The effects of psychoactive agents on calcium uptake by preparations of rat brain mitochondria

The effects of chlorpromazine and other psychoactive agents on the uptake of calcium by partially purified preparations of mitochondria from rat brain were studied in vitro. Chlorpromazine at concentrations of about 0-1 ITIM caused a marked inhibition of mitochondrial calcium transport. Perphenazine also exhibited this action and was slightly more potent than chlorpromazine. Imipramine inhibited mitochondrial calcium uptake but higher concentrations were necessary than in experiments with chlorpromazine. The sulph-oxide of chlorpromazine did not inhibit calcium transport when tested at concentrations similar to those used with chlorpromazine. Up to concentrations of 20 mM, lithium ions did not influence mitochondrial calcium uptake.     

Effects of psychoactive agents on GABA binding processes

Recent in vitro studies have revealed that benzodiazepines, opiates, barbiturates and ethanol might influence GABA binding to CNS membrane sites. Further studies of such interactions might be helpful for explaining both the mechanisms of action of these psychoactive agents and the tolerance/dependence that might result from their continued use.     

Non-cancer effects of chemical agents on children's health

This paper provides an overview about the non-cancer health effects for children from relevant chemical agents in our environment. In addition, a meta-analysis was conducted on the association between sudden infant death syndrome (SIDS) and maternal smoking during pregnancy as well as postnatal exposure to environmental tobacco smoke (ETS).In children, birth deformities, neurodevelopment, reproductive outcomes and respiratory system are mainly affected by chemical exposures. According to recent systematic reviews, evidence is sufficient for cognitive impairments caused by low lead exposure levels. Evidence for neurotoxicity from prenatal methylmercury exposure is sufficient for high exposure levels and limited for low levels. Prenatal exposure to polychlorinated biphenyls (PCB) and related toxicants results in cognitive and motor deficits.Maternal smoking during pregnancy is a risk factor for preterm birth, foetal growth deficit and SIDS. The meta-analytic pooled risk estimate for SIDS based on 15 studies is 2.94 (95% confidence interval: 2.43–3.57). Postnatal exposure to ETS was found to increase the SIDS risk by a factor of 1.72 (95% CI: 1.28–2.30) based on six studies which took into account maternal smoking during pregnancy. Additionally, postnatal ETS exposure causes acute respiratory infections, ear problems, respiratory symptoms, more severe asthma, and it slows lung growth. These health effects are also of concern for postnatal exposure to ambient and indoor air pollution.Children differ from adults with respect to several aspects which are relevant for assessing their health risk. Thus, independent evaluation of toxicity in childhood populations is essential.     

The effect of serotonergic agents on haloperidol-induced catalepsy

The effect of various classes of serotonergic agents on haloperidol-induced catalepsy was evaluated in male Sprague-Dawley rats. The 5-HT-1A agonists buspirone, ipsapirone and 8-OH-DPAT all potently reversed catalepsy. The mixed 5-HT-1A and 5-HT-1B agonist RU 24969 reversed catalepsy only at the highest dose tested. The non-selective 5-HT-1 antagonist (l)-propranolol did not affect catalepsy. The 5-HT-2 agonist DOI and 5-HT-2 antagonist mesulergine both reversed catalepsy. ICS 205-930 (5-HT-3 antagonist) reversed catalepsy at low doses only. Another 5-HT-3 antagonist, GR 38032F, had no effect on catalepsy. These studies suggest that 5-HT-1A and 5-HT-2 receptor sites are important in the serotonergic modulation of haloperidol-induced catalepsy.     

Multiple populations of serotonin receptors may modulate the behavioral effects of serotonergic agents

In order to establish a functional role for the various populations of serotonin (5-HT) receptors, behavioral studies have been conducted over the past decade with serotonergic agonists and antagonists. And, although there is reason to believe that certain behavioral effects may be mediated via particular populations of 5-HT receptors, evidence now suggests that some serotonin-mediated behaviors may be modulated by the interaction of serotonergic agents at multiple subtypes of 5-HT receptors. The generality of these effects, and the exact mechanism(s) by which they occur, have yet to be elucidated. Nevertheless, over the past year, results from several different laboratories provide a growing recognition of this novel phenomenon.     

Effects of serotonergic agents on plasma prolactin levels in pyridoxine-deficient adult male rats

Plasma concentration of prolactin was significantly reduced in pyridoxine-deficient as compared to control (pyridoxine-supplemented) adult male rats. Administration of pyridoxine to deficient rats resulted in a significant increase in plasma prolactin. The reduction in plasma prolactin in pyridoxine-deficient rats corresponded with the significantly reduced hypothalamic contents of pyridoxal phosphate and serotonin in pyridoxine-deficient rats. Plasma prolactin concentrations were also measured in response to serotonergic agents in both groups of rats. The administration of the 5HT_1A agonist (8-hydroxy 2-n-dipropylamino tetralin) resulted in a significant increase in plasma prolactin and that of the specific 5HT_1A antagonist spiroxatrine had the opposite effect. The results suggest that the hypothalamic serotonergic regulation of prolactin release is impaired in pyridoxine deficiency.     

胃肠道微生态系统及其功能研究

随着生物技术和生理科学研究的不断深入,人们对胃肠道微生物生态及其功能的研究取得了重大进步。对胃肠道微生物的多样性、不同生理时期微生物菌群的演化和特定微生物种属的研究有新的发现。胃肠道微生物生态系统的生理功能得到不断的揭示,成为许多学者和多个学科关注的焦点。     

Influence of early stress on social abilities and serotonergic functions across generations in mice

Exposure to adverse environments during early development is a known risk factor for several psychiatric conditions including antisocial behavior and personality disorders. Here, we induced social anxiety and altered social recognition memory in adult mice using unpredictable maternal separation and maternal stress during early postnatal life. We show that these social defects are not only pronounced in the animals directly subjected to stress, but are also transmitted to their offspring across two generations. The defects are associated with impaired serotonergic signaling, in particular, reduced 5HT1A receptor expression in the dorsal raphe nucleus, and increased serotonin level in a dorsal raphe projection area. These findings underscore the susceptibility of social behaviors and serotonergic pathways to early stress, and the persistence of their perturbation across generations.     

Off-target effects of psychoactive drugs revealed by genome-wide assays in yeast

To better understand off-target effects of widely prescribed psychoactive drugs, we performed a comprehensive series of chemogenomic screens using the budding yeast Saccharomyces cerevisiae as a model system. Because the known human targets of these drugs do not exist in yeast, we could employ the yeast gene deletion collections and parallel fitness profiling to explore potential off-target effects in a genome-wide manner. Among 214 tested, documented psychoactive drugs, we identified 81 compounds that inhibited wild-type yeast growth and were thus selected for genome-wide fitness profiling. Many of these drugs had a propensity to affect multiple cellular functions. The sensitivity profiles of half of the analyzed drugs were enriched for core cellular processes such as secretion, protein folding, RNA processing, and chromatin structure. Interestingly, fluoxetine (Prozac) interfered with establishment of cell polarity, cyproheptadine (Periactin) targeted essential genes with chromatin-remodeling roles, while paroxetine (Paxil) interfered with essential RNA metabolism genes, suggesting potential secondary drug targets. We also found that the more recently developed atypical antipsychotic clozapine (Clozaril) had no fewer off-target effects in yeast than the typical antipsychotics haloperidol (Haldol) and pimozide (Orap). Our results suggest that model organism pharmacogenetic studies provide a rational foundation for understanding the off-target effects of clinically important psychoactive agents and suggest a rational means both for devising compound derivatives with fewer side effects and for tailoring drug treatment to individual patient genotypes.     

Different functions for homologous serotonergic interneurons and serotonin in species-specific rhythmic behaviours

Closely related species can exhibit different behaviours despite homologous neural substrates. The nudibranch molluscs Tritonia diomedea and Melibe leonina swim differently, yet their nervous systems contain homologous serotonergic neurons. In Tritonia, the dorsal swim interneurons (DSIs) are members of the swim central pattern generator (CPG) and their neurotransmitter serotonin is both necessary and sufficient to elicit a swim motor pattern. Here it is shown that the DSI homologues in Melibe, the cerebral serotonergic posterior-A neurons (CeSP-As), are extrinsic to the swim CPG, and that neither the CeSP-As nor their neurotransmitter serotonin is necessary for swim motor pattern initiation, which occurred when the CeSP-As were inactive. Furthermore, the serotonin antagonist methysergide blocked the effects of both the serotonin and CeSP-As but did not prevent the production of a swim motor pattern. However, the CeSP-As and serotonin could influence the Melibe swim circuit; depolarization of a cerebral serotonergic posterior-A was sufficient to initiate a swim motor pattern and hyperpolarization of a CeSP-A temporarily halted an ongoing swim motor pattern. Serotonin itself was sufficient to initiate a swim motor pattern or make an ongoing swim motor pattern more regular. Thus, evolution of species-specific behaviour involved alterations in the functions of identified homologous neurons and their neurotransmitter.     

Selective updates on mechanisms of action of positive inotropic agents

Several extensive reviews concerning the actions of new positive inotropic agents in the treatment of congestive heart failure, often with reference to their mechanism of action, have recently been published [1–7]. Each of them has presented specific points of view. This review will place special emphasis on the significance of intracellular sodium activity for the modulation of myocardial inotropy; the continuing importance, after a 200 year history, of the use of cardiac glycosides as strong inotropic agents; the emerging significance of the phosphoinositide (PIP₂) pathway to provide additional second messengers for the modulation and regulation of cardiac inotropy; the contribution of the ₁-adrenergic system to cardiac inotropy; the increasing awareness of the significant involvement of adenosine and its antagonists in cardiac function; and the increasing realization that myocardial tissues are not homogeneous, i.e., that in many species the atrial and ventricular tissues are using different, even opposite mechanisms in the generation of their functional responses.     

State-dependent effects of orexins on the serotonergic dorsal raphe neurons in the rat

The serotonergic dorsal raphe (DR) neurons play an important role in sleep-wakefulness regulation. Orexinergic neurons in the lateral hypothalamus densely project to the brainstem sites including the DR. To test the effects of orexins on the serotonergic DR neurons, we applied orexin A (0.1 mM) by pressure to these neurons in unanesthetized and urethane anesthetized rats. Orexin A caused excitation in 10 of 15 neurons under unanesthetized condition. The excitation was characterized by slow onset (0-18 s), long lasting duration (15-150 s) and state-dependency. Orexin A applied during REM sleep or slow wave sleep induced significant excitation while during wakefulness, the similar amount of orexin A did not increase the firing rate any more. In the anesthetized animals, orexin A induced excitation in four of eight neurons. The excitation had slow onset and was long lasting. These results suggest that orexinergic neurons exert excitatory influence on the serotonergic DR neurons to maintain tonic activity of them, thereby participating in regulation of sleep-wakefulness cycles and other functions.     

Investigations using immunization to attenuate the psychoactive effects of nicotine

Despite the enormous health risks, people continue to smoke and use tobacco primarily as a result of nicotine addiction. As part of our immunopharmacotherapy research, the effects of active and passive immunizations on acute nicotine-induced locomotor activity in rats were investigated. To this end, rats were immunized with either a NIC-KLH immunoconjugate vaccine designed to elicit an antinicotine immune response, or were administered an antinicotine monoclonal antibody, NIC9D9, prior to a series of nicotine challenges and testing sessions. Vaccinated rats showed a 45% decrease in locomotor activity compared to a 16% decrease in controls. Passive immunization with NIC9D9 resulted in a 66.9% decrease in locomotor activity versus a 3.4% decrease in controls. Consistent with the behavioral data, much less nicotine was found in the brains of immunized rats. The results support the potential clinical value of immunopharmacotherapy for nicotine addiction in the context of tobacco cessation programs.     

Selective mortality and fertility and long run health effects of prenatal wartime exposure

Many previous studies have shown that prenatal exposure to adverse historical circumstances negatively affects long-run health. Most women who are pregnant during wars experience clearly adverse circumstances that are however not as harsh as the typically studied extreme episodes such as famines, combat and wide-scale destruction. We show that prenatal exposure to World War II (WWII) in five Western European countries did not lead to a population-wide poorer health among the elderly. We even find indications of a better than expected health. This is likely due to selective fertility and mortality. We attempt to quantify these selection effects and show that when taking them into account, the initially positively estimated health effects on almost all outcomes are substantially attenuated. Selective mortality and fertility likely occur in similar directions for many historical episodes of adversity. Our results therefore suggest that a part of the previous research on such exposures likely under estimated the true sizes of the long-run effects.     

Saccharomyces boulardii effects on gastrointestinal diseases

Health benefits attributed to probiotics have been described for decades. They include the treatment and the prevention of gastrointestinal diseases, vaginal and urinary infections and allergies. Saccharomyces boulardii, a species of yeast widely distributed, has been described as a biotherapeutic agent since several clinical trials displayed its beneficial effects in the prevention and the treatment of intestinal infections and in the maintenance of inflammatory bowel disease. All these diseases are characterized by acute diarrhoea. Administration of the yeast in combination or not with an antibiotherapy has shown to decrease significantly the duration and the frequency of diarrhoea. Experimental studies elucidated partially the molecular mechanisms triggered to improve the host health. The discovery of its anti-inflammatory and immuno-modulatory activities in correlation with the advances in the understanding of mucosal immunology opens a new field of perspectives in S. boulardii therapeutic applications.     

Centrally-mediated bombesin effects on gastrointestinal motility

Administration of bombesin into the lateral cerebral ventricle (i.c.v.) of rats results in a dose-related delay in gastric emptying and small intestinal transit. Recordings of intestinal intraluminal pressure in this species show that the i.c.v. peptide produces a dose-related increase in the frequency of duodenal contractions, and a complex inhibitory/excitatory jejunal effect at low and high doses, respectively. Intrathecal (i.th.) or i.c., but not intraperitoneal (i.p.), bombesin produces a dose-related slowing of gastrointestinal and colonic transit in mice. I.c.v. bombesin is 13.5 and 3406 times more potent in inhibition of gastrointestinal transit than when given by the i.th. or i.p. routes, respectively. Similarly, the i.c.v. peptide is 1.54 and over 11000 times more potent in slowing mouse colonic transit than when given by the i.th. or i.p. routes, respectively. The substance P analogue, D-Arg1, D-Pro2, D-Trp7,9, Leu11-Substance P (DAPTL-SP)(a reported bombesin antagonist in vitro) was not effective in blocking the gastrointestinal transit effects of the peptide in vivo. Transection of the spinal cord at the level of the second thoracic vertebra (T2) eliminates the gastrointestinal and colonic effects of i.th., but not i.c.v. bombesin. Thus, bombesin can affect motor function of the gut via activity within the brain or spinal cord of rats and mice; the activity of the peptide when given at the supraspinal level depends on an intact vagus nerve and adrenal-pituitary axis, while the activity of the peptide given at the spinal level appears to depend on the integrity of ascending spinal-supraspinal pathways.     

Using drug-discrimination techniques to study the abuse-related effects of psychoactive drugs in rats

Drug-discrimination (DD) techniques can be used to study abuse-related effects by establishing the interoceptive effects of a training drug (e.g., cocaine) as a cue for performing a specific operant response (e.g., lever pressing reinforced by food). During training with this protocol, pressing one lever is reinforced when the training drug is injected before the start of the session, and responding on a second lever is reinforced when vehicle is injected before the session. Lever choice during test sessions can then be used as an indication of whether a novel drug has effects similar to the training drug, or whether a potential therapeutic alters the effects of the training drug. Although training can be lengthy (up to several months), the pharmacological specificity of DD procedures make them a perfect complement to other techniques used to study drug-abuse phenomena, such as intravenous self-administration and conditioned place-preference procedures.