Substance abuse and psychosis. The strange case of opioids.

BACKGROUND: Psychoses correlated with substance abuse prove to be more common in cases involving cannabinoids, stimulants, hallucinogens, alcohol and polyabuse. Among substance abusers, it has not been ascertained whether opioids have a psychotic effect. OBJECTIVES: The aim of this review is to investigate whether, among substances of abuse, a distinction can be drawn between pro-psychotic and anti-psychotic agents on the basis of the relationship between these substances and psychosis. METHODS: Studies were identified by searching through multiple literature databases, including PubMed, Scopus, Web of Knowledge. Hand searches through reference lists of relevant reviews were used to complement the computer searches. RESULTS: Looking at the relationships linking substances of abuse with psychosis, a distinction can, in fact, be drawn between pro-psychotic and anti-psychotic substances. Even if there are no differences in the addictive processes involved, opiates are the only sedative drugs that possess an anti-psychotic effect. CONCLUSIONS: The whole topic of opiate agonism merits is due for reconsideration: it is not only the anticraving action of opiate agonism, but also its effectiveness on the psychopathological level that qualifies it as to be viewed as a powerful tool in treating mental illness.

Do Akiskal & Mallya's affective temperaments belong to the domain of pathology or to that of normality?

BACKGROUND: Kraepelin and Kretschmer hypothesized a continuum between full-blown affective pathology and premorbid temperaments. More recently Akiskal proposed a putative adaptive role for the four fundamental temperaments: the hyperthymic one characterized by emotional intensity, the cyclothymic one by emotional instability, the depressive one by a low energy level, and the irritable one by an excessive response to stimuli. Today it is widely debated whether affective temperaments belong to the domain of pathology or to that of normality. PURPOSE: To make clear, by applying an integrated model, the position of affective temperaments within the continuum between normality and pathology. METHODS: We reviewed several papers that explore the distribution of affective temperaments among the general population, and their involvement both in pathological conditions (somatic and psychiatric) and in human activities (professions and other occupations). RESULTS: Far from being intrinsically pathological conditions, affective temperaments seem to represent adaptive dispositions whose dysregulation can lead to full-blown affective pathology. All the temperamental types display some impact on people's lives by influencing personal skills and professional choices over a wide field of human activities. CONCLUSIONS: Affective temperaments are not problematic when they appear in a mild form, but when they occur in extreme form we have observed a gap between the hyperthymic temperament, which represents the most functional and desirable, and the cyclothymic, depressive, irritable and phobic anxious ones, which are closer to mood, anxiety, and substance use disorders, and imply a component of somatic diseases and life stressors.

The murine neutrophil-chemoattractant chemokines LIX, KC, and MIP-2 have distinct induction kinetics, tissue distributions, and tissue-specific sensitivities to glucocorticoid regulation in endotoxemia.

Lipopolysaccharide-induced CXC chemokine (LIX) is a novel murine neutrophil-chemoattractant CXC chemokine cloned as a glucocorticoid-attenuated response gene. We investigated LIX message expression in an acute endotoxemia model. LIX message peaks later than KC or macrophage inflammatory protein-2 (MIP-2) and remains elevated longer in almost all tissues. Induced LIX message expression in heart is 5- to 6-fold greater than in lung and spleen, and 20-fold greater than in liver. In contrast, KC expression is equal in heart, lung, and liver, whereas MIP-2 expression is strongest in the lung. Glucocorticoid regulation of these genes also differs. Endotoxemia-induced LIX message expression in the lung is markedly enhanced in adrenalectomized mice and strongly attenuated by dexamethasone, whereas lung KC and MIP-2 expression are unaffected by glucocorticoids. It is surprising to note that endotoxemia-induced brain expression of LIX (but not KC or MIP-2) is increased by dexamethasone. These observations suggest that LIX may have biological roles distinct from KC and MIP-2.

Sequence similarities of a subgroup of CXC chemokines related to murine LIX: implications for the interpretation of evolutionary relationships among chemokines.

The murine CXC chemokine LIX has distinctive sequence features that suggest it is a novel chemokine. Among known human chemokines, ENA-78 and GCP-2 are the two most closely related to LIX. We have recently cloned the human GCP-2 gene. Phylogenetic analysis shows that the LIX coding region is more distant from both human GCP-2 and ENA-78 than is porcine AMCF-II, the chemokine with greatest sequence similarity to LIX. Human GCP-2 and ENA-78 have very high nucleotide similarity in non-coding as well as coding sequences, which suggests that these genes are the result of an evolutionarily recent gene duplication event. If this duplication occurred during primate evolution, then non-primate species may have only a single chemokine corresponding to this pair of human genes. This example shows that a one-to-one genetic correspondence does not necessarily exist between all the chemokine genes in two different species. These observations may have important implications for other chemokines that belong to clusters of closely related genes.

Cloning and characterization of the human granulocyte chemotactic protein-2 gene.

We recently described a novel murine CXC chemokine, designated lipopolysaccharide-induced CXC chemokine (LIX). In an ongoing search for new human chemokines related to LIX, we cloned the gene for human granulocyte chemotactic protein-2 (GCP-2) as well as previously described CXC chemokine genes, including epithelial cell-derived neutrophil-activating peptide-78 (ENA-78). Both coding and noncoding portions of the GCP-2 gene have very high nucleotide similarity to ENA-78, except for the occurrence of a long interspersed DNA-1 sequence 5' of the GCP-2 gene. The GCP-2 gene encodes a propeptide of 114 amino acid residues. The predicted 77-residue mature peptide is identical with the GCP-2 protein previously isolated from MG-63 osteosarcoma cells, except for two additional residues at the carboxyl terminus. We confirmed expression of the gene by Northern analysis and by cloning a portion of the cDNA from reverse transcribed MG-63 cell RNA. Despite 85% identity of the first 270 nucleotides 5' of the transcription start sites, GCP-2 and ENA-78 show cell-specific differences in regulation. GCP-2 is induced in MG-63, but not A549 cells by TNF-alpha, IL-1beta, and LPS, while ENA-78 is expressed in both cell types. Analysis of nucleotide sequence relationships does not support the proposal, by others, that LIX is murine GCP-2. LIX is no more closely related to human GCP-2 than to human ENA-78 and is more distant from both human genes than is porcine alveolar macrophage chemotactic factor-II.

Recurrent polymorphisms in small chromosomes of Leishmania tarentolae after nutrient stress or subcloning.

Molecular karyotypes of the UC, LEM87 and LEM115 Leishmania tarentolae strains were obtained. All strains had 24-28 chromosomal bands which varied in size between 300 kb and 2.9 Mb. Several recurrent chromosomal polymorphisms occurred in LEM115 after nutrient shock or subcloning. One type of polymorphism involves the truncation of a 365-kb chromosome which contains the miniexon genes. This specific chromosome breakage appears to be induced by the nutrient shock or subcloning process and also occurs spontaneously during routine passage. Another polymorphism is the appearance of a 90-kb minichromosome (115-SNA1) after severe nutrient shock. This appears to be selection of a pre-existing cell type from a mosaic population. The 115-SNA1 minichromosome has sequence homology with a minichromosome in LEM87 cells but shows no homology with any chromosomes in 115wt or other strains. The copy number of 115-SNA1 varies with culture conditions, suggesting a relaxed centromeric control. The nature and origin of this minichromosome is not known.

Effect of gossypol on trypomastigotes and amastigotes of Trypanosoma cruzi.

Bloodstream Trypanosoma cruzi trypomastigotes isolated from infected mice undergo reduction of motility and structural damages after 5 to 45 min exposure to gossypol at concentrations ranging from 5 to 50 microM. When 1% serum albumin is added to the incubation medium, no alterations of parasites are observed, even with 100 microM gossypol. Intracellular T. cruzi amastigotes in infected Vero cell cultures exposed to 5 microM gossypol for 2 h do not show changes. Incubation with 5 microM gossypol for 48 h produces complete disruption of host cells; however, the amastigotes they contain show only minor alterations. The observations indicate that, in protein-rich media, gossypol is complexed into associations which have no activity on the different forms of the T. cruzi biological cycle.

In vitro inhibition by gossypol of oxidoreductases from human tissues.

The effect of gossypol, a polyphenolic compound with antifertility action on human males, has been investigated on the following oxidoreductases purified from human tissues: lactate dehydrogenase (EC 1.1.1.27) isozymes 1 or B4 from heart, 5 or A4 from liver and X or C4 from spermatozoa; malate dehydrogenase (EC 1.1.1.37) mitochondrial and "soluble" isozymes from heart and NADP-glutamate dehydrogenase (EC 1.4.1.4) from liver. Gossypol proved to be a powerful inhibitor of the six enzymes studied. For all of them, inhibition was of the competitive type with respect to the coenzyme and non-competitive in relation to substrate. The lowest ki values were shown for lactate dehydrogenase isozyme 1 or B4 and for the two isozymes of malate dehydrogenase. Results did not show selectivity of gossypol for the sperm-specific isozyme X or C4 of lactate dehydrogenase.

Inhibition by gossypol of oxidoreductases from Trypanosoma cruzi.

The effects of gossypol, a polyphenolic compound isolated from the cotton plant upon six oxidoreductases from cultured epimastigotes of Typanosoma cruzi were studied. Gossypol was a powerful inhibitor of the alpha-hydroxyacid and malate dehydrogenases, NAD-linked enzymes, and of glutamate dehydrogenase, malic enzyme and glucose-6-phosphate dehydrogenase, NADP-dependent enzymes. The drug did not have an effect on succinate dehydrogenase, a flavoprotein. The Ki values with respect to substrate were 0.73, 0.3 and 3.5 microM for alpha-hydroxyacid, malate and glutamate dehydrogenases, respectively, and 1.1, 0.19 and 7.8 microM with respect to the coenzyme. Inhibition was noncompetitive with respect to substrate and uncompetitive in relation to the coenzyme.

Effect of temperature upon catalytic properties of alpha-hydroxyacid dehydrogenase from Trypanosoma cruzi.

A comparative study of the effect of temperature (10, 20, 30 and 37 degrees C) upon Km and V of alpha-hydroxyacid dehydrogenase (HADH), isozyme I and II, from Trypanosoma cruzi, a parasite whose life cycle comprises stages in an insect vector, and of another enzyme with analogous substrate specificity, the lactate dehydrogenase, isozyme X (LDH X) from mouse, a homeotherm, is presented. The Km for alpha-ketoisocaproate of HADH is markedly reduced as temperature decreases. This effect can compensate the reduction in thermal energy and produce stabilization of the reaction rate. This compensation does not occur with mouse LDH X. The activation energy for both HADH isozymes is about half the value determined for mouse LDH X. Results indicate that HADH from T. cruzi is able to adjust instantaneously to thermal changes of the environment, behaving as other enzymes of terrestrial poikilothermic animals.

Effect of gossypol upon motility and ultrastructure of Trypanosoma cruzi.

Gossypol, a polyphenolic compound from the cotton plant, immobilizes and structurally alters cultured Trypanosoma cruzi epimastigotes. Ultrastructural changes observed in gossypol-treated parasites were first detected in the kinetoplast and mitochondrion. At 50 microM concentration, much disorganization was evident after 5 min of incubation. With 25 microM gossypol, the same effect occurred after 30 min. Most epimastigotes were rounded, containing various membranous structures that could not be related to known cell components.

Catalytic properties of the sperm-specific lactate dehydrogenase (LDH X or C4) from different species.

A comparative study of catalytic properties of the sperm-specific lactate dehydrogenase (EC 1.1.1.27) isozyme X or C4 from a variety of animals (boar, bull, goat, Guinea pig, man, mouse, pigeon, rabbit, and rat) is presented. Optimum concentration and Km values for pyruvate, inhibition by substrate, and activity against analog substrates (alpha-ketoacids with linear and branched chains from 4 to 6 carbon atoms) for isozyme X of different species showed significant differences. The observed properties are correlated with available evidence on the metabolic role of the enzyme.

Studies in vitro on shuttle systems of mouse spermatozoa.

Observations on systems reconstituted in vitro with different starting substrates (2-hydroxy-acids, 2-oxo-acids or leucine) indicate that a branched-chain 2-hydroxy-acid/2-oxo-acid shuttle for the transfer of reducing equivalents from cytosol to mitochondria may be operational in mouse sperm. Evidence is presented suggesting that the 2-oxo-acids produced by intramitochondrial oxidation of 2-hydroxy-acids ingressed from the cytosol can recycle back into the external phase. Observations in vitro demonstrate that, in addition to the branched-chain 2-hydroxy-acid/2-oxo-acid shuttle, the malate/aspartate system is also active in mouse sperm. On the contrary, the lactate/pyruvate redox couple does not appear to function as part of a shuttle system in mouse sperm mitochondria. The glycerol 3-phosphate shuttle probably is not functionally significant in mouse spermatozoa, since the activity of the 'soluble' glycerol 3-phosphate dehydrogenase is very low.

Inhibitory action of gossypol on enzymes and growth of Trypanosoma cruzi.

Gossypol, a phenolic compound isolated from the cotton plant, is a powerful inhibitor of nicotinamide adenine dinucleotide-linked enzymes (alpha-hydroxyacid dehydrogenase and malate dehydrogenase) of Trypanosoma cruzi, the parasite that causes Chagas' disease. Parasites at the epimastigote stage that were incubated for 5 minutes with 100 micromolar gossypol were completely immobilized. Concentrations of gossypol as low as 0.01 micromolar markedly reduced the growth rate of T. cruzi in culture.

Properties of alpha-hydroxyacid dehydrogenase isozymes from Trypanosoma cruzi.

Whole cell extracts of culture epimastigotes of Trypanosoma cruzi (Tulahuén strain) have alpha-hydroxyacid dehydrogenase activity which catalyzes the NAD-linked reaction alpha-ketoacid in equilibrium with alpha-hydroxyacid, with a variety of substrates. Two molecular forms of the enzyme have been separated by means of gel electrophoresis. These isozymes were partially purified by DEAE-cellulose chromatography and ammonium sulfate precipitation. Molecular weights were estimated and some catalytic properties were determined with purified isozymes. The faster migrating fraction (isozyme I) has a molecular weight of 85 500 and showed significant activity against linear 3-5 carbon chain substrates. The lowest Km value was obtained for pyruvate. Isozyme II (MW 60 500) utilizes linear and branched chain substrates with 4-6 carbon atoms. Its highest activity and lowest Km value were recorded with alpha-keto-isocarproate as substrate.