5-HT1A receptor agonists: recent developments and controversial issues

During the last decade, serotonin (5-HT)_1A receptors have been a major target for neurobiological research and drug development. 5-HT_1A receptors have been cloned and a variety of selective agonists, such as the aminotetraline 8-OH-DPAT and the pyrimidinylpiperazine ipsapirone, have become available. Demonstrations of apparent intrinsic activity of these ligands at 5-HT_1A receptors, however, depend highly on the particular assay system. This may be due to the possible existence of receptor subtypes and to assay (or brain region)-dependent differences in receptor reserve and the nature of receptor-effector coupling. Nevertheless, the apparent intrinsic activity of 8-OH-DPAT seems to be higher (although possibly not yet maximal) than that of the pyrimidinylpiperazines. In the brain, 5-HT_1A receptors are located presynaptically as somatodendritic receptors on 5-HT neurons and postsynaptically in particular limbic and cortical regions. Although it is generally accepted that presynaptic 5-HT_1A receptors control 5-HT neuronal activity, recent evidence suggests an additional role of postsynaptic 5-HT_1A receptors in cortex as part of a negative feedback loop. Anxiolytic and antidepressive properties of selective 5-HT_1A receptor agonists have now been confirmed by clinical studies. Although it is well established that the latter properties depend on theagonistic activity of these compounds, theoptimal level of intrinsic activity is still a matter of debate and may be dependent on the clinical indication. Such compounds may also have antiaggressive effects, and possibly anticraving effects (manifested by their alcohol intake-reducing effects in dependent animals), but the specificity of these so-called anti-impulsivity effects is still controversial and not yet tested clinically. Anticataleptic, antiemetic and neuroprotective properties have been demonstrated in different species. Behavioral studies on the mechanisms underlying the anxiolytic and antidepressive effects have examined the relative contribution of pre-and postsynaptic 5-HT_1A receptors by means of local cerebral application and lesion techniques. Most evidence points towards a critical involvement of presynaptic receptors in the anxiolytic effects of 5-HT_1A receptor agonists (although a possible contribution of postsynaptic receptors cannot be excluded). With regard to the antidepressive properties, a case can be made for the reverse; i.e., a strong involvement of postsynaptic receptors and a questionable contribution of presynaptic receptors. However, as the therapeutic effects of those 5-HT_1A receptor (partial) agonists which have been tested clinically require repeated administration, attention has been directed increasingly towards chronic studies. These studies have shown that a number of electrophysiological, biochemical, behavioral and endocrinological 5-HT_1A receptor-related events adapt differentially to repeated or sustained administration. Thus, several hypotheses accounting for the delayed onset of action have been advanced. Among these, time-dependent downregulation /desensitization of eitherpre- orpostsynaptic 5-HT_1A receptors, or cortical 5-HT₂ receptors have received much attention. However, these hypotheses have their weaknesses, and it is argued thatfunctional sensitization of particular postsynaptic 5-HT_1A receptor-mediated events remains a valuable alternate hypothesis. Basic research on the role of 5-HT_1A receptors in psychopathology and in the therapeutic effects of clinically effective therapeutics, as well as on the mechanism of action of 5-HT_1A receptor ligands, will enable rational design of ligands with particular profiles of intrinsic activity at different 5-HT_1A receptor populations, and may contribute to a more efficient treatment of a multiplicity of brain disorders.     

小耳畸形残耳软骨的生物化学研究

目的　探讨正常耳软骨与先天性小耳畸形的残耳软骨生化成分的异同 ,进而推论小耳畸形的病因。方法　选取年龄在 10岁左右 ,Tanzer分类ⅡA型的 7例先天性小耳畸形患者的残耳软骨 (A组 )。同时取 7名同龄尸体的正常耳廓耳甲部分的软骨 (B组 )。各取 7份标本做生化检查 ,测定胶原、糖胺多糖 (glycoaminoglycan ,GAG)含量 ;硫酸软骨素 (chondroitinsulfate,Chs)、硫酸角质素 (keratansulfate ,KS)和透明质酸 (hyaluronan ,HA)各占GAG的百分含量。结果　A组与B组之间胶原含量差异无显著性意义 ;GAG含量差异有显著性意义A组 (49.0 0± 2 5 .6 0 ) μg/mg比B组 (2 8.2 5± 4 .80 ) μg/mg多。在GAG中的组成部分中 ,A组HA(38.96± 4 .97) %、Chs(2 9.0 2± 4 .12 ) %、KS(32 .16± 7.4l) %与B组HA(32 .94± 3.2 4 ) %、Chs(33.10± 2 .6 1) %、KS(33.96± 1.6 6 ) %之间HA和Chs含量差异有显著性意义 ,而KS含量差异无显著性意义。结论　残耳软骨与正常耳软骨中胶原含量无差异 ,但含GAG前者比后者多。在GAG中的各成分的百分含量中 ,残耳软骨含HA较高 ,Chs较低 ,KS与正常耳软骨无差异。     

An improved method for the isolation of the major protein of the gonococcal outer membrane in an antigenically reactive form

The major outer membrane protein (protein I) has been isolated from Neisseria gonorrhoeae strain P9 in an immunologically reactive form. Membranes were sequentially extracted with the detergents sodium cholate and Empigen BB. Protein I was enriched in the Empigen-soluble fraction and was separated from other proteins and lipopolysaccharide by gel filtration chromatography on Sephadex G-200. The purified protein retained its antigenic activity with antiserum raised against the unfractionated outer membrane complex.     

The site of synthesis and functions of acute phase plasma proteins: Close relation-ship with the reticulo-endothelial system

The evidence that the acute phase glycoproteins of plasma are synthesized by the liver parenchymal cells is critically examined, and is found to be inconclusive. Some evidence is cited which favors the reticulo-endothelial system (RES) in general, and Kupffer cells in particular, as the site of synthesis of these proteins: 1. The entire RES contains non-glycogenic periodic acid Schiff-positive substances. 2. The diseases which affect glycoprotein levels are also known to affect the function of the RES. 3. When the animal is subjected to stress, the RES function is initially depressed and then stimulated. A similar biphasic behavior is shown by plasma glycoprotein levels. 4. Adrenal cortico-steriods are the major regulators of the RES function and of the synthesis of acute phase proteins. Moreover, both are stimulated at low concentrations, and depressed at high concentrations of the hormone. Some of the glycoproteins of the acute phase (prothrombin, the third component of complement, haptoglobin, transferrin and ceruloplasmin) have defense-related functions. The others seem to participate in phenomena like detoxification, promotion of phagocytosis, wound healing, prevention of tissue injury by lysosomal enzymes, prevention of trauma and recovery from inflammation. It is proposed that the acute phase proteins, together with antibodies, form major components of the defense system, and the RES attempts to deal with injury by mobilization of increased amounts of these substances.     

Comparison of Biochemical Parameters of Human Blood Serum and Seminal Plasma

Blood and semen samples obtained from 24 "normal" volunteers were analyzed for 16 different biochemical parameters. These included: Ca, Mg, K, Na, Zn, Cl, P, glycerolphosphorylcholine (GPC), carnitine, fructose, uric acid, prostatic acid phosphatase, alkaline phosphatase, glutamic oxaloacetic transaminase (SGOT), lactic dehydrogenase (LDH), and glutamic pyruvate transaminase (SGPT). With the exception of uric acid, all the biochemical constituents in seminal plasma were either significantly higher (p less than 0.001, except alkaline phosphatase which was significant at p less than 0.05) or significantly lower (p less than 0.001) than in blood serum. Further, potassium (r = 0.51); carnitine (r = 0.54); and SGOT (r = 0.70) showed a significant direct relationship in blood and seminal plasma.     

Graded changes in enamel component volumes resulted from a short tooth bleaching procedure

AimTo test the hypothesis that changes in enamel component volumes (mineral, organic, and water volumes, and permeability) are graded from outer to inner enamel after a short bleaching procedure.Materials and methodsExtracted unerupted human third molars had half of their crowns bleached (single bleaching session, 3 × 15 min), and tooth shade changes in bleached parts were analyzed with a spectrophotometer. Ground sections were prepared, component volumes and permeability were quantified at histological points located at varying distances from the enamel surface (n = 10 points/location), representing conditions before and after bleaching.ResultsTooth shade changes were significant (p < 0.001; 95% CI = −1/−8; power = 99%), and most of the enamel layer was unaffected after bleaching, except at the outer layers. Multiple analysis of covariances revealed that most of the variance of the change in enamel composition after bleaching was explained by the combination of the set of types of component volume (in decreasing order of relevance: mineral loss, organic gain, water gain, and decrease in permeability) with the set of distances from the enamel surface (graded from the enamel surface inward) (canonical R² = 0.97; p < 0.0001; power > 99%).ConclusionsChanges in enamel composition after a short bleaching procedure followed a gradient within component volumes (mineral loss > organic gain > water gain > decrease in permeability) and decreased from the enamel surface inward.     

No reduction of metabolic rate in food restricted Caenorhabditis elegans

Dietary restriction (DR) is the most consistent means of extending life span throughout the animal kingdom. Multiple mechanisms by which DR may act have been proposed but none are clearly predominant. We asked whether metabolic rate and stress resistance is altered in Caenorhabditis elegans in response to DR. DR was imposed in two complementary ways: by growing wild-type worms in liquid medium supplemented with reduced concentrations of bacteria and by using eat-2 mutants, which have a feeding defect. Metabolic rate was not reduced when we fed wild-type worms reduced food and was up-regulated in the eat-2 mutants in liquid culture, as assessed by oxygen consumption rate and heat production. The specific activity levels of the antioxidant enzymes superoxide dismutase (SOD) and catalase showed small increases when we reduced food in wild-type worms, but restricted worms acquired no elevated protection against paraquat and hydrogen peroxide. eat-2 mutants showed elevated specific activities of SOD and catalase relative to wild type in liquid culture. These results indicate that the effects imparted by DR and the eat-2 mutation are not identical, and they contradict, at least in C. elegans, the widespread belief that CR acts by lowering the rate of metabolism.     

Normalization of urinary oxalate by taurine in glycolate-fed rats

Oral feeding of sodium glycolate (50 mg/d/rat for ten days) caused a significant (P less than 0.001) increase in oxalate and taurine excretion and a decrease in liver protein content (P less than 0.05), glycolic acid oxidase levels (P less than 0.01), and glycolic acid dehydrogenase levels (P less than 0.01) as compared to normal untreated rats. Taurine (100 mg/d/rat), when administered along with glycolate, prevented these effects of glycolate as evident from normal urinary excretion of oxalate, liver protein content, glycolic acid oxidase, and glycolic acid dehydrogenase levels in glycolate- plus taurine-fed animals.     

Experimental toxicology of formaldehyde

Summary Formaldehyde is a reactive chemical which undergoes spontaneous reactions with various cellular constituents. Mutagenicity data may be interpreted on the background of this behavior. Mice are better able to reduce the irritating effect of formaldehyde than rats and to reduce their ventilation rate when formaldehyde acts on the respiratory tract. Subacute exposure of rats to concentrations higher than 2 ppm inhibits mucociliary clearance of the nasal epithelium and leads to progressive histological and ultrastructural lesions at this site. The occurrence of squamous cell carcinomas of the nasal epithelium of rats after 2 years inhalation of 14.3 ppm formaldehyde (CIIT study) is probably the result of chronic and recurrent local toxicity; this is supported by species differences in susceptibility to the tissue damaging and carcinogenic effect of formaldehyde (rat, mouse, hamster). Data on formaldehyde-DNA interaction further support the argument that a direct risk extrapolation from the formaldehyde effects in rats to those expected for man is not possible.Cancer Research and Clinical Oncology will publish in loose succession Editorials and Guest Editorials on topical and controversial problems in experimental and clinical oncology. These contributions will represent the personal opinion of the author. We would like to ask our readers to send their comments directly to the author.