[A case of acute psychotic episode after a single dose of ecstasy]. / Un cas d'épisode psychotique aigu après prise unique d'ecstasy.

Over the last 10 years or so in Europe, there has been a development of the "ecstasy" phenomenon, which is the symbol of "recreational" drugs in general. Users, either alone or in private parties, are on the increase. The phenomenon is most frequent in England and in the Netherlands, with an estimated incidence of 13-18% amongst the 18-25 years old, which may reach 52% in "exposed populations", such as individuals who go to "techno" night clubs. In France, the prevalence is uncertain, but estimated at least 5% of males between 18 and 23 years old. Several substance, with more or less the same effects, are grouped together by the term "ecstasy", the best-known one being 3,4-methylenedioxymethamphetamine (MDMA), but there are also an N-demethylated derivative (MDA), methylenedioxyethylamphetamine (MDEA), N-methyl-benzodioxazolylbutanamine (MBDB) and 4-bromo-2,5-dimethoxyphenylethylamine (2-CB or Nexus). The psychopathological consequences of MDMA in man are relatively poorly understood. On the basis of series of cases reported in the literature, acute psychosis, chronic psychosis similar to paranoid delusions, flash-back phenomena similar to with LSD, anxiety/panic states and depressive mood disorders may occur. The case which we report is therefore that of an acute psychotic episode, with residual symptomatology 6 months later, which occurred suddenly following absorption of toxic substances (alcohol and ecstasy), at least 12 hours after taking the ecstasy tablet without his knowing it, in an individual without any previous psychopathology, other than moderate social phobia. Twelve cases of acute psychotic episodes after ecstasy have been reported in the literature. Two of them occurred after a single dose and one after 2 doses. No author was able to examined the previous history of the individuals accurately, nor any possible psychopathological history. Our patient did not have any previous history of psychosis, using a standardized validated interview, which his peers and family confirmed. He did however fulfil the criteria of "social phobia". Retrospectively, we noted the extent of his psychomotor disinhibition with ecstasy, which seemed to be proportional to the intensity of his previous social inhibition. This point does not explain the psychotic episode. From a neurobiologic point of view, acute psychotic disorders are often related to dysfunction of the mesolimbic dopaminergic system. During the first 3 hours, the effect of absorption of MDMA is a massive release of the serotonin, dopamine and noradrenaline stocks. Later, an acute hyposerotoninergic state is present. In our observation, the psychotic disorder appeared at least 12 hours after taking ecstasy, during the reduction phase of the intoxication. Toxicological analysis of the blood was negative (this detection is only positive for 24 hours). Like other authors, our hypothesis is that serotoninergic dysregulation affects the dopaminergic system. Sudden disappearance of serotoninergic feedback on the dopaminergic pathways, may contribute to an increase in the mesolimbic hyperdopaminergic state. In animals, it has been shown that serotonin depletion induced by MDMA, unmasks the effects of a hyperdopaminergic state. In addition, although it has not been mentioned much in the literature, MDMA disturbs dopaminergic function either directly, or through the peptidergic systems (neurotensin, substance P, dynorphines). A consistent series of arguments therefore suggest that there is a sudden central hyperdopaminergic state, which may be related to the appearance, sometimes de novo, of an acute psychotic disorder. From the published cases, psychotic disorders following absorption of ecstasy, appear to become chronic. Most of the cases occurred in individuals, who either abused multiple substances or were chronic ecstasy users. In a case like the one we report, in an individual with good general health, who is not a drug user and who has an acute episode following a single dose, the prognosis should be good. Similarly, a team from Milan has described the experience of 3 friends who had a brief psychotic episode, following ingestion of substances containing ecstasy. These episodes resolved completely, after rehydration and anxiolytic treatment. However, after 6 months' follow-up, our patient still has psychotic symptoms, albeit mild, but which were not present before the intoxication. The patient and his psychiatrist do not envisage changing or stopping his antipsychotic treatment. Other authors have described a lesion in the serotoninergic neurons, by making a parallel with toxic effects described in animals, in particular in primates, with MDMA. Degradation of the serotoninergic cell bodies and nerve endings has been suggested to occur with high doses and/or repeated doses of MDMA. Other authors show the large variations in MDMA and MDA metabolism. (ABSTRACT TRUNCATED)

An "accidental" acute psychosis with ecstasy use.

Over the last 10 years, Europe has witnessed the development of the ecstasy phenomenon; this term is used to describe several products sharing more or less the same effects. The most widely used and hence the most well known is 3,4 MDMA, but MDA, MDEA, MBDB and even 2CB or nexus are available. The psychopathological consequences of MDMA use in man are relatively poorly understood. The case reported here involves an acute psychotic episode with residual symptoms after six months, with a sudden onset at least 12 hours after taking alcohol and ecstasy without realising it, in an individual with no previous psychopathology other than a moderate anxiety disorder. Twelve cases of acute psychotic episodes after taking ecstasy have been reported in the literature; two after taking the drug on two occasions and one after a single use. No authors have examined the previous mental state or possible previous psychopathology with any precision. The present subject had not displayed any previous psychotic behavior when tested with a proven standardized interview technique; this was confirmed by his peers and his family. He did, however, show signs of social phobia. Although the personality of an individual is a factor in taking a drug, and probably in the quality of the psychotropic effects experienced, a host of arguments favor the appearance of psychotic symptoms de novo, which were probably related to direct toxicity by MDMA and/or its metabolites on the serotoninergic neurons.

Nerve growth factor, but not epidermal growth factor, increases Fra-2 expression and alters Fra-2/JunD binding to AP-1 and CREB binding elements in pheochromocytoma (PC12) cells.

In pheochromocytoma (PC12) cells nerve growth factor (NGF) and epidermal growth factor (EGF) activate similar receptor tyrosine kinase signaling pathways but evoke strikingly different biological outcomes: NGF induces differentiation and EGF acts as a mitogen. A novel approach was developed for identifying transcription factor activities associated with NGF-activated, but not EGF-activated, signaling, using random oligonucleotide clones from a DNA recognition library to isolate specific DNA binding proteins from PC12 nuclear extracts. A protein complex from NGF-treated, but not EGF-treated, cells was identified that exhibits increased mobility and DNA binding activity in gel mobility shift assays. The binding complex was identified in supershift assays as Fra-2/JunD. The clones used as probes contain either AP-1 or cAMP response element binding (CREB) recognition elements. Time course experiments revealed further differences in NGF and EGF signaling in PC12 cells. NGF elicits a more delayed and sustained ERK phosphorylation than EGF, consistent with previous reports. Both growth factors transiently induce c-fos, but NGF evokes a greater response than EGF. NGF specifically increases Fra-1 and Fra-2 levels at 4 and 24 hr. The latter is represented in Western blots by bands in the 40-46 kDa range. NGF, but not EGF, enhances the upper bands, corresponding to phosphorylated Fra-2. These findings suggest that prolonged alterations in Fra-2 and subsequent increases in Fra-2/JunD binding to AP-1 and CREB response elements common among many gene promoters could serve to trigger broadly an NGF-specific program of gene expression.

Histamine induces nuclear factor of activated T cell-mediated transcription and cyclosporin A-sensitive interleukin-8 mRNA expression in human umbilical vein endothelial cells.

The nuclear factor of activated T cells (NFAT) mediates a cyclosporin A (CsA)- and FK506-suppressible transcriptional program in lymphocytes after antigen-stimulated phospholipase C activation. Nonlymphoid cells also express NFAT isoforms, raising the possibility that these isoforms can be regulated by other extracellular stimuli. This study sought to determine whether histamine can trigger NFAT-mediated transcription in human umbilical vein endothelial cells (HUVEC), using a retrovirus-based luciferase reporter driven by a well characterized, NFAT-specific enhancer. Luciferase levels are induced up to 60-fold over basal levels after costimulation of HUVEC with Ca2+-mobilizing drugs and a phorbol ester, a response that is 20-fold greater than that observed when HUVEC are stimulated with either drug alone. These synergistic responses are inhibited in cells treated with CsA. CsA and FK506 also inhibit the luciferase response to histamine, indicating that histamine can induce NFAT-mediated transcription in HUVEC. To identify candidate genes in HUVEC that might be regulated by NFAT, the expression of several chemokine mRNAs was measured after histamine treatment. Of the mRNAs tested, only those encoding monocyte chemotactic protein-1 (approximately 2-fold over basal) and interleukin-8 (approximately 6-fold over basal) are induced by histamine; both of these responses are suppressed by CsA and FK506. The H1 histamine receptor antagonist chlorpheniramine, but not the H2 receptor antagonist ranitidine, blocks the effects of histamine in this preparation. These data provide the first evidence for a physiological inducer of NFAT-mediated transcription in endothelial cells and support the hypothesis that NFAT participates in H1 histamine receptor-induced interleukin-8 gene expression.

The cyclosporin A-sensitive nuclear factor of activated T cells (NFAT) proteins are expressed in vascular smooth muscle cells. Differential localization of NFAT isoforms and induction of NFAT-mediated transcription by phospholipase C-coupled cell surface receptors.

Expression of the antigen-regulated, cyclosporin A-sensitive nuclear factor of activated T cells (NFAT) is not restricted to lymphoid cells, as thought initially, but the physiological inducers of NFAT-mediated transcription in non-lymphoid cells are unknown. Here, cultured vascular smooth muscle cells (VSMC) are shown to express two isoforms of the NFAT family endogenously, which are localized differentially in cells under resting conditions. Using a retroviral NFAT-specific luciferase reporter, we show that VSMC support previously unrecognized complexities in NFAT-mediated transcription, including evidence for negative regulation by Ca2+ signaling and positive regulation through co-activation of adenylyl cyclase and Ca2+ mobilization. The VSMC mitogen platelet derived growth factor-BB (PDGF-BB) induces NFAT-mediated transcription in VSMC. Thrombin and angiotensin II, which activate Galphaq-coupled receptors, are significantly weaker inducers of NFAT-mediated luciferase expression than is PDGF-BB. However, co-stimulation studies show that Galphaq receptor agonists augment the NFAT-mediated transcriptional response to PDGF-BB. This synergy can be explained in part by augmented intracellular Ca2+ transients elicited by multiple agonist challenges. These data indicate that agonists for phospholipase C-coupled receptors stimulate NFAT-mediated transcription in VSMC differentially, and that NFAT can function to integrate co-activating signals in the extracellular environment.

Induction of NFAT-mediated transcription by Gq-coupled receptors in lymphoid and non-lymphoid cells.

The nuclear factor of activated T cells (NFAT) was discovered as an inducible transcription factor activated by antigen stimulation of the T cell receptor in lymphocytes. Stimulation of NFAT-mediated transcription is now reported in both lymphoid and non-lymphoid cells following activation of a neurotransmitter receptor. Carbachol induces robust luciferase responses in Jurkat and pheochromocytoma PC12 cells expressing an NFAT-luciferase reporter construct and a Gq-coupled m3 muscarinic receptor. Cyclosporin blocks this response in PC12 cells, as in Jurkat cells. In PC12 cells expressing a Gi-coupled m2 muscarinic receptor, carbachol induces NFAT-mediated luciferase activity that is strictly dependent upon co-expression of a chimeric G alpha q/alpha i subunit, which confers Gq-effector coupling on Gi-linked receptors. These findings suggest that neurotransmitters, autacoids, or hormones acting on Gq-protein-coupled receptors may serve as physiological stimulators of NFAT in lymphoid and non-lymphoid cells.

An L-cysteine sulfinic acid-sensitive metabotropic receptor mediates increased cAMP accumulation in hippocampal slices.

The excitatory amino acid (EAA), L-cysteine sulfinic acid (L-CSA), elicited a dose-dependent increase in cAMP accumulation in adult rat hippocampus that was not blocked by ionotropic glutamate receptor antagonists. Therefore, the possibility was examined that L-CSA activates the (1S,3R)-amino-1,3-cyclopentanedicarboxylic acid (1S,3R-ACPD)-sensitive metabotropic glutamate receptor (mGluR) that increases cAMP by potentiating responses elicited by adenosine or other agonists of receptors coupled to adenylate cyclase via Gs. Like 1S,3R-ACPD, L-CSA induced a cAMP response that was inhibited by the adenosine receptor antagonist, 8-para-sulfyltheophylline, and by adenosine deaminase. In contrast to the 1S,3R-ACPD-induced cAMP response, the L-CSA-induced response was not potentiated by the adenosine uptake inhibitor, dipyridamole. Taken together with the previous finding that L-CSA does not potentiate cAMP responses elicited by agonists of receptors that activate Gs, these data suggest that L-CSA increases cAMP accumulation by activating a metabotropic EAA receptor that is different from the 1S,3R-ACPD-sensitive mGluR associated with potentiation of cAMP responses.

L-cysteine sulfinic acid as an endogenous agonist of a novel metabotropic receptor coupled to stimulation of phospholipase D activity.

A substantial body of research implicates L-cysteine sulfinic acid (L-CSA) as a neurotransmitter. However, all physiological actions of L-CSA that have been pharmacologically characterized are mediated by cross-activation of glutamate receptors, and no receptor has been identified that is primarily activated by L-CSA. We report that a receptor exists in adult rat hippocampus that is activated by L-CSA but is insensitive to several other endogenous excitatory amino acids (EAAs), including L-glutamate, L-aspartate, and L-homocysteic acid. This receptor is coupled to an increase in the activity of phospholipase D (PLD). The L-CSA-induced PLD response is not blocked by ionotropic glutamate receptor antagonists but is mimicked by the metabotropic glutamate receptor (mGluR) agonist (1S,3R)-amino-1,3-cyclopentanedicarboxylic acid. The agonist pharmacology of the PLD-coupled response is generally similar to that of mGluRs but clearly differs from that of any particular mGluR that has been characterized to date. Furthermore, this receptor is not significantly blocked by (RS)-alpha-methyl-4-carboxyphenylglycine, which blocks a variety of mGluR-mediated responses. L-CSA has little effect on mGluRs coupled to phosphoinositide hydrolysis or the potentiation of cAMP responses in adult hippocampus, indicating that L-CSA is not a broad mGluR agonist. It is commonly thought that EAAs act on the same receptor families, all of which use glutamate as their primary agonist. However, the finding that L-CSA acts on a glutamate-insensitive receptor suggests that different receptor families might exist for different EAAs.

Metabotropic excitatory amino acid receptor activation stimulates phospholipase D in hippocampal slices.

Metabotropic excitatory amino acid (EAA) receptors are coupled to effector systems through G proteins. Because various G protein-coupled receptors stimulate the hydrolysis of phosphatidylcholine by phospholipase D (PLD), we examined the possibility that metabotropic EAA receptors exist that are coupled to the activation of PLD. We found that the selective metabotropic glutamate receptor (mGluR) agonists 1S,3R-amino-1,3-cyclopentanedicarboxylic acid (ACPD) and 1S,3S-ACPD, but not the inactive isomer, 1R,3S-ACPD, induce a concentration-dependent increase in PLD activity in hippocampal slices. Selective ionotropic glutamate receptor (iGluR) antagonists did not block 1S,3R-ACPD-induced PLD stimulation. Furthermore, although selective iGluR agonists did not activate this response, the nonselective mGluR-iGluR agonists, ibotenate and quisqualate, caused significant increases in PLD activity (all in the presence of iGluR antagonists). L-2-Amino-3-phosphonopropionic acid, which blocks the mGluR that is coupled to phosphoinositide hydrolysis in various brain regions, activates PLD to the same extent as the active isomers of ACPD. These data suggest that metabotropic EAA receptors exist in hippocampus that are coupled to PLD activation and are pharmacologically distinct from phosphoinositide hydrolysis-coupled mGluRs.

Trans-ACPD-induced phosphoinositide hydrolysis and modulation of hippocampal pyramidal cell excitability do not undergo parallel developmental regulation.

The selective metabotropic glutamate receptor agonist, trans-1-aminocyclopentane-1,3-dicarboxylic acid (trans-ACPD), stimulates phosphoinositide hydrolysis and elicits a number of electrophysiological responses in the hippocampus. If these effects are mediated by the same receptor subtype, they should undergo parallel developmental regulation. Therefore, we compared the phosphoinositide hydrolysis response and the electrophysiological responses to trans-ACPD at two different developmental stages. Trans-ACPD-stimulated phosphoinositide hydrolysis was significantly greater in hippocampal slices from immature (6-11-day-old) rats than from adults. In contrast, trans-ACPD elicited decreases in spike frequency adaptation and in the amplitude of the slow afterhyperpolarization in roughly equal percentages of immature and adult CA1 pyramidal cells. Similar results were obtained using the putative endogenous agonist, glutamate. These data support the hypothesis that certain electrophysiological effects of trans-ACPD are mediated by a metabotropic glutamate receptor that is distinct from the phosphoinositide hydrolysis-linked glutamate receptor.

Selective innervation of foreign muscles following damage or removal of normal muscle targets.

The restoration of a normal pattern of neural connectivity following nerve injury depends upon the selective reinnervation of appropriate postsynaptic targets. Previous studies suggest that, in the neuromuscular system, recognition between regenerating motoneurons and target muscles depends upon the positions of origin of the motoneurons and muscles. In axolotls, portions of the motor pools of adjacent muscles overlap. We found that, following removal of a pair of adjacent hindlimb muscles, anterior and posterior iliotibialis, many regenerating iliotibialis motor axons invaded foreign muscles. A more anterior foreign muscle, puboischiofemoralis internus, received greater innervation from anterior iliotibialis motoneurons, whereas a more posterior muscle, iliofibularis, received greater innervation from posterior iliotibialis motoneurons. Furthermore, anterior iliotibialis motoneurons that reinnervated puboischiofemoralis internus occupied the rostral portion of anterior iliotibialis motor pool, which overlaps that of puboischiofemoralis internus. Anterior iliotibialis motoneurons that reinnervated iliofibularis occupied the caudal portion of the anterior iliotibialis motor pool, which overlaps that of iliofibularis. When both anterior and posterior iliotibialis were damaged so that their myofibers were permanently destroyed, the rostrocaudal origins of the motoneurons that reinnervated them were virtually the same, suggesting that the motoneurons had difficulty distinguishing between the myofiberless iliotibialis muscles. However, some iliotibialis motoneurons invaded puboischiofemoralis internus instead of their myofiberless targets. Puboischiofemoralis internus received more innervation from the anterior iliotibialis motoneurons than the positionally less appropriate posterior iliotibialis motoneurons. These data are consistent with the hypothesis that selective reinnervation of muscle depends upon a system of recognition cues based on position.

Long-term in vitro turtle preparation for the study of spinal organization.

A method by which muscles, nerves, and a section of spinal cord from a turtle can be stably maintained in vitro for many days has been developed. Tests of the viability of central and neuromuscular synapses, and the histochemical properties of muscle fibers have indicated that the preparation is viable and shows little decrement in function over a period of 3-5 days. The system allows continuous access to the muscles, nerves, and the spinal cord, as well as a controlled external environment.

Furosemide lowers intracranial pressure by inhibiting CSF production.

Furosemide administration effectively lowers intracranial pressure in newborn preterm and term rabbit pups. This effect may be due to the diuretic action of the drug, its ability to inhibit cerebrospinal fluid production or to a combination of both. To test these possibilities newborn rabbits were either injected with furosemide and left unmolested for 6 hours, or anaesthetized and subjected to ventriculocisternal perfusions. During the 6 hour postnatal period the decrease in body weight was 8 times greater in furosemide than in saline treated pups. However, no difference was noted between the average brain weights of these two groups. Secondary effects of the diuretic were noted in blood (12.5% increase in the haematocrit over control value) and in muscle in which tissue water content and NA+ concentration were decreased while K+ concentration was increased. The fact that these parameters remained unchanged in brain suggests that the lowering of intracranial pressure was not attributable to the secondary effects of the diuretic agent. However, the marked reduction in cerebrospinal production noted following furosemide administration indicates that in newborn rabbits this may represent the primary mechanism by which furosemide lowers intracranial pressure.

Activity and the formation of ocular dominance patches in dually innervated tectum of goldfish.

This study tested (1) whether blocking impulse activity in both eyes of fish with one tectum prevents the formation of ocular dominance patches, (2) whether areas receiving a high density of innervation from one eye receive a low density from the other, and (3) whether there is an electrophysiological correlate to the anatomical patches. One tectum was removed in goldfish so that the optic nerve fibers from both eyes would compete for synaptic space in the remaining tectum. The terminal arbors from the two projections initially overlapped but by 50 to 60 days segregated into ocular dominance patches, demonstrated by labeling both projections, the normal one with horseradish peroxidase and the regenerating one with tritiated proline radioautography. Alternate sections were processed for radioautography and histochemistry. All projections were drawn by "blind" observers using a camera lucida and were fully reconstructed. Both the level of patchiness within each projection and the correspondence of patches and holes between the two projections were quantified from these reconstructions. Binocular tetrodotoxin (TTX) injections from 18 to 75 days after surgery significantly reduced patchiness, as compared to controls injected with citrate-Ringers solution. When the binocular block was continued until 95 days, segregation was still significantly reduced relative to controls. These results support a hypothesis for an activity-dependent mechanism of segregation of ocular dominance patches. In controls but not TTX-blocked fish, there was a significant tendency for high density areas in one projection to receive a lower density projection from the other eye, and vice versa. However, the two projections were not entirely complementary. Survival of control fish for an additional 5 months resulted in more sharply defined patches but no increase in complementarity. Recordings of field potentials evoked by shocking either optic nerve demonstrated an electrophysiological correlate to the anatomical patches in single tectal fish. Large field potentials from one eye were generally associated with small potentials from the other eye, and vice versa. When the recording sites were marked with electrolytic lesions, there was a direct and significant correlation between the magnitude of the field potentials and the density of the anatomical ocular dominance patches.