Effect of SR 59026A, a new 5-HT(1A) receptor agonist, on sexual activity in male rats.

The effect of SR 59026A, a new selective 5-HT(1A) receptor agonist, was evaluated on sexual behaviour of male rats in different experimental conditions. SR 59026A (1-10mg/kg p.o.) stimulated the copulatory behaviour of sexually experienced rats, as evidenced by a decrease in the number of pre-ejaculatory mounts and intromissions and a shortening of the ejaculation latency. SR 59026A also facilitated the sexual behaviour of naive male rats characterized by a low level of sexual performance: over the same dose range, the percentage of naive males that copulated was significantly increased and the ejaculation latency reduced. In experiments designed to evaluate the onset of sexual satiation, SR 59026A (1 and 3mg/kg) increased significantly the number of ejaculations and delayed the time of sexual satiation. Finally, in agreement with studies on other 5-HT(1A) receptor agonists, SR 59026A did not modify the occurrence of spontaneous erections in isolated male rats. Therefore, the present study shows that SR 59026A improves the sexual performance of male rats in a number of different experimental models, and the compound may prove to be of interest for the treatment of certain states of human male sexual dysfunction.

Neurotensin receptor interaction with dopaminergic systems in the guinea-pig brain shown by neurotensin receptor antagonists.

Neurotensin has been suggested to be involved in neurological and mental disorders associated with altered dopaminergic transmission. The lack of a potent neurotensin receptor antagonist had prevented us from studying the real physiological implication of this peptide in brain function. We thus recently developed such a non-peptide neurotensin receptor antagonist, SR 48692, (2-(1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole- 3-carbonyl)amino)-adamantane-2-carboxylic acid), which appeared to be potent in various central and peripheral preparations. In the present study, we tested the pharmacological properties of SR 48692 and of two optically synthetic analogs of this compound on neurotensin binding to both adult guinea-pig brain membrane homogenates and coronal brain sections, as well as on neurotensin stimulation of the K(+)-evoked release of [3H]dopamine in guinea-pig striatal slices. Our results demonstrated that (1) high-affinity neurotensin binding sites are present in the guinea-pig brain in regions rich in both dopamine cell bodies and terminals; (2) the binding of neurotensin is inhibited by SR 48692 and its related S(+) active analog, SR 48527, with IC50 values in the nM range and (3) the non-peptide antagonist has no agonist effect but antagonizes neurotensin-induced [3H]dopamine release from guinea-pig striatal nerve terminals.

A 3D model of the peripheral benzodiazepine receptor and its implication in intra mitochondrial cholesterol transport.

A three-dimensional (3D) model of the peripheral benzodiazepine receptor (PBR) has been built using molecular dynamics simulations. The transmembrane domain of the receptor has been modeled as five alpha-helices, which are not long enough to cross the entire bilayer membrane but correspond approximately to only one phospholipid layer. The receptor model has also been tested as a cholesterol carrier, and molecular dynamics simulations have shown that it could indeed accommodate a cholesterol molecule within the five helices. All three known PBR sequences have been modeled, and no significant difference has been found between them.

Peripheral benzodiazepine receptor modulation with phagocyte differentiation.

Peripheral benzodiazepine receptor (PBR) was found to be less expressed in the immature phagocytic HL-60 and U-937 cell lines than in the more mature monocytic THP-1 cell line. Cell differentiation by several agents induced a strong enhancement of PBR density on these three phagocytic cell lines but not on the lymphocytic CEM cell line. Detailed analysis of phorbol 12-myristate 13-acetate-treated THP-1 cells showed an increased PBR expression and the rise came along with an increase of CD11a and CD11b antigens and a secretion of macrophagic cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta and IL-8. Quantitation of mRNA using polymerase chain reaction (PCR)-based technique showed that overexpression of PBR did not parallel mRNA expression, indicating a gene-independent regulation. These results suggest that PBR predominance on phagocytic cells could be related to maturation process.

Molecular cloning of a human beta 3-adrenergic receptor cDNA.

We report the molecular cloning of a beta 3-adrenergic receptor [beta 3-AR] cDNA from human brown adipose tissue. The cDNA-encoded protein is identical to the previously cloned beta 3-AR but with 6 additional amino acids at the C-terminus. The C-terminus is shared by the beta 3 receptors expressed in human neuroblastoma cells [SK-N-MC] [Mol. Pharmacol. 42 (1992) 964-970]. Furthermore, using a polymerase chain reaction strategy we have cloned and sequenced the beta 3-AR introns. Sequence analysis demonstrates that the human beta 3-AR gene comprises at least 3 exons and 2 introns and that the most abundant beta 3-AR transcripts encode a protein with an exon 3-derived C-terminus. Interestingly, although a similar organization has been found in rodent genes, the rat beta 3-AR transcripts encode a receptor with an exon 2-derived C-terminus.

[Platelet monoamine oxidase and sex hormones in a population of depressed patients]. / Monoamine oxydase plaquettaire et hormones sexuelles dans une population de déprimés.

The association between changes in platelet MAO activity and Major Depressive Episode have been demonstrated. Cyclical changes in sex hormones serum levels had never been related with changes of MAO activity in depressed patients. Platelet MAO activity, oestrogen serum levels, progesterone serum levels and testosterone serum levels, have been measured in drug free depressed patients: 22 men and 42 women. This study demonstrates no relationship between serum levels hormons and platelet MAO activity, measured in men and in women. If young women are separated from menopaused women, platelet MAO activity is negatively correlated with oestrogen serum levels, in non menopaused women. Significance of this variation in studies about the use of MAO as a biochemical marker in depression is discussed.

[Methylation of erythrocyte membrane phospholipids: correlation with membrane viscosity. Study of normal and parkinsonian subjects]. / Méthylation des phospholipides de la membrane érythrocytaire: corrélation avec la viscosité membranaire. Etude de sujets normaux et Parkinsoniens.

Plasma membranes from erythrocytes were used to study various parameters: phospholipid methylation, viscosity and fragility. These parameters were analysed in 57 normal subjects (52 +/- 3 years old) and 14 patients with idiopathic Parkinson's disease without previous treatment (71 +/- 2 years old). No significant correlations were observed between the various parameters and sex or age in the normal group. No correlation was observed between fragility and methylation or viscosity. A statistically significant correlation was found between viscosity and phospholipid methylation. In the patients with Parkinson's disease, fragility is identical to the normal group but the viscosity is increased by 25 p. 100. The increase of viscosity is more obvious among the patients with a pure or predominantly akinetic form of the disease. These results favour the previously described correlation between phospholipid methylation and viscosity of the plasma membrane and suggest a modification of these parameters in Parkinson's disease. They also suggest that the increased viscosity observed in Parkinson patients could render the receptors inaccessible to their endogenous ligands.

Detection of binding sites for spiroperidol on leukemic cells: its value for the phenotype characterization of lymphoid leukemias.

The specific binding of the dopamine antagonist spiroperidol was studied in leukemic cell samples of various phenotypes. Among these only B-cell samples from chronic lymphocytic leukemias (7/7) and some "null" cell samples from acute lymphoblastic leukemias (2/7) showed specific binding. B cells from a prolymphocytic leukemia were negative as were also T-lymphoïd and non-lymphoïd leukemic cells at different stages of maturation. This pattern can be clearly correlated with the previous results obtained with normal blood cells and on cell lines. Moreover, it suggests that the detection of spiroperidol binding sites could provide a new means of distinguishing different phenotypes among B cells and early lymphoïd cells. Our results open the way to further studies which might show a correlation between spiroperidol binding sites and the new immunological markers defining subsets among non-T lymphoïd cells, as well as defining their physiological meaning.

[L-Methionine treatment of Parkinson's disease: preliminary results]. / Traitement de la maladie de Parkinson par la L. méthionine. Premiers résultats.

Eleven patients with previously untreated Parkinson's disease were treated with L-Methionine for periods from 2 weeks to 6 months. The treatment was well supported and good improvement in clinical signs, particularly akinesia and rigidity, appeared within approximately three weeks, the effect on tremor being less marked. Therapeutic effects were similar to those observed with L-dopa treatment. Correlation of clinical effects with a marked increase in the number of 3H-Spiroperidol binding sites (Bmax) to lymphocytes was noted. This therapeutic effect suggests the role played by modifications of membrane fluidity on dopaminergic receptors, both lymphocytic and striatal, in the etiology of Parkinson's disease, and opens up new therapeutic possibilities in this disease.