Endocrine effects of chronic administration of psychoactive drugs to prepubertal male rats. II. LSD.

The endocrine effects of chronic D-lysergic acid diethylamide (LSD) administration to prepubertal animals were studied by injecting intraperitoneally three times a week for a month either 100 mug or 500 mug of the psychoactive drug per kilogram or the vehicle to groups of Sprague-Dawley male rats starting at 21 days of age. Animals injected with either dosage of LSD had smaller body weights than controls and tail length was significantly reduced in the high dosage group, plasma levels of growth hormone (GH) were decreased in the high dosage group, and pituitary levels in the low dosage group. Plasma levels and pituitary concentrations of luteinizing hormone and follicle stimulating hormone were not significantly modified by the drug. The low dosage of LSD decreased the brain levels of noradrenaline and increased those of dopamine, while the high dosage decreased those of 5-hydroxyindoleacetic acid. These data suggest that LSD, when administered chronically to developing animals, can inhibit body growth probably by altering the secretion of GH through modifications of its neuroendocrine control.     

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.     

A spin label study of the membrane effect of various psychoactive drugs in human erythrocytes

The effect of psychoactive agents with different clinical actions: three sedative neuroleptics (trifluoperazine, alimemazine tartrate, chlorpromazine), an anticholinergic agent (trihexyphenidyl hydrochloride), two tricyclic antidepressants (imipramine, desipramine) and lithium carbonate on the rotational correlation frequency (V⁺) of the spin label 16NS has been comparatively investigated in whole human erythrocytes. V⁺ was about 40% increased by the three neuroleptics, the anticholinergic agent and the antidepressant molecules at 0.2mM. By contrast, lithium did not induce any significant change in V⁺ at the same concentrations. It can be suggested that the increase in “membrane fluidity”, observed with a wide variety of drugs, is a non specific effect, unrelated to the psychotropic action, that can be ascribed to the amphiphilic properties of the tested drugs.     

Use and abuse of psychoactive drugs in the elderly.

The elderly are susceptible to many psychiatric symptoms caused by the vast array of drugs they may take. Therefore, history-taking demands a very careful look at all their medicines. In this paper some dangers of over-the-counter drugs are described, and the paradox of psychotropic drugs sometimes causing psychiatric side effects is discussed. Several types of drugs and their side effects are outlined, and suggestions are made for appropriate drug treatment in this age group.     

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.     

Chloral hydrate anesthesia alters the responsiveness of dorsal raphe neurons to psychoactive drugs

The effects of several psychoactive drugs on raphe unit activity in freely moving cats was compared with drug-induced effects in chloral hydrate anesthetized cats. The anesthesia greatly potentiated the depressant effects of LSD, phenoxybenzamine, clonidine, methiothepin, clozapine, and chlorimipramine on raphe units, but partially antagonized the depressant effects of diazepam. These results demonstrate that apparently discrepant reports of the affects of these drugs on raphe neurons in anesthetized rats versus freely moving cats are attributable to the use of anesthesia in rat studies. These data underscore the importance of conducting such drug studies in awake, freely moving animals, for which the results would be far more relevant to the issue of human drug use.     

Prescribing of psychoactive drugs for chronically ill elderly patients.

The prescribing of psychoactive drugs for 1431 chronically ill elderly patients being assessed for long-term institutional or community care was surveyed. Psychoactive drugs had been prescribed for about one quarter of the patients; benzodiazepines were the most frequently prescribed group. Judging from the extensive prescribing of flurazepam and chloral hydrate, commonly used hypnotics, the main reason psychoactive drugs were prescribed was to provide night-time sedation. Antidepressants and drugs promoted as useful in improving cognitive function were infrequently prescribed. Commendable prescribing practices included the infrequent use of "cerebral vasodilators" and barbiturates. Questionable prescribing practices included the infrequent use of tricyclic antidepressants in severely depressed patients and the use of tranquilizers in patients described by their attending physician as markedly or extremely withdrawn.     

Implications of chirality and geometric isomerism in some psychoactive drugs and their metabolites

Many drugs contain a chiral centre, or such a centre is introduced during metabolism of the drug in man and in animals. If a single chiral centre is present, the drug will normally exist as a mixture of two enantiomers, of which one may have quite different pharmacologic and/or toxic effects than the other. Chiral drugs that are used in psychiatry, and some other pharmacologically related drugs are identified, and the implications of the presence of one or two chiral centres in these drugs are discussed. Differences in pharmacologic properties of drug and metabolite enantiomers are identified and discussed. Also reviewed are the properties of some drugs used in psychiatry that both are chiral and display geometric isomerism.     

Potential protective effects of melatonin on bone marrow of rats exposed to cytotoxic drugs

Myelosuppression is the most serious, dose limiting, toxicity of cytotoxic drugs. Efforts to protect the bone marrow have been only variably successful, and no agreement exists on how to approach this problem. Melatonin, the major hormonal product of the pineal gland, is supposed to have both chemoprotective and myelostimulatory effects. This experimental study was carried out to test these two effects on the bone marrow of rats, daily intraperitoneally injected with 100 microg melatonin. Injection of 10 mg aracytin for 10 days produced a significant (P < 0.01) decrease in red blood cells count (RBCs), total leucocytic count, as well as platelets count. When melatonin was injected along with aracytin, it would significantly increase (P < 0.05) RBC count and (P < 0.01) blood platelet count. Injection of melatonin after aracytin treatment would significantly increase (P < 0.01) RBC, total leucocytic and platelet counts in comparison with rats treated with aracytin only. The effects of melatonin were more clear in rats treated with it after aracytin injection than those treated with melatonin and aracytin at the same time. Furthermore, it was found that aracytin produced a significant (P < 0.01) decrease in serum total proteins, albumin, and significantly increased the (P < 0.01) albumin/globulin ratio. Melatonin injection would significantly increase (P < 0.01) total protein, globulin, and significantly decrease (P < 0.01) the albumin/glubulin ratio when injected either with aracytin or after aracytin treatment. These results indicate that melatonin protects bone marrow, lymphoid tissues from damaging effect of cytotoxic drugs, as well as stimulating the suppressed bone marrow.     

A mathematical model to study the effects of drugs administration on tumor growth dynamics

A mathematical model for describing the cancer growth dynamics in response to anticancer agents administration in xenograft models is discussed. The model consists of a system of ordinary differential equations involving five parameters (three for describing the untreated growth and two for describing the drug action). Tumor growth in untreated animals is modelled by an exponential growth followed by a linear growth. In treated animals, tumor growth rate is decreased by an additional factor proportional to both drug concentration and proliferating cells. The mathematical analysis conducted in this paper highlights several interesting properties of this tumor growth model. It suggests also effective strategies to design in vivo experiments in animals with potential saving of time and resources. For example, the drug concentration threshold for the tumor eradication, the delay between drug administration and tumor regression, and a time index that measures the efficacy of a treatment are derived and discussed. The model has already been employed in several drug discovery projects. Its application on a data set coming from one of these projects is discussed in this paper.     

Using variation partitioning techniques to quantify the effects of invasive alien species on native urban bird assemblages

Quantifying the impacts that invasive alien species (IAS) cause on affected systems is not an easy task. Here, we explore the application of variation partitioning techniques to measure and control for the effects of possible confounding factors when studying the impact that feral pigeons, European starlings, and house sparrows cause on native urban bird communities in Mexico. We argue that these IAS are provoking a severe impact on whole assemblages of native passerines only if (a) their marginal effect is statistically significant, (b) it remains so after partialling out other explanatory variables, and (c) is larger than (or similar to) the conditional effect of these covariates. We censused passerine bird assemblages and measured habitat variables in a number of greenspaces in three replicate study areas. Then, by means of partial redundancy analyses, we decomposed the total variability in bird data as a function of IAS, physical variables and vegetation data. In one of the study areas the marginal effect of IAS on native assemblages was significant, but the conditional effect was not. We conclude that this IAS effect was confounded with other explanatory variables. In the other study areas, no (marginal or partial) significant effect was found. Without invoking interspecific competition, our results support the opportunistic hypothesis, according to which IAS can exploit ecological conditions in modern cities that native species cannot even tolerate. Finally, apart from the Precautionary Principle, we found no scientific justification to control the abundance of the three IAS in our study areas.