholamine Metabolism in Rat Brain

The authors previously reported on local cerebral glucose utilization (LCGU) and local cerebral blood flow (LCBF) in rats 1 hour after the occlusion of the left middle cerebral artery. It was found that LCGU was decreased in the ipsilateral cerebral cortex and the lateral striatum, where the LCBF was also reduced. On the other hand, LCGU was increased in the ipsilateral medial striatum, olfactory tubercle, globus pallidus, subthalamic nucleus, and lateral habenula, which are the “non-ischemic” regions and closely connected with the dopaminergic neurons. In the present work, catecholamines and their metabolites were measured using the same ischemic model rats. The results were compared with the changes in LCGU and LCBF in the various cerebral regions. Noradrenaline concentration was reduced mainly in the “ischemic” regions, such as the ipsilateral cerebral cortex and lateral striatum, and there was an increase in the “non-ischemic” lateral thalamic nucleus. On the other hand, dopamine (DA) was increased bilaterally in the regions closely connected with dopaminergic neurons. However, 3, 4-dihydroxyphenylacetic acid and homovanillic acid were increased only in the ipsilateral regions and a small decrease was found in the contralateral striatum. These changes in DA and its metabolites indicate that DA metabolism was increased ipsilaterally in both the “ischemic” and “non-ischemic” regions but it was probably inhibited on the contralateral side. Since DA agonist, apomorphine, has been reported to increase energy metabolism (LCGU) mainly in the regions closely connected with the dopaminergic neurons, the results of the present work suggest that the ischemia in the ipsilateral cortex and lateral striatum caused an increase in DA neuron activity, which may be the cause of the increased LCGU in the ipsilateral “non-ischemic” dopamine rich regions, whereas the decrease in LCGU, inspite of the increased DA metabolism in the ipsilateral cortex and lateral striatum, were probably due to the direct effects of ischemia (the depletion of glucose supply). The contralateral change in DA was thought to be a biochemical diaschisis, which was mediated neuronally via a crossed nigrostriatal pathway.

Muscimol-scopolamine interactions in the rat brain: a study with 2- deoxy-D-[1-14C]glucose

The 2-deoxy-D[1-14C]glucose method of Sokoloff was used to measure local cerebral glucose utilization (LCGU) in rats after injections of the GABA receptor agonist, muscimol (1.6 mg/kg and 4.0 mg/kg, i.v.); the muscarinic receptor antagonist, scopolamine (0.4 mg/kg and 2.0 mg/kg, i.v.); or combinations of both drugs. The aim was to identify brain regions where functional effects of GABAergic-cholinergic interactions could be seen. As noted previously, muscimol reduced LCGU in many brain regions. In contrast, scopolamine alone had no effect on LCGU in most brain regions; however, decreases were seen in the medial geniculate body, medial thalamic nucleus, and auditory and frontal cortical areas. Scopolamine increased LCGU in the cerebellar vermis and mesencephalic reticular formation. Although muscimol alone did not significantly affect LCGU in the external plexiform layer of the olfactory bulb or the anterior, periventricular, and parafascicular thalamic nuclei, rats treated with 0.4 mg/kg of scopolamine before 4.0 mg/kg of muscimol had LCGU decrements in those brain regions. Furthermore, the muscimol-induced decrease in LCGU in the medial cortex was enhanced by prior treatment with 0.4 mg/kg of scopolamine. In contrast, in certain brain regions where muscimol alone reduced LCGU (locus ceruleus; central gray matter; striatum; ventral, medial, reunients , and rhomboid thalamic nuclei; and the auditory cortex), scopolamine pretreatment antagonized these decrements. These findings suggest that endogenous cholinergic and GABAergic systems act antagonistically in some brain regions. However, in other brain regions, cholinergic transmission is required for full expression of GABAmimetic effects on LCGU.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of intravenous norepinephrine on the local coupling between glucose utilization and blood flow in the rat brain.

Norepinephrine was infused intravenously in two groups of normal, awake rats. In one group local cerebral glucose utilization (LCGU) was measured by the deoxyglucose method (Sokoloff et al. 1977b); in the other group local cerebral blood flow (LCBF) was determined by the iodoantipyrine method (Sakurada et al. 1978). The experiments were performed during a stable state in which the heart rate was reduced between 36% (LCGU experiments) and 27% (LCBF experiments). Norepinephrine infusion reduced LCGU in all 39 structures measured between - 18 and - 37% from control values obtained in a group of normal non-infused rats. The decrease in LCGU was significant (P less than 0.05) in 38 of the 39 structures tested. LCBF was increased but not statistically significantly in most of the structures examined. When the LCGU values of the various structures during norepinephrine infusion were correlated with their corresponding LCBF values, a tight correlation (r = 0.94) was found indicating a close coupling between LCGU and LCBF during norepinephrine infusion. When compared to the relationship between LCGU and LCBF in a normal, non-infused control group, the slope of the regression line was increased significantly (P less than 0.01) by the norepinephrine infusion, indicating a resetting of the coupling mechanism. This means that, at a given metabolic rate, a higher blood flow is needed to perfuse a brain structure during norepinephrine infusion than during control conditions.

Increased local cerebral glucose utilization in the basal ganglia of the rolling mouse Nagoya.

Rolling mouse Nagoya (rolling), an experimental mutant mouse, is characterized by a marked incoordination of the hind limbs and disturbance of gait. These motor disturbances have been attributed to cerebellar dysfunction, and rolling, therefore, has been regarded as an animal model of hereditary cerebellar ataxia. However, definite evidence for this possibility has not yet been provided. In the present study, local cerebral glucose utilization (LCGU) was observed by means of the [14C]deoxyglucose method in rolling (rol/rol), as well as in behaviorally normal heterozygotes (+/rol) and normal controls (+/+), in order to study functional activity of the brain in these mice. A definite increase in LCGU was found in the globus pallidus, entopeduncular nucleus, subthalamic nucleus, and substantia nigra of rolling, bilaterally. A minimal decrease in LCGU was also found in the vermis of the cerebellum. These findings reflect the markedly hyperactive state of the basal ganglia and the minimally hypoactive state in the vermis of the cerebellum in rolling. It is concluded that the dysfunction in the basal ganglia is the major cause of the motor disturbances of rolling, and that rolling may be regarded as an animal model of extrapyramidal motor disturbance.

Effects of gamma-aminobutyric acid agonist and antagonist drugs on local cerebral glucose utilization

The [14C]2-deoxy-D-glucose method of Sokoloff et al. (Sokoloff, L., M. Reivich, C. Kennedy, M.H. Des Rosiers, C. S. Patlak, K. D. Pettigrew, O. Sakurada, and M. Shinohara (1977) J. Neurochem. 28:897-916) weas used to study local cerebral glucose utilization (LCGU) in rats treated with gamma-aminobutyric acid (GABA) agonist (muscimol and 4,5,6,7-tetrahydroisoxazolo[5,4-C]pyridin-3-ol, THIP) and antagonist (bicuculline) drugs. It was of interest to determine if the pattern of LCGU responses to GABA agonists and antagonists administered systemically in vivo would reflect the known distributions of markers for central GABAergic synapses. The patterns of LCGU responses to muscimol and THIP generally were similar. Most brain regions showed dose-dependent decreases in LCGU; others showed no effects; but the red nucleus showed an increase. The GABA antagonist bicuculline produced convulsions and variable LCGU responses, depending on the time of administration. Bicuculline also partially antagonized the depressant effects of muscimol of LCGU. The magnitudes and distribution of in vivo cerebral metabolic responses to specific GABA agonists were not correlated simply with markers for GABAergic synapses. This lack of correlation indicates that additional factors, such as neural circuitry, regulate the LCGU responses to GABAergic drugs.