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Stimulation of mitochondrial biogenesis during life-time challenges both eliminates disadvantageous properties and drives adaptive selection of advantageous phenotypic variations. Intermittent fission and fusion of mitochondria provide specific targets for health promotion by brief temporal stressors, interspersed with periods of recovery and biogenesis. For mitochondria, the mechanisms of selection, variability, and heritability, are complicated by interaction of two independent genomes, including the multiple copies of DNA in each mitochondrion, as well as the shared nuclear genome of each cell. The mechanisms of stress-induced fission, followed by recovery-induced fusion and biogenesis, drive the improvement of mitochondrial functions, not only as directed by genotypic variations, but also as enabled by phenotypic diversity. Selective adaptation may explain unresolved aspects of aging, including the health effects of exercise, hypoxic and poisonous preconditioning, and tissue-specific mitochondrial differences. We propose that intermittent purposeful enhancement of mitochondrial biogenesis by stressful episodes with subsequent recovery paradoxically promotes adaptive mitochondrial health and continued healthy aging.

Udgivelsesdato: 1995-Sep-28 6-[18F]fluoro-L-DOPA (FDOPA) has been used as a tracer for the cerebral activity of L-3,4-dihydroxyphenylalanine (DOPA)-decarboxylase in studies of positron emission tomography (PET). However, the substitution of fluorine on the aromatic ring may alter the disposition and metabolism of FDOPA from that of endogenous DOPA. In the present study, the kinetics of the peripheral metabolism and the facilitated unidirectional blood-brain clearance of [3H]DOPA and FDOPA were compared in Wistar rats pretreated with carbidopa. In arterial plasma, FDOPA was O-methylated with an apparent rate constant (0.031 min-1) 3-fold that of [3H]DOPA in the same rats. The O-methylated metabolite of FDOPA (OMe-FDOPA) was eliminated from plasma at a rate constant (0.018 min-1) 3-fold that of OMe-[3H]DOPA. The mean unidirectional blood-brain clearance of FDOPA (4.5 mL.hg-1.min-1) in six brain regions was 60% higher than that of [3H]DOPA.

Serotonin 5-HT 2 receptor availability was evaluated in chronic cocaine abusers (n = 19) using positron emission tomography and F-18 N-methylspiperone and was compared to control subjects (n = 19). 5-HT 2 Receptor availability was measured in frontal, occipital, cingulate and orbitofrontal cortices using the ratio of the distribution volume in the region of interest to that in the cerebellum which is a function of B max /K d - 5-HT 2 Receptor availability was significantly higer in cingulate and orbitofrontal cortices than in other frontal regions or occipital cortex. The values were not different in normal subjects and cocaine abusers. These results did not show any changes in 5-HT 2 receptor availability in cocaine abusers as compared to the control subjects.

Udgivelsesdato: 1995-Feb Focal freezing lesions in rats cause a widespread decrease of cortical glucose utilization in the lesioned hemisphere, probably as a reflection of depressed cortical activity. The noradrenergic neurotransmitter system was implicated in these alterations when it was demonstrated that prazosin, a specific norepinephrine (NE) antagonist at alpha 1-adrenergic receptors, prevented their development. In normal rat brain, specific binding of [125I]HEAT [(+/-)2-(3-[125I]iodo-4-hydroxyphenyl)-ethyl-aminomethyl-tetralone], another selective alpha 1-adrenoreceptor ligand, was demonstrated in vivo at sites consistent with the alpha 1A- and alpha 1B-adrenoreceptor subtypes. In the present study, the effect of a freezing lesion on specific binding of [125I]HEAT in rat brain in vivo was determined three days after traumatization when cortical glucose use suggested the greatest degree of functional depression. The steady-state volumes of distribution of [125I]HEAT three days after injury were significantly increased in all the cortical areas of the lesioned hemisphere, but not in the subcortical structures. Injury did not modify the binding affinities for HEAT. However, a statistically significant increase in the number of low-affinity binding sites for this ligand was demonstrated in all cortical areas of the lesioned hemisphere, but not in subcortical structures. The traumatization did not modify Bmax estimates for the high-affinity binding of HEAT. The results support the hypothesis that changes in the noradrenergic system are of functional importance in brain injury and that at least some effects of injury are mediated by alpha 1B-adrenergic receptors.

Emerging evidence points to monocarboxylates as key players in the pathophysiology of temporal lobe epilepsy (TLE) with hippocampal sclerosis (mesial temporal lobe epilepsy, MTLE). Monocarboxylate transporters (MCTs) 1 and 2, which are abundantly present on brain endothelial cells and perivascular astrocyte endfeet, respectively, facilitate the transport of monocarboxylates and protons across cell membranes. Recently, we reported that the density of MCT1 protein is reduced on endothelial cells and increased on astrocyte plasma membranes in the hippocampal formation in patients with MTLE and in several animal models of the disorder. Because the perivascular astrocyte endfeet comprise an important part of the neurovascular unit, we now assessed the distribution of the MCT2 in hippocampal formations in TLE patients with (MTLE) or without hippocampal sclerosis (non-MTLE). Light microscopic immunohistochemistry revealed significantly less perivascular MCT2 immunoreactivity in the hippocampal formation in MTLE (n = 6) than in non-MTLE (n = 6) patients, and to a lesser degree in non-MTLE than in nonepilepsy patients (n = 4). Immunogold electron microscopy indicated that the loss of MCT2 protein occurred on perivascular astrocyte endfeet. Interestingly, the loss of MCT2 on astrocyte endfeet in MTLE (n = 3) was accompanied by an upregulation of the protein on astrocyte membranes facing synapses in the neuropil, when compared with non-MTLE (n = 3). We propose that the altered distribution of MCT1 and MCT2 in TLE (especially MTLE) limits the flux of monocarboxylates across the blood-brain barrier and enhances the exchange of monocarboxylates within the brain parenchyma.

We present the perspective that lactate is a volume transmitter of cellular signals in brain that acutely and chronically regulate the energy metabolism of large neuronal ensembles. From this perspective, we interpret recent evidence to mean that lactate transmission serves the maintenance of network metabolism by two different mechanisms, one by regulating the formation of cAMP via the lactate receptor GPR81, the other by adjusting the NADH/NAD+ redox ratios, both linked to the maintenance of brain energy turnover and possibly cerebral blood flow. The role of lactate as mediator of metabolic information rather than metabolic substrate answers a number of questions raised by the controversial oxidativeness of astrocytic metabolism and its contribution to neuronal function. Here, we present the perspective that lactate acts as a volume transmitter in brain tissue by distributing cellular signals that are relevant to the metabolic support of large neuronal ensembles. We interpret recent evidence to mean that lactate transmission is involved in the maintenance of network homeostasis by two different mechanisms; one by regulation of neuronal cAMP formation through the lactate receptor GPR81, the other by adjustment of the NADH/NAD+ redox ratio. Lactate is an intermediary metabolite in brain energy metabolism, the role of which is controversial (Dienel, 2011). Traditionally, lactate was considered a waste product with no certain function in the metabolic housekeeping when eukaryotic cells have sufficient oxygen. However, it is also held to be a “preferred” substrate of energy metabolism, in muscle (Brooks, 2009) as well as in brain (Bouzier-Sore et al., 2003; Smith et al., 2003; Wyss et al., 2011). This alleged preference revives an ancient claim of lactate’s service as nutrient for neurons that do not phosphorylate glucose to the extent required by neuronal energy metabolism (Andriezen, 1893; DiNuzzo et al., 2011). A cue to the notion of a signaling role of lactate, irrespective of any role as intermediary metabolite, is the observation that lactate regulates cerebral blood flow (Gordon et al., 2008).

Cerebral metabolic rate of oxygen consumption ( CMRO 2), cerebral blood flow ( CBF), and oxygen extraction fraction ( OEF) are important indices of healthy aging of the brain. Although a frequent topic of study, changes of CBF and CMRO 2 during normal aging are still controversial, as some authors find decreases of both CBF and CMRO 2 but increased OEF, while others find no change, and yet other find divergent changes. In this reanalysis of previously published results from positron emission tomography of healthy volunteers, we determined CMRO 2 and CBF in 66 healthy volunteers aged 21 to 81 years. The magnitudes of CMRO 2 and CBF declined in large parts of the cerebral cortex, including association areas, but the primary motor and sensory areas were relatively spared. We found significant increases of OEF in frontal and parietal cortices, excluding primary motor and somatosensory regions, and in the temporal cortex. Because of the inverse relation between OEF and capillary oxygen tension, increased OEF can compromise oxygen delivery to neurons, with possible perturbation of energy turnover. The results establish a possible mechanism of progression from healthy to unhealthy brain aging, as the regions most affected by age are the areas that are most vulnerable to neurodegeneration.

We tested the claim that decline of inter-individual CBF variability in Alzheimer’s disease (AD) is pronounced when the variability from changes of arterial CO2 tension (PaCO2) is eliminated. Specifically, we tested whether the variability of CBF in brain of patients with AD differed significantly from brain of age-matched healthy control subjects (HC). To eliminate the CO2-induced variability, we developed a novel and generally applicable approach to the correction of CBF for changes of PaCO2 and applied the method to positron emission tomographic (PET) measures of CBF in AD and HC groups of subjects. After correction for the differences of CO2 tension, the patients with AD lost the inter-individual CBF variability that continued to characterize the HC subjects. The difference (delta K1 ) between the blood-brain clearances (K1) of water (the current measure of CBF) and oxygen (the current measure of oxygen clearance) was reduced globally in AD and particularly in the parietal, occipital, and temporal lobes. We then showed that oxygen gradients calculated for brain tissue were similar in AD and HC, indicating that the low residual variability of CBF in AD may be due to low functional demands for oxidative metabolism of brain tissue rather than impaired delivery of oxygen

Type 2 diabetes and hyperglycemia with the resulting increase of glucose concentrations in the brain impair the outcome of ischemic stroke, and may increase the risk of developing Alzheimer's disease (AD). Reports indicate that glucagon-like peptide-1 (GLP-1) may be neuroprotective in models of AD and stroke: Although the mechanism is unclear, glucose homeostasis appears to be important. We conducted a randomized, double-blinded, placebo-controlled crossover study in nine healthy males. Positron emission tomography was used to determine the effect of GLP-1 on cerebral glucose transport and metabolism during a hyperglycemic clamp with 18fluoro-deoxy-glucose as tracer. Glucagon-like peptide-1 lowered brain glucose (P=0.023) in all regions. The cerebral metabolic rate for glucose was increased everywhere (P=0.039) but not to the same extent in all regions (P=0.022). The unidirectional glucose transfer across the blood–brain barrier remained unchanged (P=0.099) in all regions, while the unidirectional clearance and the phosphorylation rate increased (P=0.013 and 0.017), leading to increased net clearance of the glucose tracer (P=0.006). We show that GLP-1 plays a role in a regulatory mechanism involved in the actions of GLUT1 and glucose metabolism: GLP-1 ensures less fluctuation of brain glucose levels in response to alterations in plasma glucose, which may prove to be neuroprotective during hyperglycemia. Type 2 diabetes and hyperglycemia with the resulting increase of glucose concentrations in the brain impair the outcome of ischemic stroke, and may increase the risk of developing Alzheimer's disease (AD). Reports indicate that glucagon-like peptide-1 (GLP-1) may be neuroprotective in models of AD and stroke: Although the mechanism is unclear, glucose homeostasis appears to be important. We conducted a randomized, double-blinded, placebo-controlled crossover study in nine healthy males. Positron emission tomography was used to determine the effect of GLP-1 on cerebral glucose transport and metabolism during a hyperglycemic clamp with (18)fluoro-deoxy-glucose as tracer. Glucagon-like peptide-1 lowered brain glucose (P=0.023) in all regions. The cerebral metabolic rate for glucose was increased everywhere (P=0.039) but not to the same extent in all regions (P=0.022). The unidirectional glucose transfer across the blood-brain barrier remained unchanged (P=0.099) in all regions, while the unidirectional clearance and the phosphorylation rate increased (P=0.013 and 0.017), leading to increased net clearance of the glucose tracer (P=0.006). We show that GLP-1 plays a role in a regulatory mechanism involved in the actions of GLUT1 and glucose metabolism: GLP-1 ensures less fluctuation of brain glucose levels in response to alterations in plasma glucose, which may prove to be neuroprotective during hyperglycemia.

Neuroimaging studies of functional magnetic resonance imaging (fMRI) and electrophysiology provide the linkage between neural activity and the blood oxygenation level-dependent (BOLD) response. Here, BOLD responses to light flashes were imaged at 11.7T and compared with neural recordings from superior colliculus (SC) and primary visual cortex (V1) in rat brain--regions with different basal blood flow and energy demand. Our goal was to assess neurovascular coupling in V1 and SC as reflected by temporal/spatial variances of impulse response functions (IRFs) and assess, if any, implications for general linear modeling (GLM) of BOLD responses. Light flashes induced high magnitude neural/BOLD responses reproducibly from both regions. However, neural/BOLD responses from SC and V1 were markedly different. SC signals followed the boxcar shape of the stimulation paradigm at all flash rates, whereas V1 signals were characterized by onset/offset transients that exhibited different flash rate dependencies. We find that IRF(SC) is generally time-invariant across wider flash rate range compared with IRF(V1), whereas IRF(SC) and IRF(V1) are both space invariant. These results illustrate the importance of measured neural signals for interpretation of fMRI by showing that GLM of BOLD responses may lead to misinterpretation of neural activity in some cases.

The hypofrontality theory of the pathogenesis of schizophrenia predicts that cortical lesions cause psychosis. During a search for abnormalities of catecholaminergic neurotransmission in patients with complex partial seizures of the mesial temporal lobe, we discovered an increase of the rate of metabolism of an exogenous dopa tracer (6-[18F]fluoro-L-dopa) in the neostriatum of a subgroup of patients with a history of psychosis. When specifically assayed for this abnormality, patients with schizophrenia revealed the same significant increase of the rate of metabolism in the striatum. The finding is consistent with the theory that a state of psychosis arises when episodic dopamine excess is superimposed on a trait of basic dopamine deficiency in the striatum. The finding is explained by the hypothesis that cortical insufficiency, a proposed pathogenetic mechanism of both disorders, causes an up-regulation of the enzymes responsible for dopa turnover in the neostriatum as well as the receptors mediating dopaminergic neurotransmission.

Pain is a diverse sensory and emotional experience that likely involves activation of numerous regions of the brain. Yet, many of these areas are also implicated in the processing of nonpainful somatosensory information. In order to better characterize the processing of pain within the human brain, activation produced by noxious stimuli was compared with that produced by robust innocuous stimuli. Painful heat (47–48 degrees C), nonpainful vibratory (110 Hz), and neutral control (34 degrees C) stimuli were applied to the left forearm of right-handed male subjects. Activation of regions within the diencephalon and telencephalon was evaluated by measuring regional cerebral blood flow using positron emission tomography (15O-water-bolus method). Painful stimulation produced contralateral activation in primary and secondary somatosensory cortices (SI and SII), anterior cingulate cortex, anterior insula, the supplemental motor area of the frontal cortex, and thalamus. Vibrotactile stimulation produced activation in contralateral SI, and bilaterally in SII and posterior insular cortices. A direct comparison of pain and vibrotactile stimulation revealed that both stimuli produced activation in similar regions of SI and SII, regions long thought to be involved in basic somatosensory processing. In contrast, painful stimuli were significantly more effective in activating the anterior insula, a region heavily linked with both somatosensory and limbic systems. Such connections may provide one route through which nociceptive input may be integrated with memory in order to allow a full appreciation of the meaning and dangers of painful stimuli. These data reveal that pain-related activation, although predominantly contralateral in distribution, is more widely dispersed across both cortical and thalamic regions than that produced during innocuous vibrotactile stimulation. This distributed cerebral activation reflects the complex nature of pain, involving discriminative, affective, autonomic, and motoric components. Furthermore, the high degree of interconnectivity among activated regions may account for the difficulty of eliminating pathological pain with discrete CNS lesions.

The blood-brain permeabilities of L-[3H]tyrosine and the tyrosine hydroxylase (TH) inhibitor β-[14C]methyl-para-tyrosine ([14C]AMPT) were determined in rat striatum, a brain region rich in TH activity, and in other brain regions containing relatively little TH activity. In striatum, the unidirectional clearance rate (K1) for L-[3H]tyrosine (6.2 ml hg- −1 min−1) was significantly greater than the rates for L-[14C]AMPT (2.8 ml hg−1 min−1) and D-[14C]AMPT (0.8 ml hg−1 min−1). The apparent volume of distribution (Vf) for L-[14C]AMPT in striatum (72.5 ± 4.0 ml hg-1) did not differ from the Vf in other brain regions. The homogeneous distribution of L-[14C]AMPT in rat brain indicates that labeled AMPT is unsuitable for the study of TH in vivo by quantitative autoradiography. © 1994 Wiley-Liss, Inc.

Udgivelsesdato: 1994-Apr-4 The distribution of high-affinity binding sites for the histamine H3 agonist [3H]-N alpha-methylhistamine ([3H]NAMH, 4 nM) in the rat brain was examined by autoradiography. Binding in all brain regions was displaceable with the H3 antagonist thioperamide (2 microM). The pattern of H3 binding was heterogeneous: highest levels were in the striatum and substantia nigra, which receives sparse histaminergic innervations. Intermediate H3 binding was present in neocortex and diencephalon, while low binding was evident in the medial septum and dorsal hippocampus. Hitherto unreported H3 binding sites were noted in the dorsolateral tegmentum and in the nucleus of the solitary tract (NTS). Because the NTS receives a dense histaminergic innervation, [3H]NAMH binding in the NTS was further studied by Scatchard analysis. The presence of saturable binding (Bmax = 10 +/- 4 fmol/mg, Kd = 0.6 +/- 0.3 nM, n = 3) suggested that histamine may act via H3 receptors in the NTS.

Udgivelsesdato: 1994-null Reduction of pump flow during cardiopulmonary bypass (CPB) reduces the formation of microemboli and trauma to the blood components, reduces both rewarming of the heart and the noncoronary collateral flow, and improves surgical exposure. Recent studies indicate that a reduction in pump flow, even at normothermia, does not increase the incidence of postoperative cerebral dysfunction. We examined the cerebral consequences of 2 h of normothermic CPB in pigs carried out at pump flows of either 70 ml/kg per min or 50 ml/kg per min, and compared the results with those of a nonperfused control group. We measured the regional cerebral glucose metabolism and the regional capillary diffusion capacity simultaneously in ten different brain regions. Brain morphology, the blood-brain barrier permeability to serum proteins and the regional cerebral water content were also determined in the same animals. Glucose metabolism decreased significantly in both CPB groups (P < 0.001), and significant differences were found between the capillary diffusion capacities of the three groups (P < 0.05), with decreases in eight out of ten brain regions examined in the 50 ml/kg per min group. The results indicate that a reduction of pump flows from 70 ml/kg per min to 50 ml/kg per min is deleterious to the brain, and that a pump flow of 70 ml/kg per min itself has an injurious effect, when normothermic CPB is carried out for 2 h without the use of vasoactive drugs to maintain the blood pressure. Mean arterial blood pressure (MAP) rather than pump flow seemed to determine the adequacy of the cerebral perfusion.

Evidence from experimental animal models of Parkinson's disease (PD) suggests a characteristic pattern of metabolic perturbation in discrete, very small basal ganglia structures. These structures are generally too small to allow valid investigation by conventional positron emission tomography (PET) cameras. However, the high-resolution research tomograph (HRRT) PET system has a resolution of 2 mm, sufficient for the investigation of important structures such as the pallidum and thalamic subnuclei.Using the HRRT, we performed [(18)F]-fluorodeoxyglucose (FDG) scans on 21 patients with PD and 11 age-matched controls. We employed three types of normalization: white matter, global mean, and data-driven normalization. We performed volume-of-interest analyses of small subcortical gray matter structures. Voxel-based comparisons were performed to investigate the extent of cortical hypometabolism.The most significant level of relative subcortical hypermetabolism was detected in the external pallidum (GPe), irrespective of normalization strategy. Hypermetabolism was suggested also in the internal pallidum, thalamic subnuclei, and the putamen. Widespread cortical hypometabolism was seen in a pattern very similar to previously reported patterns in patients with PD.The presence and extent of subcortical hypermetabolism in PD is dependent on type of normalization. However, the present findings suggest that PD, in addition to widespread cortical hypometabolism, is probably characterized by true hypermetabolism in the GPe. This finding was predicted by the animal 2-deoxyglucose autoradiography literature, in which high-magnitude hypermetabolism was also most robustly detected in the GPe.

The distribution of brain oxidative metabolism values among healthy humans is astoundingly wide for a measure that reflects normal brain function and is known to change very little with most changes of brain function. It is possible that the part of the oxygen consumption rate that is coupled to ATP turnover is the same in all healthy human brains, with different degrees of uncoupling explaining the variability of total oxygen consumption among people. To test the hypothesis that about 75% of the average total oxygen consumption of human brains is common to all individuals, we determined the variability in a large group of normal healthy adults. To establish the degree of variability in different regions of the brain, we measured the regional cerebral metabolic rate for oxygen in 50 healthy volunteers aged 21-66 and projected the values to a common age of 25.Within each subject and region, we normalized the metabolic rate to the population average of that region. Coefficients of variation ranged from 10 to 15% in the different regions of the human brain and the normalized regional metabolic rates ranged from 70% to 140% of the population average for each region, equal to a two-fold variation. Thus the hypothetical threshold of oxygen metabolism coupled to ATP turnover in all subjects is no more than 70% of the average oxygen consumption of that population.

AIM: Decreased activity of the mitochondrial electron transport chain (ETC) has been implicated in the pathogenesis of Parkinson's disease (PD). This model would most likely predict a decrease in the rate of cerebral oxygen consumption (CMRO(2)). To test this hypothesis, we compared CMRO(2) and cerebral blood flow (CBF) PET scans from PD patients and healthy controls. MATERIALS AND METHODS: Nine early-stage PD patients and 15 healthy age-matched controls underwent PET scans for quantitative mapping of CMRO(2) and CBF. Between-group differences were evaluated for absolute data and intensity-normalized values. RESULTS: No group differences were detected in regional magnitudes of CMRO(2) or CBF. Upon normalization using the reference cluster method, significant relative CMRO(2) decreases were evident in widespread prefrontal, parieto-occipital, and lateral temporal regions. Sensory-motor and subcortical regions, brainstem, and the cerebellum were spared. A similar pattern was evident in normalized CBF data, as described previously. CONCLUSION: While the data did not reveal substantially altered absolute CMRO(2) in brain of PD patients, employing data-driven intensity normalization revealed widespread relative CMRO(2) decreases in cerebral cortex. The detected pattern was very similar to that reported in earlier CBF and CMRglc studies of PD, and in the CBF images from the same subjects. Thus, the present results are consistent with the occurrence of parallel declines in CMRO(2), CBF, and CMRglc in spatially contiguous cortical regions in early PD, and support the hypothesis that ETC dysfunction could be a primary pathogenic mechanism in early PD.

The distribution of brain oxidative metabolism values among healthy humans is astoundingly wide for a measure that reflects normal brain function and is known to change very little with most changes of brain function. It is possible that the part of the oxygen consumption rate that is coupled to ATP turnover is the same in all healthy human brains, with different degrees of uncoupling explaining the variability of total oxygen consumption among people. To test the hypothesis that about 75% of the average total oxygen consumption of human brains is common to all individuals, we determined the variability in a large group of normal healthy adults. To establish the degree of variability in different regions of the brain, we measured the regional cerebral metabolic rate for oxygen in 50 healthy volunteers aged 21-66 and projected the values to a common age of 25.Within each subject and region, we normalized the metabolic rate to the population average of that region. Coefficients of variation ranged from 10 to 15% in the different regions of the human brain and the normalized regional metabolic rates ranged from 70% to 140% of the population average for each region, equal to a two-fold variation. Thus the hypothetical threshold of oxygen metabolism coupled to ATP turnover in all subjects is no more than 70% of the average oxygen consumption of that population.

Udgivelsesdato: 1993-Oct Paroxetine, an antidepressant with a high affinity for serotonin (5-HT) re-uptake sites, is a potential tracer of these sites. We determined the kinetic properties of [3H]paroxetine in rat brain in vivo. Relative to [14C]iodo-antipyrine, the brain uptake index (BUI) of [3H]paroxetine was 60-70%. The unidirectional blood clearance of [3H]paroxetine were 0.05-0.12 ml g-1 min-1, lower than expected from the BUI values. The steady state volume of distribution was 3.5 ml hg-1 in the diencephalon and 1.8 ml g-1 in the cerebellum, suggesting a binding potential of unity. Autoradiographs at four hours after [3H]paroxetine injection (300 microCi, i.p.) revealed heterogeneous binding consistent with the calculated binding potentials. Binding was nearly absent from cerebellum and was highest in the dorsal raphe, superior colliculus, dorsal hypothalamus, and entorhinal cortex, but did not reach equilibrium in four hours of tracer circulation. The specific binding relative to vermis was displaced by pretreatment with fluoxetine (10 mg/kg, i.p.).

Like native DOPA, [18F]-6-fluoro-l-3,4-dihydroxyphenylalanine ([18F]FDOPA) is subject to methylation and decarboxylation. To determine the rates of formation and elimination of [18F]FDOPA metabolites, plasma from human subjects undergoing positron emission tomographic (PET) studies was analyzed by high-performance liquid chromatography (HPLC). In addition to the principal metabolite O-methyl-[18F]FDOPA (OMe-[18F]FDOPA), two decarboxylated metabolites were detected in plasma from carbidopa pretreated subjects. The concentrations of each metabolite during 90 min following tracer injection could be described as a function of the concentration of [18F]FDOPA, and two rate constants; k0, the rate of formation, and k–1, the rate of clearance. Plasma metabolite time series generated from total plasma activity curves and measured rate constants were in close agreement with the actual concentrations determined by HPLC fractionation. Population means for k0 (0.011 ± 0.002 min−1) and k–1, (0.010 ± 0.003 min−1) were used to generate “simulated” plasma curves. The measured and generated plasma curves were used as inputs for estimation of partition and decarboxylation coefficients of [18F]FDOPA in brain. The use of generated input functions from normal population means of transfer coefficients did not introduce a systematic error into the estimate of the enzyme activity. However, the high variability of these estimates in patients precludes the use of this technique as an alterative to individual HPLC measurements.

DOPA decarboxylase is the enzyme directly responsible for the synthesis of the neurotransmitters dopamine and serotonin, and indirectly of noradrenaline, in brain. We used the decarboxylation coefficient ( kD3) of 6-[18F]fluoro-DOPA (FDOPA) to denote the relative activity of l-DOPA decarboxylase in vivo in the human brain. To determine the relative enzyme activity with positron emission tomography (PET), we evaluated the model that separates the metabolism into compartments of nondiffusible and diffusible (i.e., transient) tracer metabolites. Error analysis indicated that the least-squares optimization alone was not sufficient to yield accurate estimates of kD3 in the presence of the inherent error of PET. To improve the accuracy of the kD3 estimates by optimizing the number of parameters, we introduced biological constraints which included a tracer partition volume ( Ve) common to frontal cortex and striatum, and a fixed ratio ( q) between the blood–brain barrier transport coefficients of O-methyl-[18F]fluoro-DOPA and FDOPA, the two sources of radioactivity in plasma. We found that a two-step analysis yielded sufficiently accurate estimates of kD3. The two steps include the initial estimation of the partition volume in frontal cortex and the subsequent use of this value to determine kD3 in striatum and other structures. We studied twelve healthy controls (age 45 ± 15 years). The average kD3 value was 0.081 ± 0.024 min−1 (coefficient of variation (COV) 30%) for caudate nucleus, 0.074 ± 0.013 min“1 (COV 18%) for putamen, and 0.010 ± 0.005 min−1 (COV 50%) for cerebral cortex.

L-Dopa is metabolized to 3-O-methyldopa (3OMD) by catechol-O-methyltransferase (COMT). This reduces the amount of L-dopa available for entry into brain. We studied the effect of OR-611, a new COMT inhibitor, on plasma and brain 6-[18F]-fluoro-L-dopa (6FD) metabolism in cynomolgus monkeys with positron emission tomography (PET). OR-611 pretreatment substantially reduced plasma 6FD metabolism to 3-O-methylfluorodopa (3OMFD). PET measurements of striatal 6FD concentrations showed an average 2.3-fold increase following OR-611 pretreatment, compared to the same animals in the control state. OR-611 inhibits plasma metabolism of 6FD and increases brain uptake of this L-dopa analog. OR-611 appears to be a promising agent as an adjunct to L-dopa for the treatment of patients with Parkinson's disease.

The goal of this study was the synthesis and in vivo evaluation of a non-peptide compound for studying the NK1 receptor by PET. An N-methyl analogue of CP-122, 721, i. e. CP-643, 051 was chosen. Radiolabelling was achieved by N-methylation of CP-122, 721 with [11C]methyl iodide. Within 38 min (from EOB) 680 MBq of [11C]CP-643, 051 (radiochemical yield: 7%, purity >95%, S.A.: 37 GBq/μmol) was produced. Brain uptake and distribution were studied in anaesthetised pig. In conclusion, due to low brain uptake the compound is not a suitable ligand for studying the NK1 receptor in vivo.

We evaluated a new selective serotonin reuptake inhibitor, NS 2456, to determine whether it is suited for use in PET. Racemic NS 2456 [(1RS, 5SR)-8-methyl-3-[4-trifluoromethoxy phenyl]-8-azabicyclo [3.2.1]oct-2-ene] and its N-demethylated analogue, racemic NS 2463, selectively inhibit serotonin uptake in rat brain synaptosomes. For uses in PET of the living porcine brain, racemic [11C]NS2463 as well as its radiolabelled enantiomers were used. The compounds crossed the blood-brain-barrier rapidly and accumulated preferentially in regions rich in serotonin uptake sites. However their binding potentials were relatively low and no stereoselectivity was found. Thus, neither [11C]NS 2456 nor [11C]-labelled enantiomers are ideal for PET neuroimaging of neuronal serotonin uptake sites.

The year 2010 is the centennial of the publication of the “Seven Little Devils” in the predecessor of Acta Physiologica. In these seven papers, August and Marie Krogh sought to refute Christian Bohr's theory that oxygen diffusion from the lungs to the circulation is not entirely passive but rather facilitated by a specific cellular activity substitute to secretion. The subjects of the present reevaluation of this controversy are Christian Bohr, Professor and Doctor of Medicine (1855–1911), nominated three times for the Nobel Prize; August Krogh, Doctor of Philosophy (1874–1949), Christian Bohr's assistant and later Nobel Prize laureate (1920); and Marie Krogh, née Jørgensen, Doctor of Medicine and wife of August Krogh (1874–1943). The controversy concerned is the transport of oxygen from the lungs into the bloodstream: are passive transport and diffusion capacity together sufficient to secure the oxygen supply in all circumstances or is there an additional specific (“energy consuming” or “active”) mechanism responsible for the transport of oxygen from the alveoli into the bloodstream? The present discussion purports to show that the contestants' views were closer than the parties themselves and posterity recognized. Posterity has judged the dispute unilaterally from the Nobel laureate's point of view, but it is evident that August Krogh's Nobel Prize was awarded for the discovery of a cellular activity (Christian Bohr's expression), represented by Krogh's discovery of capillary recruitment. Christian Bohr appears to have been correct in the narrower sense that the diffusion capacity at rest is not great enough to explain the transport during work; a special mechanism intervenes and optimizes the conditions under which diffusion acts. August Krogh, of course, was right in the wider sense that the transport mechanism itself is always entirely passive.

Under normal circumstances, a mixture of α-and β-D-glucopyranose (D-glucose) is the only fuel of brain energy metabolism (Pardridge 1983). The breakdown of D-glucose is regulated by complex mechanisms that influence the activities of phosphofructokinase and hexokinase. The metabolism depends indirectly on the glucose concentration of the brain intracellular and interstitial fluids. Since the tissue glucose concentration, in turn, depends directly on the glucose phosphorylation rate, the blood-brain transfer assumes a pivotal role in the supply of glucose to the brain.

In the context of compartmental analysis, a living organism can be described as an open biological system existing in a steady-state far from thermodynamic equilibrium. Thermodynamic equilibrium is a state in which no biological processes can occur because there are no potential gradients to drive them; no differences in mechanical potential to drive blood flow, in concentrations to drive diffusion, in chemical potentials to drive metabolism, in electrical potentials to drive ions, and in temperature to drive heat flow. Steady-state and thermodynamic equilibrium share the characteristic that they are invariant in time. Thermodynamic equilibrium is also invariant in space. The steady-state variance of constituent chemicals in space is the focus of compartmental analysis. Spatial variance is assigned to the interfaces between abstract compartments rather than to the living system as a whole. As the compartments by this definition are in thermodynamic equilibrium internally, they are incompatible with life but we choose to ignore this fundamental characteristic. Compartmental analysis uses the principles of biophysics and mathematics to determine the velocity of exchanges among the compartments (biochemical processes) and the relative size of the individual compartments (biochemical pools) in vivo, using tracer molecules, defined as markers that do not perturb the system. During a medical study or biological experiment, the tracer and its metabolites assume different states, each of which may be well defined but all of which change and interact as functions of time. Eventually, one or more of these states may reach the steady-state characteristic of the native system, though far from thermodynamic equilibrium. This steady-state can be maintained only in thermodynamically open systems. If energy is no longer provided or expended, potential

Oxygen is essential to brain function. Disruption of oxygen delivery to brain results in complete cessation of functional activity in the human brain in 6 s (Hansen 1984, 1985). The reason for this dramatic effect is not known with certainty. Increased potassium conductance in neuronal membranes plays a role, but the effect also suggests that oxygen reserves in brain tissue are very low in relation to the steady-state turnover, and it implies that oxygen availability is intimately related to mechanisms that subserve consciousness, because the effect is not explained by depletion of intermediary metabolites.

A number of biologically important drugs and chemicals that act in the brain do so specifically, that is, by association with membrane proteins designed to receive endogenous neurotransmitters and neuromodulators, although the endogenous ligands may not always be known. The existence of chemical receptorswas suspected before the turn of the century in the form of Langley’s concept of a “receptive” substance (Langley 1878) and Ehrlich’s “side-chain” theory (Ehrlich 1909), but modeling did not begin until the discovery of the binding of oxygen to specialized proteins, which made direct observation of receptor–ligand interaction possible. When the binding of oxygen to myoglobin was first observed to be a function of the oxygen tension in the solution (Bohr 1885), the relationship between the quantities of bound and free oxygen corresponded exactly to the relationship between the invertase reaction velocity and substrate concentration later derived by Michaelis and Menten (1913). Bohr (1904) published an equation for the interaction between hemoglobin and oxygen that antedated the equation suggested by Hill (1910) for receptor sites that interact cooperatively.

With the advent of neuroreceptor and neurotransmission imaging by means of positron emission tomography (PET) and single photon emission computed tomography (SPECT) in vivo, it is now possible to directly record the normal and patho-physiological processes served by monoamines in the brain, as well as to examine the possibilities and potential impact of treatment of disorders of monoaminergic neurotransmission. This review describes the methods of noninvasive brain imaging and the benefits that this imaging can bring to the understanding of disturbed monoaminergic neurotransmission, the mechanisms underlying the disturbances, and the impact of possible therapies.

In the context of compartmental analysis, a living organism can be described as an open biological system existing in a steady-state far from thermodynamic equilibrium. Thermodynamic equilibrium is a state in which no biological processes can occur because there are no potential gradients to drive them; no differences in mechanical potential to drive blood flow, in concentrations to drive diffusion, in chemical potentials to drive metabolism, in electrical potentials to drive ions, and in temperature to drive heat flow. Steady-state and thermodynamic equilibrium share the characteristic that they are invariant in time. Thermodynamic equilibrium is also invariant in space. The steady-state variance of constituent chemicals in space is the focus of compartmental analysis. Spatial variance is assigned to the interfaces between abstract compartments rather than to the living system as a whole. As the compartments by this definition are in thermodynamic equilibrium internally, they are incompatible with life but we choose to ignore this fundamental characteristic. Compartmental analysis uses the principles of biophysics and mathematics to determine the velocity of exchanges among the compartments (biochemical processes) and the relative size of the individual compartments (biochemical pools) in vivo, using tracer molecules, defined as markers that do not perturb the system. During a medical study or biological experiment, the tracer and its metabolites assume different states, each of which may be well defined but all of which change and interact as functions of time. Eventually, one or more of these states may reach the steady-state characteristic of the native system, though far from thermodynamic equilibrium. This steady-state can be maintained only in thermodynamically open systems. If energy is no longer provided or expended, potential

The key to tracer kinetic analysis is the concept of compartment, a group of atoms or molecules which behave in such an identically predictable manner that the introduction of a few additional but labeled atoms or molecules do not change the behavior significantly. Compartments may be large or small but they are fundamental abstractions, regardless of their size. As such they can be said to defy the very concept they were created to represent, because they require that the members are at equilibrium with each other and hence allow no interactions among each other.

Aims Gambling excitement is believed to be associated with biological measures of pathological gambling. Here, wetested the hypothesis that dopamine release would be associated with increased excitement levels in PathologicalGamblers compared with Healthy Controls. Design Pathological Gamblers and Healthy Controlswere experimentallycompared in a non-gambling (baseline) and gambling condition. Measurements We used Positron Emission Tomography(PET) with the tracer raclopride to measure dopamine D 2/3 receptor availability in the ventral striatum duringa non-gambling and gambling condition of the Iowa GamblingTask (IGT). After each condition participants rated theirexcitement level. Setting Laboratory experiment. Participants 18 Pathological Gamblers and 16 Healthy Controls.Findings Pathological Gamblers with dopamine release in the ventral striatum had significantly higher excitementlevels than Healthy Controls despite lower IGT performance. No differences in excitement levels and IGT performancewere found between Pathological Gamblers and Healthy Controls without dopamine release. Pathological Gamblersshowed a significant correlation between dopamine release and excitement level, while no such interaction wasfound in Healthy Controls. Conclusions In pathological gamblers dopamine release in the ventral striatum appearsto be associated with increased excitement levels despite lower IGT performance. The results might suggesta ‘double deficit’ function of dopamine in pathological gambling, where dopamine release reinforces maladaptivegambling through increasing excitement levels, reducing inhibition of risky decisions, or a combination of both. Thesefindings may have implications for the understanding of dopamine in pathological gambling and other forms ofaddiction.

The dopamine system is believed to affect gambling behavior in pathological gambling. Particularly, dopamine release in the ventral striatum appears to affect decision-making in the disorder. This study investigated dopamine release in the ventral striatum in relation to gambling performance on the Iowa Gambling Task (IGT) in 16 Pathological Gamblers (PG) and 14 Healthy Controls (HC). We used Positron Emission Tomography (PET) to measure the binding potential of [(11)C] raclopride to dopamine D2/3 receptors during a baseline and gambling condition. We hypothesized that decreased raclopride binding potentials in the ventral striatum during gambling (indicating dopamine release) would be associated with higher IGT performance in Healthy Controls, but lower IGT performance in Pathological Gamblers. The results showed that Pathological Gamblers with dopamine release in the ventral striatum had significantly lower IGT performance than Healthy Controls. Furthermore, dopamine release was associated with significantly higher IGT performance in Healthy Controls and significantly lower IGT performance in Pathological Gamblers. The results suggest that dopamine release is involved both in adaptive and maladaptive decision-making. These findings may contribute to a better understanding of dopaminergic dysfunctions in pathological gambling and substance related addictions.

Sensation seeking is a core personality trait that declines with age in both men and women, as do also both density and availability of the dopamine D 2/3 receptors in striatum and cortical regions. In contrast, novelty seeking at a given age relates inversely to dopamine receptor availability. The simplest explanation of these findings is an inverted-U-shaped correlation between ratings of sensation seeking on the Zuckerman scale and dopamine D 2/3 receptor availability. To test the claim of an inverted-U-shaped relation between ratings of the sensation-seeking personality and measures of dopamine receptor availability, we used PET to record [ 11 C]raclopride binding in striatum of 18 healthy men. Here we report that an inverted-U shape significantly matched the receptor availability as a function of the Zuckerman score, with maximum binding potentials observed in the midrange of the scale. The inverted-U shape is consistent with a negative correlation between sensation seeking and the reactivity (“gain”) of dopaminergic neurotransmission to dopamine. The correlation reflects Zuckerman scores that are linearly linked to dopamine receptor densities in the striatum but nonlinearly linked to dopamine concentrations. Higher dopamine occupancy and dopamine concentrations explain the motivation that drives afflicted individuals to seek sensations, in agreement with reduced protection against addictive behavior that is characteristic of individuals with low binding potentials.