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Rats trained to discriminate saline from either (+)-amphetamine, (+/-)-DOM, or (+/-)-3,4-MDA in a two-lever drug discrimination paradigm were administered doses of a novel positional isomer of 3,4-MDA, i.e. 2,3-MDA. The novel isomer produced neither amphetamine-appropriate nor DOM-appropriate responding: the 3,4-MDA stimulus did, however, generalize to 2,3-MDA.
Lakes in arid and semi-arid regions are subjected to severe ecological stress, such as organic pollution, eutrophication, and salinization, due to climate change and human activities. This study investigates Chagannur Lake, a typical arid-region lake that is representative and ecologically sensitive in Northern China's agro-pastoral ecotone, to uncover its pollution characteristics and mechanisms. We employed fluorescence spectroscopy and stable isotope analysis to trace dissolved organic matter (DOM) and nitrate sources. The DOM composition was dominated by microbial metabolic byproducts and protein-like substances, suggesting that microbial processes are key to organic matter transformation. Source apportionment revealed that pollutants primarily originated from livestock and poultry manure (37.6 %), agricultural fertilizers (35.6 %), and soil erosion (24.7 %), with agricultural fertilizers contributing most significantly in the Gogstai River (63.3 %). A structural equation model (SEM) coupling spectral and mass spectrometric data revealed that microbial transformation significantly impairs the lake's self-purification capacity, thereby promoting pollutant accumulation (path coefficient = 0.91,*p < 0.05). Moreover, microbial processes link endogenous and exogenous pollution, a mechanism effectively traced by isotopic and fluorescence indices (path coefficient = 0.55, ⁎⁎p < 0.01). These findings enhance the understanding of pollution sources and transformation mechanisms in arid-region lakes and offer foundational theoretical support for policymakers engaged in pollution control strategies.
alpha-Ethyltryptamine (etryptamine, alpha-ET) is a drug of abuse that first appeared on the clandestine market in the mid-1980s. Its pharmacological actions are poorly understood. In this investigation, it is reported for the first time that alpha-ET serves as a training drug in drug discrimination studies. Male Sprague-Dawley rats were trained to discriminate (30-min pretreatment time) 2.5 mg/kg of alpha-ET (ED(50)=1.3 mg/kg) from saline vehicle using a standard two-lever operant paradigm and a VI-15s schedule of reinforcement for appetitive reward. Once established, the alpha-ET stimulus was shown to have an onset to action of 30 min and a duration of effect of at least 4 h. In tests of stimulus generalization (substitution), the alpha-ET stimulus generalized to S(-)alpha-ET (ED(50)=1.6 mg/kg) and R(+)alpha-ET (ED(50)=1.3 mg/kg). Tests of stimulus generalization were also conducted with prototypical phenylisopropylamines: (+)amphetamine, 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM), and N-methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA). The alpha-ET stimulus generalized to DOM (ED(50)=0.4 mg/kg) and PMMA (ED(50)=0.7 mg/kg), but only partially generalized (ca. 40% maximal drug-appropriate responding) to (+)amphetamine. The results suggest that alpha-ET produces a complex stimulus.
In the present investigation, the ability of two known hallucinogens, lysergic acid dimethylamide (LSD) and (-)-2,5-dimethoxy-4-methyl-amphetamine (DOM), to substitute for the ibogaine-induced discriminative stimulus (10 mg/kg I.P., 60 min presession) was assessed in Fischer-344 rats. In these subjects, intermediate levels of generalization were observed to both agents (LSD, 63%; DOM, 66.4%). This intermediate generalization was completely blocked by pretreatment with the 5-HT2A antagonist pirenpirone, suggesting that the ibogaine-like effects of these agents are mediated by the 5-HT2A receptor. However, pirenpirone did not antagonize ibogaine itself, nor did it antagonize the ibogaine-like effects of harmaline and 12-hydroxyibogamine (noribogaine). To further evaluate the serotonergic properties of ibogaine, in vivo protection assays and in vitro binding assays were employed. Micromolar 5-HT2A affinity was observed with ibogaine (92.5 microM), 12-hydroxyibogamine (34.5 microM), and harmaline (42.5 microM). Despite the apparently low affinity of these agents, both ibogaine and harmaline, but not 12-hydroxyibogamine, produced significant protection from receptor alkylation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) when given 60 min prior to this alkylating agent. The results of these studies suggest that although ibogaine may produce some of its effects via interactions with 5-HT2A receptors, these do not appear to be essential to the ibogaine-induced discriminative stimulus.
Two analogues, 6-(2-aminopropyl)-5-methoxy-2,3-dihydrobenzofuran and 6-(2-aminopropyl)-5-methoxy-2-methyl-2,3-dihydrobenzofuran, of the hallucinogenic agent 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) were synthesized and tested in the two-lever drug discrimination paradigm. In rats trained to discriminate saline from LSD tartrate (0.08 mg/kg), stimulus generalization occurred to both of the 2,3-dihydrobenzofuran analogues but at doses more than 10-fold higher than for DOM. A possible explanation for this dramatic attenuation of LSD-like activity could involve a highly directional electrophilic binding site on the receptor that cannot accept the orientation of the unshared electron pairs on the heterocyclic oxygen atom in the benzofurans.
Stimulation of 5-HT2 receptors in mammals by agonists causes detrimental neurological, psychological, and circulatory effects. 5-HT2 antagonists block the elicited effects, but by themselves, they do not cause any apparent behavioral, neurological or subjective effects. However, 5-HT2 antagonists increase slow wave sleep and have a therapeutic action on impaired circulation, dysthymia, and negative symptoms in schizophrenia. Chronic treatment of rodents with various 5-HT2 antagonists was reported to cause an anomalous desensitization and 5-HT2 receptor down regulation. In this study we further investigated the 5-HT2 receptor regulation in vivo and in vitro by agonist and antagonist treatment. Treatment of rats with the 5-HT2 agonist, 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) (2.5 mg/kg s.c., every 8 h), rapidly caused desensitization of the head twitch response (-20% and -80% after 2 and 4 injections) and a decrease in the number of frontal cortical 5-HT2 receptors labeled with [3H]ketanserin (-24% and -41%, 24 h after 2 and 4 injections). The receptor resynthesis/degradation revealed half-times of 5 days initially to 3 days in the later drug-free period. Administration of the antagonist ketanserin (2.5 mg/kg, s.c., every 8 h) 15 min before the agonist, antagonized the acute behavioral effect but did not prevent the 5-HT2 receptor down regulation after 4 treatments. In contrast, ketanserin by itself, given 4 times, caused a reduction in the Bmax-value of [3H]ketanserin binding by 19% and given 10 times it caused a reduction in the Bmax-values by 28% and 31% of [3H]ketanserin and [3H]DOB binding in the frontal cortex. Hence 5-HT2 receptors labeled by an antagonist and an agonist ligand were similarly decreased. In vascular smooth muscle cells in culture kept for at least 24 h in a serotonin-free medium before treatment, the 5-HT2 receptor mediated 5-HT-induced inositol phosphate formation, was rapidly desensitized by agonist treatment: -20% after 15 min and -80% after 1 h incubation of the cells with 10(-5) M 5-HT or DOM. After 2 h and 24 h treatment resensitization occurred with half-times of 5 h and 12 h, respectively. Pretreatment of the cells for 15 min or 24 h with 10(-7) M of the antagonists setoperone or ketanserin, followed by extensive washing, caused a reduction in the 5-HT-induced inositol phosphate formation by about 50% with setoperone and by 30% with ketanserin. Effects of 15 min and 24 h drug pretreatment were similar.(ABSTRACT TRUNCATED AT 400 WORDS)
DOET, like DOM, exhibited pressor action in rats. This increase of blood pressure was blocked by pretreatment with cinanserin. DOET at high doses decreased the spontaneous locomotor activity of mice at the first hour but increased the activity at the second hour; a low dose was less effective. DOET also increased the rectal temperature of rats and this hyperthermic action was suppressed by pretreating the animals with cinanserin or methysergide. These actions of DOET were compared with those of DOM.
The composition of dissolved organic matter (DOM) in a soil is the product of a variety of soil processes. Changes in the composition of DOM in water discharged from soil should, therefore, give an important insight into modifications in these soil processes. We hypothesise that these processes in soils, under different grassland management regimes, would be affected to different extents by the short-term disturbance of a storm event and that evidence of this could be detected in delta(13)C and delta(15)N signatures in drainage and surface runoff waters. During a storm event we collected discharge waters from 1 ha grassland lysimeters, with or without artificial drainage, which received contrasting fertiliser inputs, and delta(13)C and delta(15)N signatures were determined. Changes in (13)C enrichment during the storm event were clearly identifiable, as were differences between plots for (13)C and (15)N, illustrating that this technique has potential to be a useful tool for identifying and investigating short- and long-term changes in soil organic matter dynamics. Copyright 1999 John Wiley & Sons, Ltd.
To address the question of whether the increased plasma concentration of interleukin 6 (IL-6) following strenuous muscular work could be related to exercise-induced muscle damage, 5 moderately active male volunteers underwent two isokinetic exercise sessions in the eccentric mode, separated by a period of 3 weeks during which the subjects underwent five training sessions. Before training, exercise was followed by severe muscle pain (delayed-onset muscle soreness; DOMS), and by significant increases in plasma IL-6 level and serum myoglobin concentration (SMb) (P < 0.001). After training, postexercise DOMS and SMb values were significantly lower than those measured before training. There was no significant difference between plasma IL-6 levels measured at the same time points before and after training. We conclude that the hypothetical relationship between exercise-induced muscle damage and increased postexercise levels of circulating IL-6 is not substantiated by the present results.
The literature indicates inconsistent results when MMPI differences between black Ss and white Ss were investigated. In general, most studies found that blacks responded in a more pathological direction. However, previous studies can be criticized because they have used students, prisoners, and hospital patients as Ss with variables that were controlled inconsistently and varied widely. In this study a comparison was made of MMPI scales for 56 black and 56 white males who were full-time employees of a large chemical company. Ss were matched for age, education, occupation, seniority, mental ability level, and socioeconomic level. The 10 standard clinical and 3 validity MMPI scales were recorded for each S as well as six experimental scales: Control (C), Dependency (DPD), Dominance (DOM), Ego Strength (ES), Anxiety Index (AI), and Internalization Ratio (IR). Using K corrected T-scores for the MMPI scales, a repeated measures analysis of variance indicated that subtests and group X subtests were significant. More specifically, blacks scored significantly higher than white Ss on the MA scale, and white Ss scored significantly higher than blacks on the PA, C, DOM, and Es scales. While the present study did find significant differences between black and white Ss on the MMPI, the scores were all well within the normal range (T less than 70), and all scales but two were less than 60.
This study examined the effect of the establishment of dominance relationships and subordination on exploratory behavior for both postpubertal and adult male rats. Prior to an open field test, subjects were housed either in isolation (IS) or in littermate pairs (PS) with mild dominance relationships without overt victory or defeat, or in pairs with clear hierarchical relationships as dominants (DOM) or subordinates (SUB). Stretch-attend postures and entries into the center area of the open-field were measured as an index of passive and active exploratory behavior, respectively, and crossings in the peripheral area were counted as activity. SUB rats, both postpubertal and adult, displayed less activity and lower levels of active exploratory behavior, whereas adult IS rats showed higher levels of active exploratory behavior compared to the other groups. Furthermore, both DOM and PS rats exhibited a more passive pattern of exploratory behavior in adulthood than in postpuberty. Thus the results show that an increase in the active exploratory pattern is inhibited by the establishment of social relationships among adult rats, while a decrease in activity is a primarily effect of subordination. The capacity to change exploratory patterns following subordination is found even in the postpubertal stage when adultlike social relationships have not yet appeared.
Introduction of the Y chromosome from a Mus musculus domesticus (Tirano) subspecies into the Mus musculus musculus C57BL/6 (B6) inbred strain background results in sex reversal in XY offspring. It has been hypothesized that the domesticus testis-determining Y (Tdy) locus is misregulated in B6 genome, thereby impairing sex determination in B6.Y(Dom) animals. The identification of a gene in the sex-determining region on the Y chromosome (Sry) as the Tdy has provided a means to experimentally examine this hypothesis. We have generated several lines of B6 transgenic mice harboring a green fluorescent protein gene directed by a Sry promoter from the domesticus (Tirano) Y chromosome. Detailed analysis of the transgene expression was conducted in both fetal and adult tissues of the transgenic mice. The domesticus Sry promoter was capable of directing the expression of the green fluorescent protein gene in a pattern similar, if not identical, to that of the endogenous B6 Sry gene. These observations suggest that the domesticus Sry promoter is not involved in the postulated misregulation of the domesticus (Tirano) Sry gene in the B6 genomic background. These results are discussed with reference to a second hypothesis invoking incompatible protein interaction(s) as a mechanism of aberrant sex determination in B6.Y(Dom) animals.
The induction of donor-specific unresponsiveness in allograft recipients would lessen the need for chronic immunosuppression and its concomitant morbidities. In view of recognized interactions between the immune and neuroendocrine systems, we hypothesized that manipulating prolactin (PRL) levels might enhance the immunosuppressive effects of donor-specific blood transfusions. Bromocriptine (BR) and domperidone (DOM), administered via osmotic pumps, were used to inhibit or increase pituitary PRL secretion, respectively, in male LEW rats treated with donor-specific transfusions (DST, Day -1), cyclosporine (CsA, 5 mg/kg, Days -1 to +1), and receiving ACI heart allografts. Neither compound had direct effects on lymphoid cells in vitro. BR had no effects on graft survival in rats treated with either BT or CsA (BR-DST, 7.0 +/- 0.7; BR-CsA, 9.2+/-3.1; CsA, 11.3 +/- 3.9 days). DOM-DST-CsA also did not affect graft survival (8.7 +/- 3.1 days). BR and CsA, similarly, had no effects in rats receiving a nonspecific transfusion (8.8 +/- 1.1 days). In contrast, BR administration in rats treated with DST and CsA unequivocally prolonged graft survival (17.0 +/- 1.4 days; P < 0.01 vs all controls), suggesting that hypoprolactinemia increased the tolerogenic effects of DST. Spleen and lymph node cells harvested from BR-DST-CsA rats on Postoperative Day 8 showed impaired responses to mitogenic or allogeneic challenges. Cytotoxic antibody levels at Day 5 were low in all groups receiving CsA. Possible mechanisms are discussed.
Two methods were used to assess the heterogeneity of capillary supply to muscles of widely differing metabolic capacity and fibre size. Using the method of capillary domains (DOM; Hoofd et al., 1985) and the closest-individual method (CI; Kayar et al., 1981) radii of Kroghian cylinders (R) can be calculated, and the heterogeneity of their lognormal distribution represented by the logarithmic standard deviation (Log SD). Both methods yield similar values for mean R in a tissue. DOM is more direct and quicker than CI, and may be particularly useful in the analysis of capillary oxygen supply during functional hypertrophy and in muscle regeneration where a broad distribution of fibre areas may be found. Despite a 500-fold range of capillary density, to a minimum of 20 capillaries mm-2, heterogeneity of capillary supply was similar in all muscles, indicating a functionally homologous spatial distribution. The relationship between number of fibres overlapped by a capillary domain, and domain area has zero correlation in most tissues but shows a negative trend in fish fast muscle, reflecting hyperplastic and hypertrophic growth. Capillary/fibre ratio is inappropriate for sparse networks whereas the cumulative fraction of domains vs fibre area shows a strong correlation, suggesting that maximal oxygen supply to muscle fibres is not restricted to contiguous capillaries, but also involves those remote from the fibre surface.
Various direct- and indirect-acting serotonin (5-HT) agonists serve as training drugs in tests of stimulus control of behavior; such agents include: 5-hydroxytryptophan, 5-methoxy-N,N-dimethyltryptamine, and fenfluramine. However, with the recent discovery of multiple populations of central 5-HT binding sites, the concept of site-selective serotonergic agents needs to be addressed. Certain 4-substituted 1-(2,5-dimethoxyphenyl)-2-aminopropanes such as DOM (4-methyl), DOB (4-bromo), and DOI (4-iodo) appear to be 5-HT2-selective agonists and serve as effective training drugs in rats. Stimulus generalization occurs among these agents regardless of which is used as the training drug, although stimulus generalization does not occur with 5-HT1A-selective agonists [e.g., 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH DPAT)] or with 5-HT1B-selective agonists [e.g., 1-(3-trifluoromethylphenyl)piperazine (TFMPP)]. 8-OH DPAT and TFMPP also serve as training drugs; the 8-OH DPAT-stimulus generalizes to other 5-HT1A agonists, but not to 5-HT1B or 5-HT2 agonists, whereas the TFMPP-stimulus generalizes to other 5-HT1B agonists, but not to 5-HT1A or 5-HT2 agonists. Classical serotonin antagonists, most of which are rather selective for 5-HT2 sites, and 5-HT2-selective antagonists are able to block the stimulus effects of DOM, DOB, and DOI, but not those of 8-OH DPAT or TFMPP. The results of such studies reveal that, in rats, site-selective 5-HT agonists produce stimulus effects that are also selective; although generalization may occur with nonselective 5-HT agonists, animals trained to discriminate site-selective 5-HT agonists apparently do not recognize other 5-HT agonists that are selective for a different site. Animals trained to discriminate such agents from saline might be useful for the identification and/or investigation of novel site-selective agonists and antagonists (for example, the 8-OH DPAT-stimulus generalizes to members of a new class of anxiolytics that display high affinity for 5-HT1A binding sites), and might also aid in the overall understanding of central serotonergic mechanisms.
It has been shown that the hallucinogenic potencies of LSD, the phenylisopropylamines, such as DOB (4-bromo-2,5-dimethoxyphenylisopropylamine) and DOI (4-iodo-2,5-dimethoxyphenylisopropylamine), and the indolealkylamines, such as DMT (dimethyltryptamine) and 5-OMe-DMT (5-methoxy-dimethyltryptamine), strongly correlate with their in vitro 5-HT2 receptor binding affinities in rat cortical homogenates. In order to ascertain if this correlation applies to human 5-HT2 receptors as well, we examined the affinities of 13 psychoactive compounds at 3H-ketanserin-labelled 5-HT2 receptors in human cortical samples. Both radioligand binding and autoradiographical procedures were used. As in rat brain, d-LSD was the most potent displacer of 3H-ketanserin specific binding with a Ki of 0.9 nM. The phenylisopropylamine DOI also displayed high affinity (Ki of 6 nM). Stereospecific interactions were found with DOB; (-) DOB had a Ki of 17 nM while (+) DOB had a Ki of 55 nM. The behaviorally active compound DOM (4-methyl-2,5-phenylisopropylamine) had an affinity of 162 nM while its behaviorally less active congener iso-DOM had an affinity of 6299 nM. The indolealkylamines 5-OMe-DMT and DMT competed with moderate affinities (207 and 462 nM, respectively). In general, Hill coefficients were significantly less than unity which is consistent with an agonist interaction with 5-HT2 receptors. MDMA, a substituted amphetamine analog was inactive with a Ki of greater than 10 microM. A strong correlation was found for the hallucinogen affinities and human hallucinogenic potencies (r = 0.97). Also, human and rat brain 5-HT2 receptor affinities were strongly correlated (r = 0.99). These results strongly support the hypothesis that the hallucinogenic effects of these drugs in humans are mediated in whole or in part via 5-HT2 receptors. Furthermore, these studies imply that treatment with 5-HT2 receptor antagonists may be effective in reversing the hallucinogenic effects caused by the ingestion of LSD and LSD-like drugs.
The objectives of this study were to determine whether the occurrence of delayed onset muscle soreness (DOMS) for the vastus lateralis muscle was associated with elevated intramuscular pressure (IMP); and to assess, whether high eccentric forces occurred at an increased muscle length (as determined by joint angle). Therefore, peak knee extension torque, peak IMP of the vastus lateralis muscle, and the joint angle at which peak torque (JAPT) occurred were determined in eight male subjects during repetitive eccentric and concentric activities until fatigue occurred. Peak torque was significantly higher for eccentric compared to concentric activity (P < 0.01) and declined significantly for both activities (P < 0.01) throughout the protocols. When comparing the start (prior to fatigue) to the end (fatigue state), mean torque for eccentric activity declined from 191 to 147 (N.m) and for concentric activity declined from 166 to 104 (N.m). In contrast, peak IMP was not significantly different between the types of activity and did not change significantly with time. At the start and the end, the mean IMP remained constant for eccentric activity at 54 mmHg (7.2 kPa) but for concentric activity was 78 mmHg (10.4 kPa) and 96 mmHg (12.8 kPa), respectively. All the subjects, however, experienced DOMS of the vastus lateralis muscle exclusively for the eccentric activity leg. The JAPT was not different between activity types and did not change significantly with time; however, a significant interaction between activity type and time was observed (P = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
The object of this study was to determine whether leukocytosis would occur in response to eccentric exercise, to concentric exercise, and/or to possible increases in serum cortisol levels. Eight men performed 2 bouts of exercise at 46% VO2max for 40 min. Subjects initially walked up a 10% grade (UW); 2 weeks later they jogged down a 10% grade (DJ), a form of eccentric exercise known to induce delayed onset muscle soreness (DOMS). Venous blood samples were drawn before and after each exercise bout (0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, and 5 h). Total and differential WBCc and serum cortisol levels were assessed. Results were analyzed using repeated measures ANOVA (2 x 11). Subjects experienced severe DOMS after DJ. There was a significant difference in TWBCc (p less than 0.0001) between UW and DJ. Post-hoc testing revealed no significant increase over baseline values for UW; after DJ there was a 46% increase over baseline values (p less than 0.05) initially seen at 1.0 h. These increases in TWBCc were predominantly a reflection of increases in neutrophils which were significant (p less than 0.0001) when compared to baseline values at 1.0, 1.5 and 2.0 h (approximately 60%). No significant neutrophil increases were seen after UW. Cortisol levels were similar for both groups pre-exercise (UW = 367.1 +/- 38.6, DJ = 320.2 +/- 44.16 nmol.L-1 means +/- SE) and decreased similarly for both groups after exercise, and thus were not related to the post-exercise neutrophilia.(ABSTRACT TRUNCATED AT 250 WORDS)