In vivo neutralization of endogenous brain fractalkine increases hippocampal TNFalpha and 8-isoprostane production induced by intracerebroventricular injection of LPS.

Fractalkine is a chemokine widely and constitutively expressed in the brain and, as suggested by in vitro studies, it is involved in brain inflammatory responses. In this study, we have investigated the in vivo anti-inflammatory potential of fractalkine in a model of neuroinflammation induced by intracerebroventricular injection of lipopolysaccharide (LPS) in rats. LPS induces a rapid and acute production of the pro-inflammatory cytokine, TNFalpha, in hippocampus and cerebrospinal fluid (CSF), and an increase of 8-isoprostane levels, a marker of oxidative stress, in hippocampus. Although intracerebroventricular injection of fractalkine has no effect on TNFalpha and 8-isoprostane production, neutralization of endogenous fractalkine within the brain with a specific anti-fractalkine antibody potentiates LPS effects. These data emphasize the involvement of constitutive brain fractalkine in the control of inflammatory reaction in CNS.

Effects of repeated treatments with an extract of Ginkgo biloba (EGb 761) on cerebral glucose utilization in the rat: an autoradiographic study.

1. The autoradiographic method based on 2-deoxy-D[1-14C]glucose ([14C]DG) was used to determine glucose utilization in 49 discrete structures of rat brain under control conditions and after the animals had received repeated treatment with an extract of Ginkgo biloba (EGb 761). 2. Oral administration of EGb 761 (50 or 150 mg/kg/day) to adult male rats for 15 days did not modify body weight, mean arterial blood pressure, the concentrations of glucose or hemoglobin in blood, blood gases or arterial pH. 3. EGb 761 treatments produced only slight-to-moderate changes in glucose utilization in the various brain structures; i.e. decreases to an extent not exceeding 18.4% at the 50 mg/kg dose or 11.7% at the 150 mg/kg dose. 4. Glucose utilization was significantly decreased only in the frontoparietal somatosensory cortex, nucleus accumbens, cerebellar cortex and pons and only with the 50 mg/kg dose of EGb 761. 5. Although the four brain structures affected by EGb 761 treatment do not, in themselves, constitute a specific functional system of the CNS, these effects appear useful in explaining mechanisms underlying the clinical use of EGb 761 in treating problems associated with deficient somatosensory processing (e.g. impairment of "vigilance") and vestibular mechanisms (e.g. vertiginous syndromes).

Effect of eliprodil, an NMDA receptor antagonist acting at the polyamine modulatory site, on local cerebral glucose use in the rat in the rat brain.

The present investigation examined the effect of eliprodil, an atypical NMDA receptor antagonist that acts at the polyamine modulatory site, on local cerebral glucose utilization using the quantitative autoradiographic 2-[14C]deoxyglucose method in the conscious rat. Eliprodil, at doses of 3, 10 and 30 mg/kg i.p., did not increase cerebral glucose use in any of the 82 different brain regions studied. However, in some of the regions examined, local cerebral glucose utilization was slightly reduced, the most pronounced decreases being measured in some extrapyramidal, sensorimotor and limbic areas (dentate gyrus, septum, lateral habenula, amygdala). This decrease in glucose utilization was dose-dependent: no significant change was noted after 3 mg/kg i.p. of eliprodil, while 18 (at 10 mg/kg, i.p.) and 29 (at 30 mg/kg, i.p.) regions displayed a moderate (20-25%) though significant decrease in glucose use. These data demonstrate that the pattern of alterations in glucose use produced by eliprodil is different from that induced by NMDA channel blockers or competitive NMDA receptor antagonists. The fact that blockade of the polyamine modulatory site is not associated with an activation of specific limbic circuits may explain why, at neuroprotective doses, eliprodil is devoid of those unwanted side effects (including intrinsic neurotoxicity on cortical neurons) associated with NMDA channel blockers.

Effects of dorsal raphe nucleus stimulation on cerebral blood flow and flow-metabolism coupling in the conscious rat.

In the present study, we have investigated the effects of an activation of the ascending serotonergic pathway on the cerebral blood supply to a number (63) of well-defined neuroanatomical structures. To this end, we have measured the local cerebral blood flow during electrical stimulation of the dorsal raphe nucleus. Measurement of regional blood flow was performed in the conscious rat through the use of the [14C]iodoantipyrine autoradiographic technique. Stimulation of the dorsal raphe nucleus induced increases (> 15% compared to control) in cerebral blood flow in 17 structures of which statistical significance (P < 0.05) was achieved in nine; raphe stimulation significantly decreased flow in three regions. The greatest increases (+71 and +46%) were found in the frontal sensorimotor and posterior parietal cortices. Other increases were noted in relay stations of the extrapyramidal and limbic systems. Stimulation induced a decrease in two regions of the primary auditory system and in the lateral habenular nucleus. These results show that activation of the serotonergic pathway in the conscious rat effects regional cerebral blood flow heterogeneously, differing from the widespread increase in glucose utilization that we previously observed using the same experimental paradigm. Statistical analyses indicated that activation of the dorsal raphe nucleus resulted in a global modification of the flow-metabolism ratio. Moreover, in 19 out of 31 regions analysed, this ratio is significantly altered as compared to control. The dichotomy between raphe-induced changes in flow and glucose-metabolism could be explained by one or both of two hypotheses; firstly there could be a direct serotonergic innervation of cerebral resistance vessels; secondly, during raphe stimulation it could be that glucose use is not the primary determinant of tissue perfusion.

Elevated tissue endothelin content during focal cerebral ischemia in the rat.

To study the involvement of endogenous endothelin (ET) in the development of cerebral ischemia, we measured by radioimmunoassay brain tissue content of immunoreactive (ir)-ET-1 in a model of focal cerebral ischemia in the rat. Permanent occlusion of the middle cerebral artery (OMCA) was accompanied after 24 h by a progressive but marked elevation of ir-ET-1 in the ipsilateral compared with the contralateral hemisphere (119% after 24 h; 184% after 48 h and 459% after 72 h). The pial vessels and the arteries of the circle of Willis did not respond with ir-ET-1 production. The increase in ir-ET-1 content in tissues was first observed in the caudate nucleus (after 24 h) and later in the cortex (after 48 h), which was more variably injured. Transient ischemia followed by recirculation led to a slight increase of ir-ET-1, which also appeared after 24 h of recirculation. This study demonstrates that during permanent OMCA, the tissue content of ir-ET-1 markedly and progressively increases, whereas less severe ischemia (transient) is accompanied by a modest elevation of ir-ET-1 levels. These results suggest that endogenous ir-ET-1 production is involved in the development and the severity of ischemic injury.

[Postoperative acute adrenal insufficiency]. / Insuffisance surrénalienne aiguë postopératoire.

Acute adrenal insufficiency is an uncommon complication of lung cancer and adrenal metastasis resection. Diagnosis is difficult to establish but an early recognition and treatment may be life-saving. A 55-year-old man underwent right upper lobectomy and adrenalectomy for lung carcinoma with right adrenal metastasis. Anaesthesia was obtained with propofol, alfentanil, atracurium and isoflurane. Blood pressure remained stable throughout surgical procedure and blood loss was about 3,000 ml. Several hours after the end of the procedure which was uneventful the circulator status worsened. The blood pressure was initially controlled with 500 ml of gelatin. External blood loss was about 200 ml. Clinical examination, chest X-ray and ECG were normal. Postoperative laboratory data showed a serum sodium at 134 mmol-1.l-1 and a serum potassium 5.1 mmol.l-1; haemoglobin concentration was 93 g.l-1. Arterial blood gas analysis, with a 5.1.min-1 nasal O2 flow showed a PaO2 at 108 mmHg, a PaCO2 at 30 mmHg and a pH at 7.44. Twelve hours later, a transient cardiac arrest occurred which responded to fluid load, dopamine and dobutamine. Six hours later, the patient went in ventricular fibrillation responding to an external electric countershock. No change in clinical status was noticed, except hyperthermia at 39.5% degrees C. Serum potassium concentration before cardiac arrest was 4.7 mmol-l-1. Main considered diagnoses were septic shock and acute adrenal insufficiency. Antibiotics (imipenem, amikacin and vancomycin) and hormonal treatment (hydrocortisone 200 mg.day-1), after blood samples had been obtained for bacteriological and hormonal examinations. The patient's condition improved dramatically within 48 hours. Shock was under control, dopamine and dobutamine were rapidly discontinued.(ABSTRACT TRUNCATED AT 250 WORDS)

Peripheral type benzodiazepine binding sites following transient forebrain ischemia in the rat: effect of neuroprotective drugs.

Recent studies have demonstrated that measurement of peripheral type benzodiazepine binding sites (PTBBS) levels may be useful as an index for quantification of neuronal damage. In the present study, we investigated the accuracy of this index as a marker of neuronal damage induced by transient forebrain ischemia in the rat (4-vessel occlusion model). Seven days after ischemia, a good correlation was found between the increase of PTBBS levels (measured using [3H]PK 11195 as a specific radioligand) in hippocampal, striatal and cortical homogenates and the duration of ischemia. The progression of PTBBS increase was examined from 3 h to 14 days of recirculation. Increase in the maximal number of binding sites (Bmax) rather than an effect on the affinity (KD) for the radioligand was found in the 3 brain regions. Treatment of the animals with 1,3 butanediol (BD) prior to ischemia resulted in a neuroprotective effect as assessed by an improved neurological score and histological studies. The protective effect of BD was also correlated with a reduced expression of PTBBS as compared to ischemic animals not treated with the drug. No protective effects, on neurological score or PTBBS level were afforded by MK-801, a noncompetitive N-methyl-D-aspartate (NMDA) antagonist, R-phenylisopropyladenosine (RPIA), an adenosine A1 receptor agonist, or BN 52021, an antagonist of platelet-activating factor (PAF). These results suggest that PTBBS provide a useful marker of neuronal damage in a transient forebrain ischemia model and confirm the beneficial effect on ischemic damage exerted by BD.

The quantification of brain lesions with an omega 3 site ligand: a critical analysis of animal models of cerebral ischaemia and neurodegeneration.

Previous investigations have indicated that the detection and quantification of omega 3 (peripheral type benzodiazepine) binding site densities that are associated with reactive astroglia and macrophages could be of widespread applicability in the localization and indirect assessment of neural tissue damage in the central nervous system. In the present study, we analyze the usefulness of this approach in a number of experimental models that are characterized by (or putatively involve) neuronal degeneration. One week after the systemic administration of the excitotoxin, kainate, a marked increase in omega 3 site densities (as assessed by [3H]PK 11195 binding) was noted, an increase that was most prominent in known regions of selective vulnerability (hippocampus and septum). However, the kainate-induced omega 3 site proliferation was not a function of the dose administered, a marked interstudy variation was observed, and the binding increase was prevented by the administration of the anticonvulsant, clonazepam. The densities of omega 3 sites were studied, by autoradiography (using [3H]PK 11195 or [3H]PK 14105 as ligands), in 4 groups of Fischer 344 rats aged 3, 12, 22 and 30 months. No age-related changes were noted except in the 30-month-old group in which discrete and focal increases (reflecting tumoral processes) were observed in various brain regions. In spontaneously hypertensive, stroke-prone rats, omega 3 binding increases were observed concomitant with the development of stroke-related neurological signs. With autoradiography, the omega 3 site increase was localized to focal increases in the boundary zones between major cerebral arteries (and corresponding to regions of ischaemic or haemorrhagic infarction). Focal cerebral ischaemia was studied in rats and mice. Subsequent to middle cerebral artery occlusion in normotensive (Wistar/Kyoto) and spontaneously hypertensive rats, the density of omega 3 sites in the ipsilateral hemisphere was markedly elevated, the increase being greater in the spontaneously hypertensive rats. The increases in omega 3 labelling in these two strains matched the absolute volumes of infarctions, determined previously. Middle cerebral artery occlusion in the mouse also increased hemispheric levels of omega 3 sites; the maximum values were obtained between 4 and 8 days following the induction of focal ischaemia. These results demonstrate the feasibility of using omega 3 sites as a marker of excitotoxic, ischaemic and proliferative damage in the rodent brain. Binding measurement in tissue homogenates is an economic and time-efficient approach, whereas the autoradiographic detection of omega 3 sites allows the localization of brain lesions with a macroscopic or microscopic level of anatomical resolution.(ABSTRACT TRUNCATED AT 400 WORDS)

Time course of effects of unilateral lesions of the nucleus basalis of Meynert on glucose utilization by the cerebral cortex. Positron tomography in baboons.

In order to investigate the effects of a partial cholinergic deafferentation on the functional activity of the cortex, the cerebral metabolic rate of glucose (CMRGlu) was measured with positron emission tomography and 18F-2-fluoro-2-deoxy-D-glucose in 5 baboons (Papio anubis) both before and serially following stereotaxic electrocoagulation of the left nucleus basalis of Meynert (NbM). Four days postlesion, significant metabolic depression was present in the entire ipsilateral cerebral cortex, most marked in the frontotemporal region, and which slowly recovered close to normal within 6-13 weeks. Postmortem studies showed that the lesions were located largely in the NbM, and that a significant decrease in choline-acetyltransferase (ChAT) activity was present in the ipsilateral frontal, temporal and parietal cortices. The animal with the most limited histological lesion showed the least decrease in both ChAT activity and CMRGlu. There was a highly significant linear correlation between the regional cortical decreases in CMRGlu (early postlesion data) and in ChAT activity. These results indicate that cholinergic deafferentation induces a proportional metabolic depression in the cortex. However, compensatory mechanisms operate to restore the cortical metabolic activity gradually despite sustained cholinergic denervation, pointing to pre- and/or postsynaptic adaptation (plasticity). Moreover, unilateral NbM lesions also induced a significant reduction in contralateral CMRGlu, which also demonstrated recovery. Several mechanisms are discussed to explain this contralateral effect, but the most likely implicates a transcallosal depression of function as a result of ipsilateral effects of the NbM lesion. These metabolic effects of cholinergic deafferentation in the primate provide new insight into the mechanisms of cortical dysfunction, and the recovery thereof, following subcortical lesions. In addition, our findings have some relevance to the cortical consequences of cholinergic deafferentation observed in dementia of Alzheimer type.

Ifenprodil and SL 82.0715 as cerebral anti-ischemic agents. I. Evidence for efficacy in models of focal cerebral ischemia.

Recent studies have strongly implicated the excitatory neurotransmitter glutamate in the cascade of pathological mechanisms that cause neuronal loss after certain types of brain ischemia. The neurotoxic effects of glutamate are mediated, at least in global ischemia, via NMDA receptors. In the present study we have examined the effects of compounds that possess NMDA receptor antagonist properties (ifenprodil, SL 82.0715 [(+/-)-alpha-(4-chlorophenyl)-4-[(4-fluorophenyl)methyl]- 1-piperidineethanol] and 1-[1-(2-thienyl)cyclohexyl]piperidine) on the histological consequences of focal, as opposed to global, cerebral ischemia in both the rat and the cat. Ifenprodil (0.3-3 mg/kg i.v.) administered as a perfusion over 3 hr after occlusion of the feline middle cerebral artery reduced the volume of infarcted tissue (measured 4 days after occlusion) in a dose-related manner. At the highest dose a 42% reduction of infarcted volume was noted, essentially in cortical tissue. In an identical protocol, a derivative of ifenprodil, SL 82.0715, reduced the volume of infarction in a manner comparable to that described for ifenprodil. As SL 82.0715 possesses better p.o. bioavailability, this compound was also evaluated in the rat, again after middle cerebral artery occlusion. First administered 30 min after the induction of ischemia, SL 82.0715 (1 and 10 mg/kg p.o.) reduced infarction volume by 34 and 48%, respectively. The quantitative histology was performed 2 days after middle cerebral artery occlusion. The noncompetitive receptor antagonist, 1-[1-(2-thienyl)cyclohexyl]piperidine, administered (1 mg/kg i.p.) before the induction of focal ischemia, similarly and significantly decreased the final volume of infarction. As both ifenprodil and SL 82.0715 are noncompetitive antagonists of the NMDA receptor, two conclusions may be drawn from the present investigation. First, NMDA antagonism by ifenprodil and its derivative is an effective approach for tissue sparing in animal models of stroke and brain infarction. Second, these pharmacological observations provide evidence for the involvement of excitatory amino-acid induced-neurotoxicity in the evolution and consequences of focal cerebral ischemia.

Temporal evolution of regional energy metabolism following focal cerebral ischemia in the rat.

Focal cerebral ischemia in the rat was induced by occlusion of the left middle cerebral artery. The temporal evolution of regional energy metabolism was studied over the 14 days consequent to the induction of ischemia in the frontal, cingulate, parietal, and occipital cortices as well as in the striatum. Regional concentrations of adenosine triphosphate (ATP), phosphocreatine, and lactate and, in addition, glucose and the cerebral/plasma glucose ratio (C/P) were measured in the hemispheres both ipsilateral and contralateral to the occlusion. Two hours after middle cerebral artery occlusion, the biochemical changes were severe in the striatum and moderate in cortical regions. Later on (at 24 and 48 h), an overall aggravated metabolic status was noted while lactate declined and glucose markedly increased. These latter biochemical changes likely indicate a marked inhibition of the rate of glucose utilization. At 48 h, the energy reserves (ATP, phosphocreatine) of parietal cortex no longer equaled those of other cortical regions, but abruptly fell to the levels found in the striatum without any increase in lactate level. Finally, at 7 and 14 days, the levels of the various metabolites in most cortical regions returned toward control values, although signs of a depressed glucose metabolism remained. However, in both striatum and parietal cortex, ATP and phosphocreatine concentrations, although higher than those observed at 48 h, remained significantly decreased. Our present biochemical study permits the classification of these selected brain regions into three categories. First there are those that are outside the area of infarction: the frontal, cingulate, and occipital cortices. These regions show little temporal evolution of brain energy metabolism but, notwithstanding, they are regions in which glucose use would appear to be greatly depressed. Second is a region considered to be the focus of infarction: the striatum. The caudate-putamen is a region with early and profound metabolic disturbances with no final restitution. Last is the region of metabolic penumbra--the parietal cortex, in which there is a time-related exacerbation of the consequences of middle cerebral occlusion in the rat.

The quantification of cerebral infarction following focal ischemia in the rat: influence of strain, arterial pressure, blood glucose concentration, and age.

Focal cerebral ischemia was induced by occlusion of the middle cerebral artery in rats. The volumetric assessment of infarcted tissue, 2 days following occlusion, was calculated from the examination of eight preselected coronal sections. Five differing rat strains were examined. A small and variable infarcted volume was seen in Wistar-Kyoto rats; Sprague-Dawley rats had a relatively large, but still variable, infarcted volume. Of the normotensive rat strains, the most reproducible volume of infarcted tissue was seen in Fischer-344 rats; also the absolute value of the infarcted volume did not vary from one series to another in this strain. Chronic arterial hypertension, studied in both normal and stroke-prone spontaneously hypertensive rats, was associated with significantly larger infarction volumes. Age does not change the volume of necrosis: Fischer-344 rats were studied at 3, 9, and 20 months of age, and no significant differences were noted between these ages. Experimental diabetes was induced by the administration of streptozotocin 3 days prior to middle cerebral artery occlusion. Severe hyperglycemia (greater than 400 mg/dl) was associated with a considerably increased volume of infarction. The variability of the resultant lesion is high in the most commonly studied strains, but our results suggest that, for studies in normotensive rats, the use of the Fischer-344 strain produces a standardized and repeatable infarction that may be significantly modified by experimental interventions. Age is not a factor that affects the occlusion-induced infarction; in contrast, both chronic arterial hypertension and experimental diabetes aggravate the histological consequences of middle cerebral artery occlusion in the rat. We conclude that quantitative histological evaluation of infarct size allows a meaningful assessment of the gravity of focal cerebral ischemia.

Influence of ascending serotonergic pathways on glucose use in the conscious rat brain. I. Effects of electrolytic or neurotoxic lesions of the dorsal and/or median raphé nucleus.

The regional cerebral metabolic effects of manipulations of the central serotonergic pathways are largely unknown. To address this topic, we have examined the consequences of electrolytic lesions of the rostral (median and/or dorsal) raphé nuclei on local cerebral glucose utilization (CMRglu) in the unanaesthetized rat brain. These studies were complemented by comparing control rats to rats that received prior intraventricular administration of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT). CMRglu was determined in 56 neuroanatomically defined regions of the central nervous system in lightly restrained rats, by the quantitative autoradiographic 2-deoxyglucose technique. In all, 6 groups of rats were studied: sham-lesioned rats, rats with electrolytic lesion of the median, dorsal, or both these raphé nuclei; sham-injected and 5,7-DHT pretreated rats. The efficacy of both electrolytic and neurotoxic lesions was verified, in each animal, by neurochemical microassay of 5-hydroxytryptamine and its metabolite in samples of striatum, hippocampus and prefrontal cortex. Chronic interruption of serotonergic transmission was remarkable for the lack of resultant change in CMRglu. In rats that were subjected to electrolytic lesions of both median and dorsal raphé nuclei, discrete and significant decreases in CMRglu were observed in the red nucleus, substantia nigra and inferior olivary nucleus only. The rats subjected to 5,7-DHT treatment displayed no significant changes in CMRglu in all the brain regions analyzed, despite an 80% decrease in the concentrations of endogenous 5-hydroxytryptamine. Thus, it would appear that a viable serotonergic transmission is not a major determinant of integrated functional activity, even in those brain structures that receive rich raphé projections. Two hypotheses are advanced for this lack of change: firstly, the chronic reduction of 5-hydroxytryptamine levels is accompanied by compensatory changes in this or other neurotransmitter systems; secondly, serotonergic neurones may exert a phasic--rather than tonic--influence on glucose use in the mammalian brain.

Influence of ascending serotonergic pathways on glucose use in the conscious rat brain. II. Effects of electrical stimulation of the rostral raphé nuclei.

Although lesions of the rostral raphé nuclei have minimal effects on integrated functional activity, as studied by the 2-deoxyglucose technique, the repercussions of activating the ascending serotonergic pathways have yet to be reported in the literature. To examine this question, we studied the consequences of the electrical stimulation of the rostral (median or dorsal) raphé nuclei on local cerebral glucose use in the conscious rat. Glucose use was determined by quantitative autoradiography in 105 defined brain structures. Raphé stimulation increased glucose utilization in a number of well-defined structures and pathways, dorsal raphé stimulation being systematically more effective than median raphé stimulation. Of all the neocortical regions studied, only the somatosensory cortex displayed a columnar and laminar pattern of increased glucose use that was restricted to the somatotopic delineation of the rat's head and face. Increased glucose use was seen in almost all key elements of the extrapyramidal system with the notable exception of the caudate-putamen. The thalamic nuclei that were activated by rostral raphé stimulation included those that subserve the processing of somesthetic, accessory visual and limbic information. Raphé stimulation-induced decreases in local cerebral glucose use were never observed. Almost all of the induced changes could be prevented or obtunded by prior intraventricular administration of the serotonergic neurotoxin 5,7-dihydroxytryptamine, suggesting that the majority of the raphé-induced changes in integrated functional activity were mediated via the activation of serotonergic neurones. The magnitude and pattern of the increases in glucose use could not always be correlated with the regional density of serotonergic innervation nor with the distribution of 5-hydroxytryptamine receptor subtypes in the adult brain. However, the pattern of increased cortical glucose use closely matches the selective serotonergic innervation of the somatosensory cortex found in early postnatal development. Thus, it would appear that the 2-deoxyglucose technique reveals functional units in the cortex that are innervated at an early ontogenic stage. We postulate that the discrete and highly organized changes in integrated functional activity that follow raphé stimulation are due to serotonin acting in a phasic manner on restricted, possibly specialized, postsynaptic structures.(ABSTRACT TRUNCATED AT 400 WORDS)

Imaging of primary and remote ischaemic and excitotoxic brain lesions. An autoradiographic study of peripheral type benzodiazepine binding sites in the rat and cat.

Seven days after unilateral middle cerebral artery occlusion in rats, peripheral type benzodiazepine binding sites (PTBBS), using [3H]PK 11195 as a specific radioligand, were greatly increased in the cortical and striatal regions surrounding the focus of infarction with smaller increases in the ventrolateral and posterior thalamic complexes and in the substantia nigra, all ipsilateral to the occlusion. Similarly, PTBBS increases were observed in the caudate nucleus and entorhinal cortex of cats likewise subjected to prior unilateral occlusion of the middle cerebral artery. Intrastriatal administration of N-methyl-D-aspartate (250 nmol) in the rat resulted in a dramatic ipsilateral increase in PTBBS levels in the striatum and in the deeper laminae of the ipsilateral frontoparietal cortex. Intrastriatal kainic acid administration (12 nmol) also elicited PTBBS increases ipsilaterally in rat striatum and cortex; a bilateral elevation of PTBBS levels was observed in the hippocampus. With all these interventions there existed a good spatial correlation between the PTBBS increase and neuronal loss as assessed either histologically or by the autoradiographic detection of the putative neuronal marker [3H]SCH 23390 (a D1 dopamine receptor ligand). Moreover, a glial proliferation of non-neuronal cells (macrophage and glial cells) was observed in brain regions noted to have increased PTBBS levels. PTBBS autoradiography thus constitutes a suitable technique for the localization of damaged areas in several experimental models of brain injury. PTBBS label not only the primary lesions but also functionally related areas and could further our understanding of phenomena such as partial neuronal loss and diaschisis. The study of PTBBS could be envisaged for the detection, localization and quantification of all neuropathological situations which engender a glial reaction or macrophage invasion and is potentially applicable to both experimental and human subjects, in which both autoradiographic and tomographic approaches could be undertaken.

Cortical hypometabolism and its recovery following nucleus basalis lesions in baboons: a PET study.

The cerebral metabolic rate for glucose was measured serially with positron emission tomography and [18F]fluorodeoxyglucose in five baboons with stereotactic electrocoagulation of the left nucleus basalis of Meynert (NbM). Four days after lesion, a significant metabolic depression was present in the ipsilateral cerebral cortex, most marked in the frontotemporal region, and which recovered progressively within 6-13 weeks. These data demonstrate that adaptive mechanisms efficiently compensate for the cortical metabolic effects of NbM-lesion-induced cholinergic deafferentation. Moreover, unilateral NbM lesions also induced a transient reduction in contralateral cortical metabolic rate, the mechanisms of which are discussed. Explanation of these effects of cholinergic deafferentation in the primate could further our understanding of the metabolic deficits observed in dementia of the Alzheimer's type.

Effects of the GABA receptor agonist, progabide, upon local cerebral glucose utilization.

The effects of a specific GABA receptor agonist, progabide, have been examined on local cerebral glucose utilization through the use of the autoradiographic [14C]2-deoxyglucose technique in conscious rats. The intraperitoneal administration of progabide (80-320 mg.kg-1) resulted in a heterogeneous pattern of significantly reduced glucose utilization throughout the 50 discrete regions of the brain that were studied. Insignificant decreases in local cerebral glucose use were noted following the low dose of progabide (80 mg.kg-1). Following progabide (160 mg.kg-1), reductions of approximately 20% in glucose utilization were observed in most of the extrapyramidal system (substantia nigra, pars compacta and reticulata; globus pallidus; caudate nucleus), some thalamic nuclei (lateral geniculate body, anterior and ventrolateral thalamic nuclei), a number of areas related to the limbic system (cingulate cortex; amygdala; hypothalamus; lateral habenula; nucleus accumbens; dorsal hippocampus as well as the CA3 field) and the raphé nuclei. In contrast, layer IV of the neocortex, the cerebellum and cerebellar nuclei, displayed only minimal (10-15%) reductions in glucose utilization. At the highest dose (320 mg.kg-1) examined, progabide effected widespread though heterogeneously distributed decreases in glucose use. The overall pattern of decreased glucose use seen with progabide was different from that noted with previously studied GABA-mimetic drugs, such as muscimol, except for those changes observed in the extrapyramidal and sensory-motor areas for which similar dose-response relationships occurred. A significant correlation was observed between progabide-induced decreases in glucose utilization and in serotonin synthesis in a number of brain areas. The pattern of progabide-induced changes in integrated functional activity is compatible with its neurochemical spectrum and could indicate the loci at which its anticonvulsant, antidepressant and extrapyramidal activities are initiated.