Increased densities of binding sites for the ‘peripheral-type’ benzodiazepine receptor ligand [H]PK 11195 in rat brain following portacaval anastomosis

Using quantitative receptor radioautography, binding sites for the ‘peripheral-type’ benzodiazepine receptor ligand [³H]PK 11195 were studied in rats 4 week after end-to-side portacaval anastomosis and in sham-operated controls. Portacaval anastomosis resulted in region-selective increases in density of [³H]PK 11195 binding sites in cerebellum, pons > thalamus, cerebral cortex > hippocampus > striatum. Possible mechanisms implicated in these changes include (i) the action of endogenous ligands for the mitochondrial benzodiazepine receptor such as octadecaneuropeptide and (ii) neurotoxic actions of ammonia. In view of the proposed role of these receptors as modulators of intermediary metabolism and neurosteroid biosynthesis, such changes could contribute to the neurochemical mechanisms responsible for portal-systemic encephalopathy.     

Two binding sites for [3H]PBR28 in human brain: implications for TSPO PET imaging of neuroinflammation

[¹¹C]PBR28, a radioligand targeting the translocator protein (TSPO), does not produce a specific binding signal in approximately 14% of healthy volunteers. This phenomenon has not been reported for [¹¹C]PK11195, another TSPO radioligand. We measured the specific binding signals with [³H]PK11195 and [³H]PBR28 in brain tissue from 22 donors. Overall, 23% of the samples did not generate a visually detectable specific autoradiographic signal with [³H]PBR28, although all samples showed [³H]PK11195 binding. There was a marked reduction in the affinity of [³H]PBR28 for TSPO in samples with no visible [³H]PBR28 autoradiographic signal (K_i=188±15.6 nmol/L), relative to those showing normal signal (K_i=3.4±0.5 nmol/L, P<0.001). Of this latter group, [³H]PBR28 bound with a two-site fit in 40% of cases, with affinities (K_i) of 4.0±2.4 nmol/L (high-affinity site) and 313±77 nmol/L (low-affinity site). There was no difference in K_d or B_max for [³H]PK11195 in samples showing no [³H]PBR28 autoradiographic signal relative to those showing normal [³H]PBR28 autoradiographic signal. [³H]PK11195 bound with a single site for all samples. The existence of three different binding patterns with PBR28 (high-affinity binding (46%), low-affinity binding (23%), and two-site binding (31%)) suggests that a reduction in [¹¹C]PBR28 binding may not be interpreted simply as a reduction in TSPO density. The functional significance of differences in binding characteristics warrants further investigation.     

Autoradiographic localization of peripheral benzodiazepine binding sites in the cat brain with [H]PK 11195

“Peripheral type” benzodiazepine binding sites were labelled in cat brain membranes by using [³H]PK 11195. This ligand binds to the “peripheral type” binding sites in a reversible, specific and saturable manner. Cat brain binding sites density (6&#x0303; pmol/mg prot.) was higher than in the rat. Pharmacological specificity was demonstrated by the potency order of displacing agents: PK 11195 > RO5-4864 > dipyridamole > diazepam > clonazepam. A similar characterization was performed in slide mounted brain sections where [³H]PK 11195 also labelled the “peripheral type” benzodiazepine binding sites. The high percentage of specific binding (80%) at 1 nM of [³H[PK 11195 made possible the autoradiographic studies on binding sites distribution. These sites were heterogeneously distributed in the grey matter and absent in white matter. Visual, auditory and other specific sensory relay stations were highly labelled. The blood pressure regulating nuclei, the vestibulo-cerebellar and the extrapyramidal motor system also presented a very high binding density. As previously described in the rat brain, choroid plexus was also strongly labelled by [³H]PK 11195 in the cat.     

PET imaging of serotoninergic neurotransmission with [11C]DASB and [18F]altanserin after focal cerebral ischemia in rats

The use of selective serotonin reuptake inhibitors has shown functional improvement after stroke. Despite this, the role of serotoninergic neurotransmission after cerebral ischemia evolution and its involvement in functional recovery processes are still largely unknown. For this purpose, we performed in parallel in vivo magnetic resonance imaging and positron emission tomography (PET) with [¹¹C]DASB and [¹⁸F]altanserin at 1, 3, 7, 14, 21, and 28 days after middle cerebral artery occlusion (MCAO) in rats. In the ischemic territory, PET with [¹¹C]DASB and [¹⁸F]altanserin showed a dramatic decline in serotonin transporter (SERT) and 5-HT_2A binding potential in the cortex and striatum after cerebral ischemia. Interestingly, a slight increase in [¹¹C]DASB binding was observed from days 7 to 21 followed by the uppermost binding at day 28 in the ipsilateral midbrain. In contrast, no changes were observed in the contralateral hemisphere by using both radiotracers. Likewise, both functional and behavior testing showed major impaired outcome at day 1 after ischemia onset followed by a recovery of the sensorimotor function and dexterity from day 21 to day 28 after cerebral ischemia. Taken together, these results might evidence that SERT changes in the midbrain could have a key role in the functional recovery process after cerebral ischemia.     

A novel PET protocol for visualization of breast cancer resistance protein function at the blood–brain barrier

Breast cancer resistance protein (BCRP) is the most abundant multidrug efflux transporter at the human blood–brain barrier (BBB), restricting brain distribution of various drugs. In this study, we developed a positron emission tomography (PET) protocol to visualize Bcrp function at the murine BBB, based on the dual P-glycoprotein (P-gp)/Bcrp substrate radiotracer [¹¹C]tariquidar in combination with the Bcrp inhibitor Ko143. To eliminate the contribution of P-gp efflux to [¹¹C]tariquidar brain distribution, we studied mice in which P-gp was genetically knocked out (Mdr1a/b^(−/−) mice) or chemically knocked out by pretreatment with cold tariquidar. We found that [¹¹C]tariquidar brain uptake increased dose dependently after administration of escalating doses of Ko143, both in Mdr1a/b^(−/−) mice and in tariquidar pretreated wild-type mice. After 15 mg/kg Ko143, the maximum increase in [¹¹C]tariquidar brain uptake relative to baseline scans was 6.3-fold in Mdr1a/b^(−/−) mice with a half-maximum effect dose of 4.98 mg/kg and 3.6-fold in tariquidar (8 mg/kg) pretreated wild-type mice, suggesting that the presented protocol is sensitive to visualize a range of different functional Bcrp activities at the murine BBB. We expect that this protocol can be translated to the clinic, because tariquidar can be safely administered to humans at doses that completely inhibit cerebral P-gp.     

The interaction between β- and α2-adrenoceptors in cerebral cortical membranes: Isoproterenol-induced increase in [H]clonidine binding in rats

The pretreatment of rat cerebral cortical membranes with 10 or 100 μM isoproterenol at 37°C for 40 min caused a significant elevation of the B_max value of [³H]clonidine binding but pretreatment at 4°C did not affect the value. The isoproterenol-induced increase in the B_max value of the binding was higher in 50 mM Tris-HCl buffer (pH 7.7) than in Krebs-Ringer solution. In 50 mM Tris-HCl buffer (pH 7.7), treatment with isoproterenol reduced the B_max value of [³H]dihydroalprenolol binding but neitherK_d nor B_max of [³H]WB 4101 binding was affected by this treatment. Fitty μM propranolol or 100 μM GTP produced a significant reduction in isoproterenol-induced elevation of the B_max value of [³H]clonidine binding. In contrast, 100 μM cyclic AMP did not affect the control binding and 0.1 or 1 mM theophylline did not affect the isoproterenol-induced elevation of the binding. The only B_max value in high affinity binding of [³H]clonidine was increased by isoproterenol.It is suggested that isoproterenol increases the density of α₂-adrenoceptors in a temperature-dependent manner. The direct interaction between β- and α₂-receptor molecules and/or their indirect interaction, mediated by GTP regulatory proteins, would exist in the cerebral cortical membranes of rats.     

Imaging endogenous opioid peptide release with [11C]carfentanil and [3H]diprenorphine: influence of agonist-induced internalization

Understanding the cellular processes underpinning the changes in binding observed during positron emission tomography neurotransmitter release studies may aid translation of these methodologies to other neurotransmitter systems. We compared the sensitivities of opioid receptor radioligands, carfentanil, and diprenorphine, to amphetamine-induced endogenous opioid peptide (EOP) release and methadone administration in the rat. We also investigated whether agonist-induced internalization was involved in reductions in observed binding using subcellular fractionation and confocal microscopy. After radioligand administration, significant reductions in [¹¹C]carfentanil, but not [³H]diprenorphine, uptake were observed after methadone and amphetamine pretreatment. Subcellular fractionation and in vitro radioligand binding studies showed that amphetamine pretreatment only decreased total [¹¹C]carfentanil binding. In vitro saturation binding studies conducted in buffers representative of the internalization pathway suggested that μ-receptors are significantly less able to bind the radioligands in endosomal compared with extracellular compartments. Finally, a significant increase in μ-receptor-early endosome co-localization in the hypothalamus was observed after amphetamine and methadone treatment using double-labeling confocal microscopy, with no changes in δ- or κ-receptor co-localization. These data indicate carfentanil may be superior to diprenorphine when imaging EOP release in vivo, and that alterations in the ability to bind internalized receptors may be a predictor of ligand sensitivity to endogenous neurotransmitter release.     

Deep-learning-based attenuation correction in dynamic [15O]H2O studies using PET/MRI in healthy volunteers

Quantitative [¹⁵O]H₂O positron emission tomography (PET) is the accepted reference method for regional cerebral blood flow (rCBF) quantification. To perform reliable quantitative [¹⁵O]H₂O-PET studies in PET/MRI scanners, MRI-based attenuation-correction (MRAC) is required. Our aim was to compare two MRAC methods (RESOLUTE and DeepUTE) based on ultrashort echo-time with computed tomography-based reference standard AC (CTAC) in dynamic and static [¹⁵O]H₂O-PET. We compared rCBF from quantitative perfusion maps and activity concentration distribution from static images between AC methods in 25 resting [¹⁵O]H₂O-PET scans from 14 healthy men at whole-brain, regions of interest and voxel-wise levels. Average whole-brain CBF was 39.9 ± 6.0, 39.0 ± 5.8 and 40.0 ± 5.6 ml/100 g/min for CTAC, RESOLUTE and DeepUTE corrected studies respectively. RESOLUTE underestimated whole-brain CBF by 2.1 ± 1.50% and rCBF in all regions of interest (range −2.4%– −1%) compared to CTAC. DeepUTE showed significant rCBF overestimation only in the occipital lobe (0.6 ± 1.1%). Both MRAC methods showed excellent correlation on rCBF and activity concentration with CTAC, with slopes of linear regression lines between 0.97 and 1.01 and R² over 0.99. In conclusion, RESOLUTE and DeepUTE provide AC information comparable to CTAC in dynamic [¹⁵O]H₂O-PET but RESOLUTE is associated with a small but systematic underestimation.     

β-adrenoceptor stimulation-induced increase in the number of α2-adrenoceptors of cerebral cortical membranes in rats

Effects of pre-treatment of synaptic membranes with β-adrenoceptor agonists and cholera toxin on [³H]clonidine and [³H]yohimbine binding were examined in rat cerebral cortex. Pre-incubation of cerebral cortical membranes with isoproterenol (10 or 200 μM) or dobutamine (1, 10 or 200 μM) at 37 °C for 40 min caused a significant elevation of specific [³H]clonidine binding but treatment with salbutamol (10 or 200 μM) did not. Scatchard analysis showed that 200 μM isoproterenol treatment resulted in a significant elevation of high affinity component of [³H]clonidine binding which was significantly decreased by the addition of 10μM GTP. A significant elevation in high affinity [³H]clonidine binding was observed by treatment with 100 μg/ml cholera toxin, while a significant decrease in low affinity one was by the treatment. Specific [³H]yohimbine binding was also elevated by 10 or 200 μM isoproterenol treatment. It is suggested that stimulation of β-receptors, presumably β₁-subtype could elevate the number of agonist and antagonist binding sites in α₂-receptors in synaptic membranes by partially mediated by stimulatory and/or inhibitory GTP binding regulatory proteins.     

Regulation of central and peripheral benzodiazepine receptors in progesterone-treated rats

The effects of progesterone treatment to male rats on cortical and hippocampal central benzodiazepine (BZ) receptors and peripheral BZ binding sites (PBS) in kidney, testis and heart were evaluated. Chronic progesterone treatment resulted in a 30% elevation of the density of central BZ receptors in cerebral cortex accompanied by a 24% augmentation of PBS in the kidney. No significant change in the density of central BZ receptors in the hippocampus or of PBS in the testis or heart was observed. No change in the affinity of [³H]flunitrazepam and [³H]PK 11195 binding to central BZ receptors and PBS, respectively, was observed. The increase in PBS in the kidney might be associated with the natriuretic effect of this hormone and the adaptatory increase in aldosterone secretion. The up-regulatory effect of progesterone on cortical central BZ receptors may be involved in the neurobehavioral activities of progesterone.     

Optimization of supervised cluster analysis for extracting reference tissue input curves in (R)-[(11)C]PK11195 brain PET studies

Performance of two supervised cluster analysis (SVCA) algorithms for extracting reference tissue curves was evaluated to improve quantification of dynamic (R)-[¹¹C]PK11195 brain positron emission tomography (PET) studies. Reference tissues were extracted from images using both a manually defined cerebellum and SVCA algorithms based on either four (SVCA4) or six (SVCA6) kinetic classes. Data from controls, mild cognitive impairment patients, and patients with Alzheimer''s disease were analyzed using various kinetic models including plasma input, the simplified reference tissue model (RPM) and RPM with vascular correction (RPMV_b). In all subject groups, SVCA-based reference tissue curves showed lower blood volume fractions (V_b) and volume of distributions than those based on cerebellum time-activity curve. Probably resulting from the presence of specific signal from the vessel walls that contains in normal condition a significant concentration of the 18 kDa translocation protein. Best contrast between subject groups was seen using SVCA4-based reference tissues as the result of a lower number of kinetic classes and the prior removal of extracerebral tissues. In addition, incorporation of V_b in RPM improved both parametric images and binding potential contrast between groups. Incorporation of V_b within RPM, together with SVCA4, appears to be the method of choice for analyzing cerebral (R)-[¹¹C]PK11195 neurodegeneration studies.     

Maximal densities of μ, δ, and κ receptors are differentially altered by focal cerebral ischaemia in the mouse

Though opioids are known to have neuroprotective properties, little information is available on the functional state of opioidergic receptors following focal cerebral ischaemia. The present study investigated the evolution of the B_max and K_d for [³H]DAMGO, [³H]DADLE, and [³H]U69,593, respectively, for the μ, δ, and κ opioidergic receptors after permanent focal cerebral ischaemia in mice. While the various K_d were unchanged, μ and δ B_max values were precociously decreased in frontoparietal cortices, earlier than κ receptors, reflecting infarct extension with time. The B_max values for μ and δ receptors were also altered in non-infarcted tissues, such as tissues at risk (e.g., temporal auditory cortex) and exofocal (e.g., contralateral and non-infarcted) cortices. These results suggest that, in non-infarcted areas, the observed changes reflect functional modifications to focal ischaemia.     

Intracellular acidification alters myogenic responsiveness and vasomotion of mouse middle cerebral arteries

Intracellular pH (pH_i) in the vascular wall modulates agonist-induced vasocontractile and vasorelaxant responses in mesenteric arteries, whereas effects on myogenic tone have been unsettled. We studied the role of Na⁺,HCO₃⁻ cotransporter NBCn1 in mouse isolated middle cerebral arteries and the influence of pH_i disturbances on myogenic tone. Na⁺,HCO₃⁻ cotransport was abolished in arteries from NBCn1 knockout mice and steady-state pH_i ∼0.3 units reduced compared with wild-type mice. Myogenic tone development was low under control conditions but increased on treatment with the NO-synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME). This effect of L-NAME was smaller in arteries from NBCn1 knockout than wild-type mice. Myogenic tone with L-NAME present was significantly lower in arteries from NBCn1 knockout than wild-type mice and was abolished by rho-kinase inhibitor Y-27632. The arteries displayed vasomotion, and this rhythmic contractile pattern was also attenuated in arteries from NBCn1 knockout mice. No differences in membrane potential or intracellular [Ca²⁺] were seen between arteries from NBCn1 knockout and wild-type mice. We propose that NO production and rho-kinase-dependent Ca²⁺ sensitivity are reduced at low pH_i in pressurized mouse middle cerebral arteries. This likely impedes the ability to adjust to changes in perfusion pressure and regulate cerebral blood flow.     

Kinetic modeling without accounting for the vascular component impairs the quantification of [11C]PBR28 brain PET data

The positron emission tomography radioligand [¹¹C]PBR28 targets translocator protein (18 kDa) (TSPO) and is a potential marker of neuroinflammation. [¹¹C]PBR28 binding is commonly quantified using a two-tissue compartment model and an arterial input function. Previous studies with [¹¹C]-(R)-PK11195 demonstrated a slow irreversible binding component to the TSPO proteins localized in the endothelium of brain vessels, such as venous sinuses and arteries. However, the impact of this component on the quantification of [¹¹C]PBR28 data has never been investigated. In this work we propose a novel kinetic model for [¹¹C]PBR28. This model hypothesizes the existence of an additional irreversible component from the blood to the endothelium. The model was tested on a data set of 19 healthy subjects. A simulation was also performed to quantify the error generated by the standard two-tissue compartmental model when the presence of the irreversible component is not taken into account. Our results show that when the vascular component is included in the model the estimates that include the vascular component (2TCM-1K) are more than three-fold smaller, have a higher time stability and are better correlated to brain mRNA TSPO expression than those that do not include the model (2TCM).     

Autoradiographic distribution of α2 adrenoceptors, NAIBS, and 5-HT1A receptors in human brain using [H]idazoxan and [H]rauwolscine

The regional distribution of [³H]idazoxan and [³H]rauwolscine was studied autoradiographically in human brain. [³H]Idazoxan binds with high affinity to α₂ adrenoceptors as well as to non-adrenergic sites (NAIBS). [³H]Rauwolscine, besides binding to α₂ adrenoceptors, also binds to 5-HT_1A receptors. Both radioligands labelled the same population of α₂ adrenoceptors, defined as the epinephrine-displaceable binding component. The highest densities of α₂ adrenoceptors occur in the leptomeninges, cerebral cortex and claustrum; lower densities were visualised in the basal ganglia, thalamus, pons, substantia nigra, cerebellum and medulla oblongata; no α₂ adrenoceptors were detected in amygdala and nucleus ruber. NAIBS were present in all the examined brain areas, with the highest densities found in the basal ganglia and substantia nigra. The finding that certain brain regions, such as the amygdala, contained NAIBS but no detectable α₂ adrenoceptors, suggests that the binding sites are independent from each other. The regional distribution of 5-HT_1A receptors labelled by [³H]rauwolscine is in agreement with previous studies using [³H]8-OH-DPAT.     

HMBG1 mediates ischemia–reperfusion injury by TRIF-adaptor independent Toll-like receptor 4 signaling

High-mobility group protein box-1 (HMGB1) has recently been recognized as a novel candidate in a specific upstream pathway promoting inflammation after brain ischemia. However, its downstream pathway and underlying mechanism have yet to be elucidated. The HMGB1 level in the acute cerebral infarct (ACI) group was significantly increased compared with that of control group, and correlated with the severity of neurologic impairment of ACI patients. Further, recombinant human HMGB1 (rhHMGB1) had no effect on microglia derived from mice lacking the Toll-like receptor 4 (TLR4^−/−). Intracerebroventricular injection of rhHMGB1 in TLR4^+/+ mice cause significantly more injury after cerebral ischemia–reperfusion than control group. But, TLR4^−/− mice administered with rhHMGB1 showed moderate impairment after ischemia–reperfusion than TLR4^+/+ mice. To determine the potential downstream signaling of HMGB1/TLR4 in cerebral ischemic injury, we used the ischemic–reperfusion model with Toll/interleukin-1 receptor domain-containing adaptor-inducing interferon-β knockout mice (TRIF^−/−) and evaluated the activity and expression of TRIF pathway-related kinases. The results suggest that the TRIF pathway is not likely to be involved in TLR4-mediated ischemia brain injury. Finally, we found that TLR4 expressed by immigrant macrophages was involved in the development of ischemic brain damage. These results suggest that HMBG1 mediates ischemia–reperfusion injury by TRIF-adaptor independent Toll-like receptor 4 signaling. The TLR4 expressed by immigrant macrophages may be involved in the development of ischemic brain damage.     

Long-term test–retest reliability of striatal and extrastriatal dopamine D2/3 receptor binding: study with [11C]raclopride and high-resolution PET

We measured the long-term test–retest reliability of [¹¹C]raclopride binding in striatal subregions, the thalamus and the cortex using the bolus-plus-infusion method and a high-resolution positron emission scanner. Seven healthy male volunteers underwent two positron emission tomography (PET) [¹¹C]raclopride assessments, with a 5-week retest interval. D_2/3 receptor availability was quantified as binding potential using the simplified reference tissue model. Absolute variability (VAR) and intraclass correlation coefficient (ICC) values indicated very good reproducibility for the striatum and were 4.5%/0.82, 3.9%/0.83, and 3.9%/0.82, for the caudate nucleus, putamen, and ventral striatum, respectively. Thalamic reliability was also very good, with VAR of 3.7% and ICC of 0.92. Test–retest data for cortical areas showed good to moderate reproducibility (6.1% to 13.1%). Our results are in line with previous test–retest studies of [¹¹C]raclopride binding in the striatum. A novel finding is the relatively low variability of [¹¹C]raclopride binding, providing suggestive evidence that extrastriatal D_2/3 binding can be studied in vivo with [¹¹C]raclopride PET to be verified in future studies.     

Distribution of α-adrenergic, β-adrenergic and dopaminergic receptors in discrete hypothalamic areas of rat

Catecholamine receptor binding sites were measured in discrete hypothalamic nuclei or regions as well as in certain extrahypothalamic areas of the adult male rat. For each assay, discrete areas were microdissected from frozen tissue sections and pooled from several animals. Specific high affinity binding sites were assessed at fixed ligand concentrations for [³H]p-aminoclonidine (PAC) and [³H](2-C 2′,6′-(CH₃O)₂ phenoxyethylamino)-methylbenzodioxan (WB-4101) for α-adrenergic receptor sites, for [³H]dihydroalprenolol (DHA) for β-adrenergic receptor sites, and for [³H]2-amino-6, 7-dihydroxy-1,2,3,4-tetrahydronaphtalene (ADTN) and [³H]spiroperidol in the presence of cinanserin for dopaminergic receptor sites.Regional variations in [³H]WB-4101 binding were relatively small in magnitude, with most hypothalamic and extrahypothalamic areas possessing between 60 and 90% of the binding in frontal cortex. [³H]PAC binding showed a wider range of binding density across brain areas than did [³H]WB-4101, but, in general, variations in [³H]PAC binding paralleled those in [³H]WB-4101 binding. In hypothalamus, binding was characterized as being predominantly to α₁-receptors in the of [³H]WB-4101 and to α₂-receptors in the case of [³H]PAC. The medial hypothalamic areas exhibited a somewhat higher density of these α-adrenergic sites than did the lateral hypothalamus (perifornical hypothalamus and medial forebrain bundle). Also, the ratio of [³H]PAC to [³H]WB-4101 binding differed in different hypothalamic areas, ranging from 1.5:1 to 4:1. The median eminence was exceptional in that it contained appreciable [³H]PAC but no significant [³H]WB-4101 binding sites at the radioligand concentrations tested. Binding of [³H]DHA to β-adrenergic receptors varied over approximately a 3-fold range in the different hypothalamic areas, with binding highest in the medial forebrain bundle and the medial preoptic area, and lowest in the periventricular, dorsomedial and posterior hypothalamic nuclei, the median eminence and the zona incerta. The ratio of β-adrenergic to α-adrenergic binding sites was generally lower in the medial than in the lateral hypothalamic areas and higher in the extrahypothalamic areas examined than in the hypothalamus. With regard to [³H]spiroperidol and [³H]ADTN binding to dopaminergic sites, the striatum, nucleus accumbens and olfactory tubercle showed a greater density of [³H]spiroperidol than of [³H]ADTN sites, in contrast to the hypothalamus where [³H]ADTN binding was more predominant. Within the hypothalamus, [³H]ADTN binding was relatively uniform, while [³H]spiroperidol binding was quite high in four hypothalamic areas (lateral perifornical area, medial forebrain bundle, paraventricular and dorsomedial nuclei), intermediate in the median eminence and arcuate nucleus, and low or not detectable in all other hypothalamic areas.     

Epileptic negative myoclonus: SPECT, PET, and video/EEG studies and the dramatic effects of levetiracetam

An 18-year-old woman presented with epileptic negative myoclonus (ENM) as her major seizure pattern for 4 years. Her seizures were characterized by intermittent postural lapse of the right limbs for a period of hours to 2 days. Ictal electroencephalography (EEG)–electromyography showed a silent period that was time-locked to generalized spike–wave discharges. Video/EEG monitoring demonstrated marked improvement of ENM after oral administration of levetiracetam. Cranial magnetic resonance imaging was normal, but 2-deoxy-2-[¹⁸F]fluoro-d-glucose positron emission tomography during frequent ENM showed hypometabolism in the left frontoparietal cortex. Technetium-99m-ethyl cysteinate dimer single-photon emission computed tomography revealed hyperperfusion over the left parietal cortex and putamen. Here, we document the short-term effects of levetiracetam in this subject with nearly isolated ENM and the neuroimaging results during ENM. Long-term follow-up is in progress to evaluate the clinical evolution and long-term effects of levetiracetam on ENM.     

Chronic administration of antidepressant drugs increases the density of cortical [H]prazosin binding sites in the rat

Administration of antidepressants (imipramine, citalopram) or antidepressant neuroleptics (levomepromazine, chlorprothixene) for 14–24 days enhanced by 20–30% the density of [³H]prazosin binding sites in the membranes from the cerebral cortex of the rat, without significant change in their affinity.