Mood, cognition and serotonin transporter availability in current and former ecstasy (MDMA) users: the longitudinal perspective.

Although 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is a known serotonergic neurotoxin in different animal species, there is to date no conclusive evidence of its neurotoxicity in humans. MDMA use was associated with impairments of psychological well-being, verbal memory and altered serotonergic functioning in a number of cross-sectional studies. Due to inherent methodological limitations, such as the notorious polydrug use of ecstasy users and lack of control of possible pre-existing differences between ecstasy users and control participants, researchers have called for well-controlled, prospective longitudinal studies to shed more light on the issue of MDMA neurotoxicity to the human brain. This longitudinal study investigated whether mood, cognition and central serotonin transporters (SERT) would deteriorate with continued MDMA use and whether or not they would recover over increasing periods of MDMA abstinence. In a repeated-measures design, 11 current and ten ex-ecstasy users, and 11 polydrug (but not MDMA) and 15 drug-naive controls participated three times within approximately two years. Both ecstasy user groups reported a polydrug use pattern besides heavy ecstasy use. Subjective reports of ecstasy use or abstinence were verified by toxicological analyses. On each trial, the participants underwent a cognitive test battery and filled in the Symptom Check List. The availability of central SERT was assessed with positron emission tomography using the McN5652 ligand for all groups at t1, and only for the ecstasy user groups on follow-ups. The factor Group yielded significant results in the SCL-90 scales Global Severity Index, Anxiety, Obsessive/compulsive and Interpersonal sensitivity, with the ex-ecstasy users reporting the highest symptom scores. There were significant Group effects in all measures of verbal memory, with the lowest performance in the group of ex-ecstasy users. The repeated-measures analyses yielded no significant Group x Time interactions in any SCL-90 scales or measures of memory performance, with the exception of AVLT 1 immediate recall. Thus the ex-ecstasy users' psychopathological symptoms and memory performance failed to improve, and the current ecstasy users' failed to deteriorate, over time relative to the other groups. While there was a significant effect of Group in all brain regions examined (except the control region white matter), the current users' SERT availability seems to have recovered in the mesencephalon, as indicated by a significant Group x Time interaction. Reduced SERT availability might be a transient effect of heavy ecstasy use, since it partially recovered as the current users reduced their MDMA use. However, this measure may not necessarily be a valid indicator of the number or integrity of serotonergic neurons. Ex-ecstasy users' verbal memory showed no sign of improvement even after over 2.5 years of abstinence and thus may represent persistent functional consequences of MDMA neurotoxicity. However, alternative causes such as pre-existing group differences cannot be completely ruled out in spite of the longitudinal design.

Mood, cognition and serotonin transporter availability in current and former ecstasy (MDMA) users.

RATIONALE: Chronic recreational ecstasy (MDMA) use has often been reported to be associated with psychopathology, memory impairments and serotonergic alterations. However, the findings have not been consistent. OBJECTIVES: To attempt to replicate these findings, to investigate whether such alterations would be reversible and whether they could be predicted by parameters of previous drug use. METHODS: In a cross-sectional design, 30 current and 31 ex-ecstasy users with ecstasy abstinence of at least 5 months, and 29 polydrug and 30 drug-naive controls were compared on measures of psychopathology, cognitive performance and serotonin transporter availability. RESULTS: The groups did not differ significantly in age, gender distribution, education level and premorbid intelligence. The ecstasy groups did not differ significantly from polydrug controls on most of the relevant parameters of concomitant illegal drug use. Reported drug use was confirmed by hair and urine analyses. All three groups of drug users exhibited significantly elevated psychopathology compared with drug-naive controls. Only ex-ecstasy users were significantly impaired on verbal recall. Current ecstasy users showed significantly reduced distribution volume ratios of serotonin transporter availability in the mesencephalon and caudate nucleus. Regression analyses indicated that psychopathology and serotonergic alterations were best predicted by the number of ecstasy tablets taken on a typical event. CONCLUSION: The results indicate that verbal memory impairments were possibly aggravated after prolonged ecstasy abstinence while there was tentative evidence of serotonergic recovery. On the other hand, self-reported elevated psychopathology appeared to be associated with polydrug use in general and not specifically with ecstasy use.

The structure of McN-5652.

The configuration of the diastereoisomers of 6-(4-methylthiophenyl)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline 1 (McN-5652) is determined and unequivocally assigned by NMR spectroscopy (NOE measurements) and an X-ray structural analysis of the trans diastereoisomer. The enantiomers of cis-1 are separated by preparative HPLC on a chiral phase. One of the enantiomers of cis-1 represents the precursor for imaging the serotonin 5-HT transporter with positron emission tomography (PET).

Morphology and physiology of auditory and vibratory ascending interneurones in bushcrickets.

Auditory/vibratory interneurones of the bushcricket species Decticus albifrons and Decticus verrucivorus were studied with intracellular dye injection and electrophysiology. The morphologies of five physiologically characterised auditory/vibratory interneurones are shown in the brain, subesophageal and prothoracic ganglia. Based on their physiology, these five interneurones fall into three groups, the purely auditory or sound neurones: S-neurones, the purely vibratory V-neurones, and the bimodal vibrosensitive VS-neurones. The S1-neurones respond phasically to airborne sound whereas the S4-neurones exhibit a tonic spike pattern. Their somata are located in the prothoracic ganglion and they show an ascending axon with dendrites located in the prothoracic, subesophageal ganglia, and the brain. The VS3-neurone, responding to both auditory and vibratory stimuli in a tonic manner, has its axon traversing the brain, the suboesophageal ganglion and the prothoracic ganglion although with dendrites only in the brain. The V1- and V2-neurones respond to vibratory stimulation of the fore- and midlegs with a tonic discharge pattern, and our data show that they receive inhibitory input suppressing their spontaneous activity. Their axon transverses the prothoracic ganglion, subesophageal ganglion and terminate in the brain with dendritic branching. Thus the auditory S-neurones have dendritic arborizations in all three ganglia (prothoracic, subesophageal, and brain) compared to the vibratory (V) and vibrosensitive (VS) neurones, which have dendrites almost only in the brain. The dendrites of the S-neurones are also more extensive than those of the V-, VS-neurones. V- and VS-neurones terminate more laterally in the brain. Due to an interspecific comparison of the identified auditory interneurones the S1-neurone is found to be homologous to the TN1 of crickets and other bushcrickets, and the S4-neurone also can be called AN2. J. Exp. Zool. 286:219-230, 2000.

Induction of posterior vitreous detachment in rabbits by intravitreal injection of tissue plasminogen activator following cryopexy.

The purpose of this study was to generate intravitreal plasmin after intravitreal injection of tissue plasminogen activator (TPA) and cryopexy, and to assess its proteolytic effect on the vitreoretinal border region.Twenty-four hr after a mild cryopexy, 25 microg recombinant tissue plasminogen activator (TPA) was injected into the vitreous cavity, the fellow eye received an intravitreal injection of the same volume of buffered salt solution. Light, scanning and transmission electron microscopy was performed in 24 eyes that underwent vitrectomy 1 week later. Plasmin was measured prior and 2 hr after intravitreal TPA injection (4 eyes). Hyaluronic acid (8 eyes) and vitronectin (4 eyes) were measured 1 week after TPA- or BSS-injection and compared to untreated controls. In all eyes treated with TPA, histopathologic examination by scanning and transmission electron microscopy demonstrated a complete detachment of the vitreous from the surface of the retina as well as from the posterior surface of the lens. After BSS-injection, vitreous cortex attachment to the retina was demonstrated in all eyes. Two hr after TPA-injection, plasmin increased to 9.75 mU ml(-1)(s.d.+/-2.3). Neither a decrease of hyaluronic acid nor an increase of transglutaminase, that might alter the vitreous structure leading to a collapse of the vitreous, were detected in treated eyes. There was no increase of vitronectin indicating proliferative activity.A temporary breakdown of the blood-retinal barrier by cryopexy combined with intravitreal injection of TPA is a sufficient technique to induce a posterior vitreous detachment enzymatically. The method may be useful prior to mechanical vitrectomy.

[Etiology of corneal opacities after plasminogen activator-induced fibrinolysis of the anterior chamber]. / Zur Ursache kornealer Trübungen nach Gewebeplasminogen-Aktivator-induzierter Fibrinolyse in der Vorderkammer.

BACKGROUND: After treatment of anterior chamber fibrinous reactions by tissue plasminogen activator (TPA), irreversible corneal opacifications (calcium phosphate) have been observed. To understand the mechanism of these opacifications an animal model was developed. MATERIAL AND METHODS: In rabbits the lens was removed by phacoemulsification. The surgical procedure was completed by an injection of TPA (25 micrograms) into the anterior chamber. In a second group TPA fibrinolysis (25 micrograms) was induced 10 min after injection of autologous blood. In a third group 25 micrograms of TPA was injected into the anterior chamber after circumscribed mechanical lesion of the corneal endothelium. Changes in corneal structure and transparency were determined by biomicroscopy and histopathologic examination. RESULTS: After lensectomy or mechanically induced lesion of the corneal endothelium followed by TPA injection, sharply defined interpalpebral corneal opacifications developed within 3 to 8 days. Histologically, deposits were located in Bowman's membrane and in superficial stromal layers. No opacifications developed after fibrinolysis of an intracameral clot. CONCLUSIONS: Corneal opacifications as seen in humans after fibrinolysis by intracameral injection of TPA requires a temporary disturbance of the endothelial function. This allows phosphate (buffer of TPA) and calcium (aqueous humour) to distribute within the corneal stroma. Then there are insoluble calcium phosphate precipitates because of recovery of the endothelial function and dehydration of the cornea.

Dopamine D2 receptor binding and cerebral glucose metabolism recover after D-penicillamine-therapy in Wilson's disease.

Regional cerebral glucose metabolism (rCMRGlc) and dopamine D2 receptor binding were measured in a 31-year-old, severely affected, untreated patient with Wilson's disease of 3 years' duration using positron emission tomography and 18F-deoxyglucose and 18F-methylspiperone ([18F]MSP), respectively. There was a severe reduction of striatal and extrastriatal rCMRGlc as well as of striatal [18F]MSP accumulation rate. After 1 year of treatment with D-penicillamine, striatal and extrastriatal rCMRGlc and striatal [18F]MSP accumulation rate reached almost normal levels. It is hypothesized that recovery of motor functions due to copper trapping therapy was associated with an increase in basal ganglia activity and a re-expression or upregulation of dopamine D2 receptors.

Tactile exploration of shape after subcortical ischaemic infarction studied with PET.

We studied the cerebral activations related to restitution of hand function in five patients with first hemiplegic subcortical stroke due to ischaemic infarction in the area of the basal ganglia or thalamus. In two subjects, involvement of the cortico-spinal tract was demonstrated by magnetic evoked potentials. The subjects were requested to discriminate rectangular parallelepipeda of identical mass with their affected hands. Regional cerebral blood flow (rCBF) was measured with PET after intravenous bolus injection of [15O]butanol, at rest and during task execution. Evaluation of the rCBF changes was based on pixel-by-pixel t statistics of spatially standardized and averaged PET images and on a statistical distribution analysis of regions of interest in the individual subjects. For anatomical localization of the significant rCBF changes, a computerized brain atlas (Greitz et al. J Comput Assist Tomogr 1991; 15: 26-38) and a matching procedure that directly aligns individual PET and high resolution magnetic resonance images were used. The rCBF at rest and the task-induced rCBF changes varied from subject to subject, as did the residual neurological deficits at the time of PET scanning. In all subjects there were large activation areas in the motor and the sensory hand area contralateral to the affected hand. Poor performance of the task was correlated with a low rCBF in the contralateral sensorimotor cortex at rest and a bilateral activation of the primary sensorimotor cortex during task performance. The premotor cortex, ipsilateral and anterior cerebellum, contralateral to the affected hand, were also significantly activated. Further activations were observed in the contralateral premotor cortex, supplementary motor area and bilaterally in the posterior cingulate cortex, but were less consistent among the subjects. Our data suggest that recovery from hemiplegic stroke is associated with a marked reorganization of the cerebral activation patterns, including common and subject-specific activation sites. With respect to task-specific information processing a lower discrimination rate of objects compared with controls was associated with diminished activations in parietal lobe.

Pharmacokinetics and radiation dose of oxygen-15 labelled butanol in rCBF studies in humans.

In this positron emission tomography (PET) study in humans we determined the pharmacokinetics and radiation dose of oxygen-15 labelled butanol, a recently introduced tracer for regional cerebral blood flow (rCBF). This report includes a description of the automated preparation of 15O-butanol which allows repetitive activation studies, each 15 min apart. Dynamic rCBF studies were extended by prolonged measurements up to 15 min after injection over different organs such as brain, liver, kidneys and bladder. All measurements were done with a whole-body PET camera PC4096-15WB. Based on the pharmacokinetic data in 13 subjects the radiation doses to single organs were calculated according to MIRD pamphlet No. 11 and the effective dose defined by ICRP 60 as an indicator of radiation dose to the total body. The liver received the highest radiation dose of about 2.2 mGy per 1500 MBq of injected 15O-butanol, which is the typical amount of administered tracer in one rCBF measurement. The dose to the kidneys was 1.6 mGy, to the stomach 0.8 mGy, and to the brain 0.16 mGy. The effective dose was 0.54 mGy, which was similar to that of H2(15)O, but lower than the effective dose from C15O2 in amounts typically applied in human rCBF studies.

Comparison of the physiology of the auditory receptor organs in Gryllus bimaculatus and Ephippiger ephippiger: CSD recordings within the auditory neuropiles.

The syllables of the song of the tettigoniid Ephippiger ephippiger consist of a series of short sound impulses with a broad-banded frequency spectrum. Syllables of the song of the gryllid species Gryllus bimaculatus are nearly pure tones with sharply tuned frequency maxima. A comparison of the physiology of the auditory receptor organs of both species was carried out by using acoustical stimuli with different carrier frequencies and time-amplitude patterns. The neuronal ensemble activity of receptor cell groups of the tympanal organ was measured within the prothoracic ganglion using the CSD technique. In E. ephippiger, response maxima were found at carrier frequencies mirroring the broad frequency content of the conspecific song. The receptor cells of E. ephippiger are highly sensitive to transient sound impulses. In G. bimaculatus, the receptor cell population is more sharply tuned to the basic frequencies of the natural songs; pure tones represent more effective stimuli than transient sound signals. The causes for these species-specific differences are discussed with regard to probable adaptations of the receptor organs to the parameters of the conspecific songs.

The influence of plasma glucose levels on fluorine-18-fluorodeoxyglucose uptake in bronchial carcinomas.

PET studies with 2-18F-fluorodeoxyglucose (FDG) were carried out in 15 patients with bronchial carcinomas, first under fasting conditions and then 2 days later during intravenous infusion of a 20% glucose solution which raised the plasma glucose level from 84.6 +/- 14.7 to 168.3 +/- 23.6 mg/100 ml (n = 15, p < 0.001). Tumor metabolism was quantified by the dose absorption ratio (DAR) of FDG uptake [DAR = tissue concentration/(injected dose/body weight)] and also by the rate of glucose consumption (MR) as measured by the Patlak graphical approach in 12 patients. The DAR decreased from 5.07 +/- 1.89 under fasting conditions to 2.84 +/- 0.97 (-41.8% +/- 15%, n = 15, p < 0.001) during glucose infusion, while the MR remained constant (4.71 +/- 2.38 mg/100 ml/min versus 4.96 +/- 2.46 mg/100 ml/min, n = 12, ns). Correction of the DAR data by plasma glucose level eliminated the significant difference between the fasting and glucose load [4.24 +/- 1.59 versus 4.70 +/- 1.45 (n = 15, ns)], but considerable changes in individual patients remained. These data indicate that the DAR of FDG uptake in bronchial carcinomas is influenced significantly by plasma glucose levels. Dynamic quantification of glucose metabolism using the Patlak approach is less dependent on the plasma glucose level and appears advantageous when high reproducibility is needed.

Individual somatotopy of primary sensorimotor cortex revealed by intermodal matching of MEG, PET, and MRI.

A method for comparing estimated magnetoencephalographic (MEG) dipole localizations with regional cerebral blood flow (rCBF) activation areas is presented. This approach utilizes individual intermodal matching of MEG data, of rCBF measurements with [15O]-butanol and positron emission tomography (PET), and of anatomical information obtained from magnetic resonance (MR) images. The MEG data and the rCBF measurements were recorded in a healthy subject during right-sided simple voluntary movements of the foot, thumb, index finger, and mouth. High resolution 3D-FLASH MR images of the brain consisting of 128 contiguous sagittal slices of 1.17-mm thickness were used. MEG/MR integration was performed by superimposing the 3D head coordinate system constructed during the MEG measurement onto the MR image data using identical anatomical landmarks as references. PET/MR integration was achieved by a phantom-validated iterative front-to-back-projection algorithm resulting in one integrated MEG/PET/MR image. The estimated dipole locations followed the somatotopic organisation of the task-specific rCBF increases as evident from PET, although they did not match point-to-point. Our results demonstrate that intermodal matching of MEG, PET and MR data provides a tool for relating estimated neuromagnetic field locations to task-specific rCBF changes in individual subjects. Our method offers the perspective of refined dipole modelling.

Estimation of local cerebral glucose utilization by positron emission tomography: comparison of [18F]2-fluoro-2-deoxy-D-glucose and [18F]2-fluoro-2-deoxy-D-mannose in patients with focal brain lesions.

A comparative PET study of [18F]2-fluoro-2-deoxy-D-glucose (FDG) and [18F]2-fluoro-2-deoxy-D-mannose (FDM) uptake was performed in 13 patients with focal brain lesions. Differences between FDG and FDM with respect to model rate constants, lumped constant, and estimated metabolic rate for glucose were determined on a regional basis. Across whole brain, the transport rate constant K1* was almost unchanged, whereas k2*, describing the transport back from tissue to plasma, was 6% higher, and the phosphorylation rate constant k3* was 9% lower for FDM compared to FDG. This implies a 20% lower lumped constant for FDM. No significant regional variability of this differential tracer behavior was observed in normal or in lesioned brain tissue. Thus, results from previous FDG studies, where the radiotracer was not 100% pure FDG but contained varying amounts of FDM, can easily be corrected by adjustment of the lumped constant employed in metabolic quantitation.

Radiation stability of organic matter in liquid and frozen H2O, NH3 and water-ammonia mixtures.

The redox properties of irradiated liquid and frozen H2O, NH3 and H2O/NH3 mixtures at 298 K and 77 K, resp., towards some simple organic molecules have been checked by injecting carrierfree 11C atoms and analyzing their chemical state by means of radiochromatography. The reactions and the stability of organic products versus radiation dose (in this study by MeV protons) depend on temperature, phase state, mobility of radicals, their concentration and reactivity. Especially dangerous are the reactive OH and O2H radicals which oxidize organic material to inorganic CO2. Highest stability has been found at low temperatures (solid state, reduced mobility of radicals) and for systems containing H-donors (H2O/NH3 mixtures), which reduce the concentration of oxidizing radicals. The fact that many bodies in space consist of H2O-ice with NH3 and CH4 additives at temperatures between 10 and 150 K is promising in view of the survival of organic matter under high doses of radiation.

Hot atoms in cosmic chemistry.

High energy chemical reactions and atom molecule interactions might be important for cosmic chemistry with respect to the accelerated species in solar wind, cosmic rays, colliding gas and dust clouds and secondary knock-on particles in solids. "Hot" atoms with energies ranging from a few eV to some MeV can be generated via nuclear reactions and consequent recoil processes. The chemical fate of the radioactive atoms can be followed by radiochemical methods (radio GC or HPLC). Hot atom chemistry may serve for laboratory simulation of the reactions of energetic species with gaseous or solid interstellar matter. Due to the effective measurement of 10(8)-10(10) atoms only it covers a low to medium dose regime and may add to the studies of ion implantation which due to the optical methods applied are necessarily in the high dose regime. Experimental results are given for the systems: C/H2O (gas), C/H2O (solid, 77 K), N/CH4 (solid, 77K) and C/NH3 (solid, 77 K). Nuclear reactions used for the generation of 2 to 3 MeV atoms are: N(p,alpha) 11C, 16O(p,alpha pn) 11C and 12C(d,n) 13N with 8 to 45 MeV protons or deuterons from a cyclotron. Typical reactions products are: CO, CO2, CH4, CH2O, CH3OH, HCOOH, NH3, CH3NH2, cyanamide, formamidine, guanidine etc. Products of hot reactions in solids are more complex than in corresponding gaseous systems, which underlines the importance of solid state reactions for the build-up of precursors for biomolecules in space. As one of the major mechanisms for product formation, the simultaneous or fast consecutive reactions of a hot carbon with two target molecules (reaction complex) is discussed.