Eye-tracking patterns in schizophrenia. An analysis based on the incidence of saccades.

Saccades occurring when tracking a sine-wave target and when fixating a stationary target were studied in the following three groups: schizophrenics, other psychiatric inpatients, and normal controls. The frequency of saccades when tracking and when fixating was significantly greater among schizophrenics than among the two comparison groups. The pattern of occurrence of saccades within cycles of the sine movement was similar in the three groups; the greatest occurrence was at the highest target velocity and the lowest occurrence was at reversal points. The data are interpreted as consistent with the hypothesis of a failure on inhibiting mechanisms.

New arylpiperazine derivatives as antagonists of the human cloned 5-HT(4) receptor isoforms.

New derivatives of arylpiperazine 9 were designed from ML 10302, a potent 5-HT(4) receptor agonist in the gastrointestinal system. Compounds were synthesized by condensation of a number of available arylpiperazines or heteroarylpiperazines with 2-bromoethyl 4-amino-5-chloro-2-methoxybenzoate. They were evaluated in binding assays on the recently cloned human 5-HT(4(e)) isoform stably expressed in C6 glial cells with [(3)H]GR 113808 as the radioligand. The affinity values (K(i)) depended upon the substituent on the aromatic ring. A chlorine atom produced a marked drop in activity (K(i) > 100 nM), while a m-methoxy group gave a compound with nanomolar affinity (K(i) = 3 nM). The most potent compounds were the heterocyclic derivatives with pyrimidine, pyrazine, pyridazine, or pyridine moieties (compounds 9r, 9t, 9u, 9x, respectively). K(i) values for 9a and 9r were determined for the 5-HT(4(a)), 5-HT(4(b)), 5-HT(4(c)), and 5-HT(4(d)) receptor isoforms transiently expressed in COS cells. The results indicated that the compounds were not selective. They produced an inhibition of the 5-HT-stimulated cyclic AMP synthesis in the C6 glial cells stably expressing the 5-HT(4(e)) receptor and shifted the 5-HT concentration-effect curve on adenylyl cyclase activity with pK(D) values of 7.44 and 8.47, respectively. In isolated human atrial myocytes, 9r antagonized the stimulatory effect of 5-HT on the L-type calcium current (I(Ca)) with a K(D) value of 0.7 nM.

Pharmacological characterization of the human 5-HT(4(d)) receptor splice variant stably expressed in Chinese hamster ovary cells.

The recently identified C-terminal splice variant of the human 5-HT(4) receptor, the h5-HT(4(d)) receptor, was stably expressed in a CHO cell line at 493+/-25 fmol mg(-1) protein. We analysed its pharmacological properties by measuring binding affinities and 5-HT(4) ligand-induced cyclic AMP production. The pharmacological binding profile determined in competition studies with the specific antagonist [(3)H]-GR113808 revealed a rank order of affinity of 5-HT(4) ligands for the h5-HT(4(d)) receptor that was consistent with those previously reported for other 5-HT(4) receptor isoforms. In adenylyl cyclase functional assays, the h5-HT(4(d)) receptor displayed equipotent coupling for all 5-HT(4) agonists tested (EC(50) in the range of 1 - 6 nM). EC(50) values were lower than those previously obtained with the 5-HT(4(e)) receptor stably expressed in CHO cells indicating that the 5-HT(4(d)) receptor was more efficiently coupled to its effector than the 5-HT(4(e)) receptor isoform. Moreover, in terms of agonist efficacy (E(max)), the benzamide derivative, renzapride displayed full agonist properties at the h5-HT(4(d)) receptor (same E(max) as 5-HT) whereas it was previously shown to be a partial agonist at the h5-HT(4(e)) receptor. A constitutive activity of the h5-HT(4(d)) receptor was observed in CHO cells in the absence of any 5-HT(4) ligand. Surprisingly, two 5-HT(4) ligands, SB204070 and RS39604 which are described as highly potent antagonists in various biological models, revealed partial agonist properties at the h5-HT(4(d)) receptor. We conclude that C-terminal tails of 5-HT(4) receptor isoforms may directly influence their functional properties.

Exploration of the ligand binding site of the human 5-HT(4) receptor by site-directed mutagenesis and molecular modeling.

Among the five human 5-HT(4) (h5-HT(4)) receptor isoforms, the h5-HT(4(a)) receptor was studied with a particular emphasis on the molecular interactions involved in ligand binding. For this purpose, we used site-directed mutagenesis of the transmembrane domain. Twelve mutants were constructed with a special focus on the residue P4.53 of helix IV which substitutes in h5-HT(4) receptors the highly conserved S residue among the rhodopsin family receptors. The mutated receptors were transiently expressed in COS-7 cells. Ligand binding or competition studies with two h5-HT(4) receptor agonists, serotonin and ML10302 and two h5-HT(4) receptor antagonists, [(3)H]-GR113808 and ML10375 were performed on wild type and mutant receptors. Functional activity of the receptors was evaluated by measuring the ability of serotonin to stimulate adenylyl cyclase. Ligand binding experiments revealed that [(3)H]-GR113808 did not bind to mutants P4.53A, S5.43A, F6.51A, Y7.43A and to double mutant F6.52V/N6.55L. On the other hand mutations D3.32N, S5.43A and Y7.43A appeared to promote a dramatic decrease of h5-HT(4(a)) receptor functional activity. From these studies, S5.43 and Y7.43 clearly emerged as common anchoring sites to antagonist [(3)H]-GR113808 and to serotonin. According to these results, we propose ligand-receptor complex models with serotonin and [(3)H]-GR113808. For serotonin, three interaction points were selected including ionic interaction with D3.32, a stabilizing interaction of this ion pair by Y7.43 and a hydrogen bond with S5.43. [(3)H]-GR113808 was also docked, based on the same type of interactions with S5.43 and D3.32: the proposed model suggested a possible role of P4.53 in helix IV structure allowing the involvement of a close hydrophobic residue, W4.50, in a hydrophobic pocket for hydrophobic interactions with the indole ring of [(3)H]-GR113808.

Isolation of the serotoninergic 5-HT4(e) receptor from human heart and comparative analysis of its pharmacological profile in C6-glial and CHO cell lines.

RT - PCR technique was used to clone the human 5-HT(4(e)) receptor (h5-HT(4(e))) from heart atrium. We showed that this h5-HT(4(e)) receptor splice variant is restricted to brain and heart atrium. Recombinant h5-HT(4(e)) receptor was stably expressed in CHO and C6-glial cell lines at 347 and 88 fmol mg(-1) protein, respectively. Expression of h5-HT(4(e)) receptors at the cell membrane was confirmed by immunoblotting. The receptor binding profile, determined by competition with [(3)H]-GR113808 of a number of 5-HT(4) ligands, was consistent with that previously reported for other 5-HT(4) receptor isoforms. Surprisingly, we found that the rank order of potencies (EC(50)) of 5-HT(4) agonists obtained from adenylyl cyclase functional assays was inversely correlated to their rank order of affinities (K(i)) obtained from binding assays. Furthermore, EC(50) values for 5-HT, renzapride and cisapride were 2 fold lower in C6-glial cells than in CHO cells. ML10302 and renzapride behaved like partial agonists on the h5-HT(4(e)) receptor. These results are in agreement with the reported low efficacy of the these two compounds on L-type Ca(2+) currents and myocyte contractility in human atrium. A constitutive activity of the h5-HT(4(e)) receptor was observed in CHO cells in the absence of any 5-HT(4) ligand and two 5-HT(4) antagonists, GR113808 and ML10375, behaved as inverse agonists. These data show that the h5-HT(4(e)) receptor has a pharmacological profile which is close to the native h5-HT(4) receptor in human atrium with a functional potency which is dependent on the cellular context in which the receptor is expressed.

Two-dimensional anxiety: A confirmation using a computerized neuropsychological testing of attentional performance.

The aim of this study was to assess the effects of anxiety on attentional performance with neutral stimuli. It was set up as follows: a fourfold comparison was made of trait anxiety and state anxiety. Sixty-two undergraduate students were included in the study, and four groups of subjects were set up by a median split of the scores obtained on the Spielberger Trait and State Anxiety Inventory (STAI): high trait-high state (N = 18); high trait-low state (N = 11); low trait-low state (N = 23); low trait-high state (N = 10). A computerized battery of neuropsychological tests, the ACE battery, was administered to provide a multidimensional assessment of attention. The ACE battery comprises five tests which assess the following aspects of attention: ability to monitor a routine task; temporal preparation; visual detection; memory span; visual spatial attention and memory. High state anxious subjects displayed impairment in executive functions, manifested by a significantly higher level of motor preparation in a simple reaction time (RT) task and a speed accuracy trade-off in a divided attention task; high trait anxious subjects performed significantly better on the visual detection task. No trait x state interaction was found. It was concluded that high state anxiety is associated with psychomotor alertness and high trait anxiety with perceptual alertness. These two dimensions of psychometric anxiety seem to have effects on attention that are independent of one another and which should be analysed separately in the future.

[Childhood aphasia with epilepsy. Remission with antiepileptic treatment]. / Aphasie de l'enfant avec épilepsie. Evolution régressive sous traitement antiépileptique

The authors describe an example of an aphasic syndrome peculiar to children. This syndrome, which has previously been described by several authors, is characterized by an unusual form of aphasia, by its association with epileptic attacks, and by its onset in the absence of any apparent aetiology. In such cases, the effectiveness of anti-epileptic treatment on the aphasia is variable, often quite poor; on the other hand, in the case described in this report, administration of anti-epileptic treatment was followed by spectacular regression of the aphasia.

[Visual tracking disorders in schizophrenia. Review of the literature and methodological considerations]. / Les perturbations de la poursuite visuelle dans la schizophrénie. Revue de la littérature et considérations méthodologiques.

Since Holzman expressed the hypothesis that eye-tracking dysfunctions might be a genetic indicator of schizophrenia, the researches on the performances of schizophrenics in eye-tacking tasks have been numerous. The correlation between the results of all these researches leaves little doubt on the existence of eye-tacking dysfunctions in schizophrenics. But these distrubances must be precised. Up to now, the studies have used tests that were too complex in their interpretation (pendulum test) and they have been limited to a global appreciation of eye-tacking. To take into account the psychological parameters that may interfere with success in this type of tests, the coming researches should focus on elementary eye-motor activities.

[Present trends in biological psychiatry research on psychoses (author's transl)]. / Orientation actuelle des recherches en psychiatrie biologique dans les psychoses.

Most of the present biological hypothesis postulate biogenic amines disorders in schizophrenia: transmethylation and dopaminergic theory. Other systems which can modulate this neuro-transmitter, specially in the mesolimbic dopaminergic system, may be concerned: nor-epinephrine, serotonin or endorphins. A dysfunction in arousal and cerebral dominance has been described by the quantitative electroencephalography. Other electrophysiological studies are consistent with these results; they indicate an impairment of the level of arousal to which the disorders of attention and adaptation could be related. In affective psychoses the major hypothesis bear on norepinephrine or serotonin disorders. But other substances may have a role: acetylcholine and dopamine as well as electrolytic modifications of cell membranes or immunological or neuroendocrine disturbances. This biological and physiological fundamental research has numerous practical consequences as the discovery of compounds with a more specific effect, the research of biological and biochemical diagnostic indices, or the drawing up of biological indices for neuroleptics, antidepressants or lithium sensitivity.

[Exploration of memory disorders in anxiety states]. / Exploration des troubles de la mémoire dans les états anxieux.

According to cognitive model of anxiety, memory process in anxious patients is usually tested by comparing the incidental recall of positive and negative, threatening and non threatening, self and other-referenced words. Contrary to expectation, the results indicate relatively poorer memory for threatening material in anxious patients and no bias in favour of the recall of self referent negative words. At the opposite this memory bias can be evidenced in patients with panic disorder. The bias for anxiety words is better evidenced in the subgroups with the higher arousal level or when there is a mood induction by reading first an anxiogenic text. Consistent with prediction a perceptive pre-attentional bias can be shown for the great majority of the subjects studied in recent researches.

[Normality, normativity and marginality]. / Normalité, normativité et marginalité.

Different points of view about sense of "normality" for psychiatrists are reviewed. It appears that there is not any satisfactory criterion which defines the limit between normal and abnormal. In the field of mental processes, normality is a valuation which is not independent of the psychiatrist's own values, and of his socio-cultural mode of thinking. One of the consequences of this is the risk of "normativity". Normativity indeed terms the imposition of norms on the subject which correspond to the ideal of the psychiatrist or to the ideal of the society, without respecting the individuality of the subject. It is recalled that social abnormality, or "marginality", i.e. the non-respect of social norms, should not be confused with psychiatric abnormality.

Impaired attention in depressive states: a non-specific deficit?

Although cognitive research on attention has advanced significantly in recent years, these advances have produced few specific hypotheses regarding the attentional impairment seen in depression, and few experiments designed to test them. We review the limited neuropsychological literature on impaired attention in depressive states, with emphasis on areas where the findings of modern cognitive research might be applied in the future to design more sophisticated tests of attentional impairment. At present, it is not possible to determine whether the attentional deficits seen in depression are specific to this disorder, or whether they represent a final common pathway of impaired cognition seen in many different mental and organic deficit states, such as schizophrenia and dementias.

Bulimia in the late nineteenth century: the observations of Pierre Janet.

In 1903 Pierre Janet published perhaps the first detailed descriptions of patients with bulimia. Janet's observations, although anecdotal, are consistent with modern studies suggesting an association between bulimia and major affective disorder and between bulimia and anxiety disorders. Janet's writings also support the belief that bulimia is more prevalent today than a century ago.

Evidence for a sex-specific residual effect of cannabis on visuospatial memory.

BACKGROUND: In an exploratory study, we used a novel computerized battery of neuropsychological tests of attention to assess residual cognitive impairment in marijuana users. METHODS: We compared 25 college students who were heavy marijuana smokers (who had smoked a median of 29 days in the last 30 days) with 30 students who were light smokers (who had smoked a median of 1 day in the last 30 days). All subjects were tested after a supervised period of abstinence from marijuana and other drugs lasting at least 19 h. RESULTS: Differences between the overall groups of heavy and light smokers did not reach statistical significance on the four subtests of attention administered. However, upon examining data for the two sexes separately, marked and significant differences were found between heavy- and light-smoking women on the subtest examining visuospatial memory. On this test, subjects were required to examine a 6 x 6 'checkerboard' of squares in which certain squares were shaded. The shaded squares were then erased and the subject was required to indicate with the mouse which squares had formerly been shaded. Increasing numbers of shaded squares were presented at each trial. The heavy-smoking women remembered significantly fewer squares on this test, and they made significantly more errors than the light-smoking women. These differences persisted despite different methods of analysis and consideration for possible confounding variables. CONCLUSIONS: This observation suggests that it may be important to study the residual effects of marijuana on men and women separately-particularly since women have been greatly underrepresented in previous studies in this area.

Anti-SSA/Ro52 autoantibodies blocking the cardiac 5-HT4 serotoninergic receptor could explain neonatal lupus congenital heart block.

The 52-kDa SSA/Ro (Ro52) ribonucleoprotein is an antigenic target strongly associated with the autoimmune response in mothers whose children develop neonatal lupus and congenital heart block. When sera from patients with systemic lupus erythematosus were used as autoimmune controls in an enzyme immunoassay to screen for antibodies against the human serotoninergic 5-HT4-receptor, a high correlation was found between the presence of anti-Ro52 protein antibodies in such sera and antibodies reacting with a synthetic peptide, corresponding to the second extracellular loop of the human 5-HT4 receptor (amino acid residues 165-185). Homology scanning between the 5-HT4 peptide and the sequence of the Ro52 protein indicated two potential common epitopes located between residues 365 and 396 of the Ro52 protein. Cross-reactivity was found between the peptide derived from the 5-HT4 receptor, and a peptide corresponding to residues 365-382 of the Ro52 protein. Autoantibodies, affinity-purified on the 5-HT4 receptor peptide, specifically recognized both the Ro52 protein and the 5-HT4 receptor protein in immunoblots. The affinity-purified antibodies antagonized the serotonin-induced L-type Ca channel activation on human atrial cells. This effect could explain the electrophysiological abnormalities in neonatal lupus.