Biomedical subjects

G Perrault

Publications and source records attributed to G Perrault.

At least 37 records · Page 2Linked to original sources

PubMed1999

Dopamine D3 receptor agonists produce similar decreases in body temperature and locomotor activity in D3 knock-out and wild-type mice.

The function of the dopamine (DA) D3 receptor, a member of the D2-like family, has not been firmly established. It has been reported that the potency of DA receptor agonists in producing hypothermia and hypolocomotion in rodents correlates more strongly with the in vitro affinity for, or potency (mitogenesis test) at the D3 than the D2 subtype. In order to investigate further the role of D3 receptors in hypothermia and hypolocomotion, we tested the effects of ip administration of three DA receptor agonists reported to be selective for the D3 receptor subtype (7-OH-DPAT, quinelorane and PD 128907) on core temperature and spontaneous locomotor activity in homozygous (D3-/-), heterozygous (D3+/-) mutant and wild-type (D3+/+) mice. Quinelorane (0.003-0.3 mg/kg), PD 128907 (1-10 mg/kg) and 7-OH-DPAT (0.1-3 mg/kg) induced hypothermia and decreased locomotion to a similar extent in the three genotypes. Additionally, the putatively selective DA D3 receptor antagonist PNU 99194A (3-20 mg/kg i.p.) increased locomotor activity in habituated mice and reversed the hypothermia induced by 30 microg/kg of quinelorane, with no apparent difference between D3-/-, D3+/- and D3+/+ genotypes. The spontaneous level of locomotor activity of mutants (D3-/- or D3+/-) was found to be either at, below, or above that of controls, with no consistent trend between different batches of mice. These results show that the presence of DA D3 receptors is not necessary for the expression of these effects induced by the three agonists or the antagonist supposedly selective for the D3 receptor subtype. This raises the question of the involvement of the D3 receptor in these behavioural effects and the issue of the in vivo selectivity of these four compounds for the D3 receptor subtype. Alternatively, possible adaptive mechanisms taking place in D3-/- mice might have compensated for the absence of DA D3 receptors.

Animals↗

PubMed1999

Pharmacological studies on synthetic flavonoids: comparison with diazepam.

The present experiments compared the central BZ-omega binding characteristics and pharmacological profiles of two synthetic flavonoids (6-bromoflavone and 6-bromo-3'-nitroflavone) with those of the benzodiazepine (BZ) diazepam. In vitro experiments showed that while diazepam displaced [3H]flumazenil binding to the GABA(A) receptor in membranes from rat cerebellum and spinal cord, two brain areas enriched in the BZ-omega1 and BZ-omega2 receptor subtypes, with nearly equivalent half maximally effective concentrations, 6-bromo-3'-nitroflavone was somewhat more potent in displacing [3H]flumazenil binding to membranes from rat cerebellum (IC50 = 31 nM) than from spinal cord (IC50 = 120 nM), indicating selectivity for the BZ-omega1 receptor subtype. 6-Bromoflavone displayed weak (IC50 = 970 nM) affinity for the BZ-omega1 and no affinity for the BZ-omega2 (IC50 > 1000 nM) receptor subtypes. Diazepam, but not the synthetic flavonoids increased the latency to clonic seizures produced by isoniazid, thereby indicating that neither 6-bromoflavone nor 6-bromo-3'-nitroflavone display detectable intrinsic activity at GABA(A) receptors in vivo. Results from two conflict tests in rats showed that 6-bromoflavone (3-10 mg/kg) and 6-bromo-3'-nitroflavone (0.3-1 mg/kg) elicited anxiolytic-like activity in the punished drinking test, while both drugs were inactive in the punished lever pressing test. The positive effects displayed by the synthetic flavonoids in the punished drinking procedure were smaller than that of diazepam and were not antagonized by the BZ receptor antagonist flumazenil. In two models of exploratory activity, 6-bromoflavone (3-30 mg/kg) and 6-bromo-3'-nitroflavone (0.3-1 mg/kg) produced anxiolytic-like effects in the rat elevated plus-maze test, whereas both compounds failed to modify the behavior of mice in the light/dark test over a wide dose-range. The effects in the elevated plus-maze were antagonized by flumazenil. In the mouse defense test battery, where mice were confronted with a natural threat (a rat), 6-bromoflavone and 6-bromo-3'-nitroflavone failed to decrease flight reactions after the rat was introduced into the test area and risk assessment behavior displayed when subjects were constrained in a straight alley, and only weakly affected risk assessment of mice chased by the rat and defensive biting upon forced contact with the threat stimulus. In a drug discrimination experiment 6-bromoflavone and 6-bromo-3'-nitroflavone up to 30 and 3 mg/kg, respectively, did not substitute for the BZ chlordiazepoxide. Taken together, these results failed to demonstrate that the synthetic flavonoids 6-bromoflavone and 6-bromo-3'-nitroflavone possess anxiolytic-like properties similar or superior to that of diazepam, as was suggested previously. Furthermore, they question the contribution of BZ-omega receptors to the behavioral effects of 6-bromoflavone and 6-bromo-3'-nitroflavone.

Animals↗

PubMed1999

Dopamine D2 receptor knock-out mice are insensitive to the hypolocomotor and hypothermic effects of dopamine D2/D3 receptor agonists.

The dopamine (DA) D2-like family of receptors is comprised of three subtypes, the D2, D3, and D4 receptors. It has been suggested that the potency of DA receptor agonists to produce hypothermia and hypolocomotion in rodents correlates more strongly with the in vitro affinity for, or potency (mitogenesis test) at the D3 than at the D2 subtype. However, it has recently been reported that when tested in DA D3 receptor knock-out mice, several DA D2/D3 receptor agonists (7-OH-DPAT, PD 128907 and quinelorane) induced levels of hypothermia and decreases of locomotor activity similar to those obtained in control (wild-type) mice. These results do not argue in favour of an implication of DA D3 receptors in these in vivo effects. In order to investigate whether the DA D2 receptor is the subtype that mediates hypothermia and hypolocomotion produced by DA D2/D3 receptor agonists, we tested the effects of ip administration of the DA D2/D3 receptor agonists 7-OH-DPAT and PD 128907, on core temperature and locomotor activity in DA D2 receptor knock-out mice (homozygotes: D2(-/-) and heterozygotes: D2(+/-)), and in wild-type (D2(+/+)) mice. 7-OH-DPAT (0.1-3 mg/kg) and PD 128907 (1-10 mg/kg) induced hypothermia and decreased locomotion in D2(+/+) mice, but had no effects in D2(-/-) mice; the magnitude of the hypothermic and locomotor-reducing effects of these two agonists in D2(+/+) mutants was approximately half that of D2(+/+) mice. During the first 10 min in the activity chambers, the level of spontaneous locomotor activity of D2(-/-) individuals was almost 50% below that of D2(+/+) mice; basal locomotor activity of D2(+/-) mice was between that of D2(-/-) and D2(+/+) individuals. Neither type of mutant showed spontaneous catalepsy or deficits in forelimb muscle strength (grip-strength test). These results show that the presence of DA D2 receptors is necessary for the expression of the locomotor- and core temperature-decreasing effects of DA D2/D3 receptor agonists such as 7-OH-DPAT and PD 128907.

Animals↗

PubMed1999

Behavioral effects of acute and chronic fluoxetine in Wistar-Kyoto rats.

It has been previously reported that Wistar-Kyoto (WKY) rats may be useful in the study of the biological mechanisms involved in stress-related disorders. In the present study, WKY were treated acutely or chronically (one daily i.p. injection for 22-24 days) with the selective 5-HT reuptake inhibitor and clinically effective antidepressant and anxiolytic fluoxetine (5 and 20 mg/kg) and exposed to the forced swimming test (FST) and to the elevated plus-maze (EPM) at different times postinjection (30, 60, min or 24 h). In the FST, WKY failed to respond to fluoxetine, regardless of treatment. In the EPM, acute fluoxetine (20 mg/kg) produced anxiolytic-like effects when animals were tested 24 h, but not 30 min after drug administration. Positive effects in the EPM were evident on both conventional (open-arm activity) and ethological (risk assessment) measures in the absence of effect on activity measures (total and closed-arm entries). No evidence for anxiolytic-like activity was observed following chronic fluoxetine. These results indicate that WKY rats are resistant to fluoxetine treatment in the FST, while their behavior may be modified in the EPM when animals received a single fluoxetine challenge 24 h before testing. Overall, these findings provided little evidence that WKY rats may represent a valid model of stress-related disorders.

Analysis of Variance↗

PubMed1999

Differences in anxiolytic-like profile of two novel nonbenzodiazepine BZ (omega) receptor agonists on defensive behaviors of mice.

The present experiments compared the behavioral effects of two novel BZ (omega) receptor agonists, the pyridazinone Y-23684 (1-30 mg/kg) and the pyrido[1,2-a]benzimidazole RWJ-46771 (0.01-0.3 mg/kg) with the BZs diazepam (0.5-3 mg/kg) and clobazam (1-30 mg/kg) in the mouse defense test battery (MDTB), a model for the screening of anxiolytic drugs. In the MDTB, Swiss mice were confronted with a natural threat (a rat) and situations associated with this threat. Primary measures taken during and after rat confrontation were flight, risk assessment, defensive threat/attack, and escape attempts. Results showed that clobazam and Y-23684 significantly modified all defense responses in the presence of the rat at doses that did not decrease spontaneous locomotor activity. These drugs decreased avoidance reactions after the rat was introduced into the runway, reduced flight speed and risk assessment activities of mice chased by the rat, increased risk assessment displayed when subjects were constrained in a straight alley, and reduced defensive threat and attack behaviors upon forced contact. Diazepam significantly decreased all but one (number of avoidances when the rat was first introduced into the runway) defensive behaviors. RWJ-46771 reduced risk assessment in the chase test, avoidance responses, flight speed, and defensive threat and attack reactions, but these effects occurred in the great part at motor-impairing doses, suggesting that the decrease in defensiveness may have been contaminated by behavioral suppression. Finally, following the removal of the rat from the runway, only Y-23684 reduced escape behavior at doses that did not decrease spontaneous behavior. Taken together, these findings demonstrate that Y-23684 displayed anxiolytic-like activity comparable to that of BZs in the MDTB. Although RWJ-46771 significantly modified most defensive behaviors, the effects may have been confounded by decreases in locomotor activity.

Aggression↗

PubMed1999

Discriminative stimulus effects of drugs acting at GABA(A) receptors: differential profiles and receptor selectivity.

The GABA(A) receptor complex contains a number of binding sites at which a variety of psychotropic drugs, including benzodiazepines, barbiturates, and some neurosteroids, act to potentiate or inhibit the effect of the transmitter. Many studies have reported that these drugs can produce discriminative stimulus actions, but the cueing effects of compounds acting at different sites to enhance the effects of GABA are not identical. The discriminative stimulus effects of benzodiazepines have been analyzed in detail, and there is also a great deal of information available on the effects of nonbenzodiazepine compounds acting at BZ(omega) recognition sites, which form part of the GABA(A) receptor complex. Of particular interest are compounds with selectivity for the BZ1(omega1) receptor subtype including zolpidem, zaleplon, and CI 218,872. BZ1(omega1)-selective drugs substitute for the discriminative stimulus produced by chlordiazepoxide only partially and at sedative doses. This is consistent with the view that sedative effects of BZ(omega) receptor agonists are mediated by the BZ1(omega1) receptor subtype, whereas the discriminative stimulus produced by chlordiazepoxide may be produced by activity at the BZ2(omega2) subtype. Analysis of this hypothesis is complicated by the variety of levels of intrinsic activity shown by different drugs.

Animals↗

PubMed1999

Reduction of oral ethanol self-administration in rats by monoamine oxidase inhibitors.

Evidence for a role of dopamine and serotonin in the control of ethanol intake in animals suggests that monoamine oxidase (MAO) inhibitors, which increase the synaptic availability of serotonin and dopamine by blocking their metabolism, might have efficacy in the treatment of alcohol dependence. The aim of the present study was, therefore, to evaluate several MAO inhibitors for their capacity to affect ethanol self-administration in rats trained to self-administer ethanol (10% v/v) orally in a free-choice two-lever operant task. The nonselective and irreversible MAO inhibitors, phenelzine (3-10 mg/kg), tranylcypromine (1-3 mg/kg), and nialamide (30 mg/kg), decreased rates of responding maintained by ethanol reinforcement. The reversible MAO-A inhibitor, befloxatone (0.3-3 mg/kg), and the irreversible MAO-A inhibitor, clorgyline (10-30 mg/kg), also reduced ethanol self-administration. However, befloxatone-induced effects leveled off at a 50% decrease. The irreversible MAO-B inhibitors, pargyline (30 mg/kg) and l-deprenyl (3-10 mg/kg) also decreased responding maintained by ethanol reinforcement; these results are consistent with previous findings that both drugs decreased ethanol intake in mice. In conclusion, the present results showing that several MAO inhibitors decreased ethanol self-administration in rats are consistent with previous findings that synaptic levels of serotonin and dopamine play a critical role in the control of ethanol self-administration.

Alcohol Drinking↗

PubMed1999

Study of the modulatory activity of BZ (omega) receptor ligands on defensive behaviors in mice: evaluation of the importance of intrinsic efficacy and receptor subtype selectivity.

1. This study examined the hypothesis that the anxiolytic effects of benzodiazepine (BZ (omega)) receptor ligands may be associated with actions at a defined receptor subtype and/or their level of intrinsic activity using the mouse defense test battery. 2. This test has been designed to assess defensive reactions of Swiss mice confronted with a natural threat (a rat) and situations associated with this threat. Primary measures taken before, during and after rat confrontation were escape attempts, flight, risk assessment and defensive threat and attack. 3. The drugs used were the non-selective BZ (omega) receptor full agonist diazepam, the non-selective BZ (omega) receptor partial agonist bretazenil and the beta-carboline abecarnil which acts as a full agonist on GABAA receptors containing the alpha 1- and the alpha 3-subunits and as a partial agonist at receptors containing the alpha 2- and the alpha 5-subunits. The drugs were given alone and diazepam was co-administered with either bretazenil or abecarnil. 4. When administered alone, diazepam attenuated several defensive responses including risk assessment activities, defensive threat/attack reactions upon forced contact with the rat and escape attempts following the removal of the rat from the apparatus. Unlike diazepam, bretazenil was devoid of significant activity on defense and abecarnil displayed depressant activity. 5. Bretazenil blocked all behavioral effects of diazepam on defense behaviors. The co-administration of diazepam and abecarnil produced a behavioral profile similar to that observed when diazepam was administered alone, indicating that abecarnil did not influence the effects of diazepam on defense. By contrast, diazepam completely antagonized the sedative effects of abecarnil. 6. These findings indicate that only BZ (omega) ligands with high intrinsic efficacy at all BZ (omega) receptor subtypes display clear and specific effects on defensive behaviors in mice, and suggest that GABAA receptors containing the alpha 3 subunit might represent the primary target involved in the modulatory action of diazepam on defensive behaviors.

Analysis of Variance↗

PubMed1999

Prepulse inhibition of the startle reflex in rats: effects of compounds acting at various sites on the NMDA receptor complex.

Prepulse inhibition (PPI) of the startle reflex in rats is disrupted by N-methyl-D-aspartate (NMDA) receptor non-competitive antagonists (phencyclidine-like compounds). In order to explore more thoroughly the control exerted by NMDA receptors on PPI, we assessed the effects of i.p. administration, in Sprague-Dawley rats, of compounds acting as antagonists or agonists at the five binding sites of the NMDA receptor complex. The non-competitive NMDA receptor antagonists phencyclidine (1-6 mg/kg) and MK-801 (dizocilpine: 0.05-0.2 mg/kg) robustly and dose-dependently disrupted PPI. A similar effect was obtained with the competitive NMDA receptor antagonists CGS 19755 (1-20 mg/kg) and CPP (3-20 mg/kg), but not with the cation Mg2+ (100 and 200 mg/kg), the glycine/NMDA binding site antagonist L-701,324 (1-10 mg/kg), or the polyamine/NMDA binding site antagonist eliprodil (3-20 mg/kg). Potentiation of glutamatergic neurotransmission by NMDA (10-50 mg/kg), and the glycine/NMDA site partial agonist d-cycloserine (1-30 mg/kg) also failed to modify PPI, though d-cycloserine diminished PPI at higher doses (50-200 mg/kg). Co-administration of sub-threshold doses of CPP (3 mg/kg) and phencyclidine (2 mg/kg) resulted in an additive effect, disrupting PPI. In contrast, co-administration of L-701,324 (6 mg/kg) with phencyclidine (2 mg/kg), eliprodil (20 mg/kg), or CPP (3 mg/kg), did not disrupt PPI. These results demonstrate that PPI-disrupting effects can only be obtained with phencyclidine-like compounds and NMDA receptor competitive antagonists. Treatment with compounds that potentially augment glutamatergic tone were without effect. Finally, despite the permissive control of the glycine/NMDA binding site on glutamatergic neurotransmission, the glycine/NMDA binding site antagonist L-701,324 did not produce synergistic activity when combined with antagonists at the glutamate, polyamine/NMDA or phencyclidine-like compound binding sites.

Acoustic Stimulation↗

PubMed1999

Comparison of the pharmacological properties of classical and novel BZ-omega receptor ligands.

The experiments in this study compared the pharmacological properties of several BZ-omega receptor ligands, including the imidazobenzodiazepine imidazenil, the beta-carboline abecarnil, the pyridazinone Y-23684, the pyrido [1,2-a]benzimidazole RWJ 46771 and the 1,6-naphthyridin-2(1H)-one derivative SX-3228, with the prototypical BZs diazepam, clobazam and bretazenil. In in vitro experiments diazepam, bretazenil, imidazenil and Y-23684 displaced [3H]flumazenil binding non-selectively in membranes from rat cerebellum and spinal cord, two brain areas enriched in the BZ-omega 1 and BZ-omega 2 receptor subtypes, respectively. In contrast, abecarnil, RWJ 46771 and SX-3228 were more potent in displacing [3H]flumazenil binding to membranes from rat cerebellum than from spinal cord or hippocampus, indicating selectivity for the BZ-omega 1 receptor subtype. The in vivo experiments showed that all compounds increased the latency to clonic seizures produced by isoniazid. However, the maximal increase in latency induced by diazepam, clobazam, abecarnil, RWJ 46771 and SX-3228 was greater than that of bretazenil, imidazenil and Y-23684, thereby indicating that these latter compounds have low intrinsic efficacy. In the punished drinking, the punished lever pressing and the elevated plus-maze tests in rats, three models of anxiety, diazepam, clobazam and imidazenil elicited clear anxiolytic-like effects but at doses which were close to those producing hypolocomotion, ataxia and myorelaxation as measured in activity cages, the rotarod and the loaded grid tests, respectively. In contrast, bretazenil and Y-23684 induced anxiolytic-like activity at much lower doses than those which impaired motor performances. The magnitude of the positive effects of Y-23684 was similar to that of the reference BZs, suggesting that it may become a valuable alternative to currently used agents for the treatment of anxiety disorders. Abecarnil, RWJ 46771 and SX-3228 produced weaker or non-specific anxiolytic-like effects as they decreased anxiety-related behaviours at doses similar or close to those impairing motor performance. However, unlike the other compounds they induced myorelaxation at doses which were 3-10 times higher than those needed to produce decrease in exploratory activity. It is suggested that the behavioural profiles of abecarnil, RWJ 46771 and SX-3228 may be attributed to their selectivity for the BZ-omega 1 receptor subtype which may account for their sedative activity, thereby masking other effects including anxiolytic-like activity. This suggests that BZ receptor modulation of anxiety may involve BZ receptor subtypes other than BZ-omega 1.

Animals↗

PubMed1999

Clearance of man made mineral fibres from the lungs of sheep.

OBJECTIVES: To compare the clearance rate, the related pathology, and the chemical and morphological changes of three man made mineral fibres (MMMFs) in the sheep model of pneumoconiosis. METHODS: Fibrous particles were extracted from lung parenchyma and analysed by transmission electron microscopy (TEM) and energy dispersive spectroscopy (EDS). RESULTS: The concentration of MMMF11, MMMF21, refractory ceramic fibre (RCF-1), and crocidolite asbestos fibres decreased with time according to a slow and a fast kinetic component. There was a statistical difference in the four regression lines as a function of time and the type of fibres (p < 0.001). The diameter of MMMFs decreased during the course of the time, whereas the crocidolite fibres did not seem to show any change. There was a statistical difference in the four regression lines as a function of time (p = 0.037) and type of fibres (p < 0.001). Ferruginous bodies were counted in the 40 sheep for which the latency period was 2 years. No typical ferruginous bodies were found in the groups exposed to MMMFs. The geometric mean concentration of asbestos bodies in the group exposed to crocidolite was 2421 bodies/g lung tissue (95% CI 385 to 15260). CONCLUSIONS: The number of initially retained fibres decreased with time according to a slow and a fast kinetic component. MMMF11 and MMMF21 have similar clearance, faster than RCF-1 and crocidolite. The geometric mean diameter and length of MMMF decreased with time, but crocidolite did not. After 2 years in the sheep tracheal lobe, ferruginous bodies were not found in all three MMMF groups but were substantial in the crocidolite group. Clearance is thought to proceed through dissolution and macrophage translocation.

Animals↗

PubMed1998

Characterization of the behavioral profile of the non-peptide CRF receptor antagonist CP-154,526 in anxiety models in rodents. Comparison with diazepam and buspirone.

The present series of experiments compared the behavioral effects of the novel non-peptide CRF antagonist CP-154,526 with those of diazepam and the 5-HT1A receptor partial agonist buspirone in classical animal models of anxiety including conflict tests (punished lever pressing and punished drinking tests in rats) and exploratory models (elevated plus-maze test in rats, light/dark choice and free-exploration tests in mice), and a recently developed mouse defense test battery (MDTB) which has been validated for the screening of anxiolytic drugs. Results from both conflict procedures showed that diazepam (2.5-10 mg/kg, i.p.) produced clear anxiolytic-like effects, whereas buspirone (2.5 mg/kg, i.p.) displayed anticonflict activity in the punished drinking test only. CP-154,526 (0.6-20 mg/kg) was devoid of significant activity in both procedures. In the elevated plus-maze, diazepam (2 mg/kg, i.p.) produced significant effects on traditional (i.e. spatio-temporal) and ethologically derived (i.e. risk assessment and directed exploration) indices of anxiety. Buspirone (1-4 mg/kg, i.p.) reduced risk assessment activities only, and CP-154,526 (0.6-20 mg/kg, i.p.) did not modify the indices of anxiety in the elevated plus-maze. In the light/dark test, diazepam (2.5-5 mg/kg, i.p.) and CP-154,526 (10-40 mg/kg, i.p.) affected all behavioral indices of anxiety, while buspirone reduced risk assessment activities at the highest doses only (10 and 15 mg/kg, i.p.). In the free-exploration test, diazepam (1 mg/kg, i.p.) reduced avoidance responses towards novelty, as indicated by the increase in exploratory activity in a novel compartment and the decrease in risk assessment. CP-154,526 failed to affect the former behavior and weakly reduced the latter (5 and 20 mg/kg, i.p.). Buspirone (1.25-5 mg/kg, i.p.) was inactive in this test. Finally, in the MDTB, diazepam (0.5-3 mg/kg, i.p.) attenuated all defensive reactions of mice confronted with a rat stimulus (i.e. flight, risk assessment and defensive attack) or with a situation associated with this threat (i.e. contextual defense). Buspirone (1.25-5 mg/kg, i.p.) reduced defensive attack and contextual defense, while CP-154,526 (5-20 mg/kg, i.p.) affected all defensive behaviors, with the exception of one risk assessment measure. The finding that CP-154,526 displayed positive effects in mice but not in rats may be due to increased sensitivity to environmental stress of the strains used (i.e. BALB/c, Swiss) and/or to the fact that animals were exposed to unavoidable stress stimuli which may lead to a significant activation of the CRF system. Although in mice the anxiety-reducing potential of CP-154,526 is superior to that of the atypical anxiolytic buspirone, it is smaller in terms of the magnitude of the effects and the number of indices of anxiety affected than that of diazepam.

Animals↗

PubMed1998

Preferential involvement of D3 versus D2 dopamine receptors in the effects of dopamine receptor ligands on oral ethanol self-administration in rats.

There is evidence that dopamine transmission is involved in reinforcement processes and the present study investigated the relative involvement of D3 versus D2 dopamine receptors in the effects of dopamine ligands on the reinforcing action of ethanol. Rats were trained to self-administer ethanol (10% v/v) orally in a free-choice two-lever operant task using a saccharin-fading procedure. When preference in responding for ethanol over water had developed the rats were tested with several dopamine agonists and antagonists. Pretreatment with the non-selective dopamine agonist, apomorphine (0.01-0.1 mg/kg), the preferential D2 agonist, bromocriptine (1-10 mg/kg) and the selective D3 agonists, 7-OH-DPAT (0.003-0.1 mg/kg), PD 128907 (0.1-3 mg/kg), (+)3PPP (0.3-3 mg/kg), quinelorane (0.0001-0.003 mg/kg) and quinpirole (0.003-0.03 mg/kg), resulted in dose-dependent decreases in responding for ethanol. The relative potencies of the dopamine agonists to decrease ethanol self-administration were highly correlated with their published potencies to produce in vitro functional D3 but not D2 responses. Active doses could be considered as those selectively stimulating receptors involved in the control of dopamine release, suggesting that reduction of dopamine transmission was associated with a decrease in ethanol-reinforced responding. This conclusion was further supported by the finding that pretreatment with the D2/D3 dopamine antagonists, haloperidol (0.1-0.4 mg/kg) and tiapride (10-60 mg/kg), decreased responding for ethanol at doses which have been shown previously to block dopamine transmission.

Alcohol Drinking↗

PubMed1998

Angular and fibrous particles in lung in relation to silica-induced diseases.

INTRODUCTION: The lung concentration of angular and fibrous particles was measured in cases of lung fibrosis only, in cases of lung fibrosis and lung cancer, and in cases of lung cancer only. These patients worked in different trades (mining, foundries, construction and were not a homogeneous group of exposed workers. MATERIAL AND METHODS: Particles, both angular and fibrous, were extracted from lung parenchyma by a bleach digestion method, mounted on copper microscopic grids by a carbon replica technique, and analyzed by transmission electron microscopy (TEM) and energy-dispersive spectroscopy (EDS). The quartz concentration was also determined by X-ray diffraction (XRD) on a silver membrane filter after extraction from the lung parenchyma. RESULTS: (1) Lung cancer and lung fibrosis cases retained more metal-rich particles (P = 0.02) and more angular particles of all sorts (P = 0.009) than did lung fibrosis cases only, and the differences were statistically significant. (2) However, more quartz was retained in the lungs in lung fibrosis cases than in lung fibrosis or lung cancer cases, but the difference in the concentrations was not statistically significant. (3) More ferruginous bodies were retained in the lungs in lung cancer and lung fibrosis cases than in cases of lung fibrosis only, and the difference in the concentrations was statistically significant (P = 0.02). CONCLUSION: Results obtained from lung tissue must always be interpreted cautiously. However, these results are consistent with the hypothesis that workers in some trades such as foundries were exposed not only to quartz but also to asbestos, ceramic fibers, metal-rich non fibrous particles, and other likely carcinogenic chemicals. The wide range of particle types identified in the lungs of these workers illustrates the complexity of trying to determine disease origins in these work environments. Epidemiology studies have to control for the exposure to these carcinogens as well as for smoking habits.

Aged↗

PubMed1998

Behavioral effects of phenelzine in an experimental model for screening anxiolytic and anti-panic drugs: correlation with changes in monoamine-oxidase activity and monoamine levels.

This study investigated the effects of acute and chronic (one daily i.p. injection for 14 days) treatments with the non-selective irreversible monoamine-oxidase (MAO) inhibitor phenelzine (10 and 30 mg/kg) on defensive behaviors of Swiss mice in the mouse defense test battery (MDTB) which has been designed for screening anxiolytic and anti-panic drugs. In the MDTB, subjects were confronted with a natural threat (a rat) and situations associated with this threat. MAO-A and MAO-B activities and levels of brain monoamines (serotonin (5-HT), dopamine (DA) and norepinephrine (NE)) and their deaminated metabolites were subsequently measured. Behavioral results showed that acute administration of phenelzine did not specifically modify defensive behaviors. By contrast, after chronic treatment, phenelzine produced a significant reduction in avoidance distance when the rat was approaching, an effect which is consistent with an anti-panic-like action. In addition, phenelzine displayed weak anxiolytic-like effects as it increased risk assessment responses when mice were constrained in one part of the apparatus facing the rat which remained at a constant distance. No other specific drug effect was observed. These behavioral changes were associated with a dramatic increase in 5-HT levels, in particular after chronic treatment, while levels of DA and NE increased only slightly. Importantly, no significant differences in DA and NE levels between acute and chronic regimens were observed. Levels of deaminated metabolites of monoamines were markedly decreased. Measurements of MAO activity revealed substantial reductions in both type A and B forms with a full inhibition of both forms being observed only after chronic treatment with phenelzine. These results suggest that the effects of phenelzine may be due mainly to its effects on the 5-HT system and presumably related to the full inhibition of MAO-A and/or MAO-B.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1998

Limited anxiolytic-like effects of non-benzodiazepine hypnotics in rodents.

The present experiments compared the anxiolytic-like effects of the benzodiazepine (BZD) hypnotic triazolam with those of four non-BZD hypnotics including one non-selective (zopiclone) and three omega1-BZD selective (zolpidem, zaleplon and SX-3228) receptor ligands, in classical animal models including conflict tests (punished lever pressing and punished drinking tests in rats) and exploratory models (elevated plus-maze test in rats and light/dark choice test in mice), and a recently developed mouse defence test battery (MDTB) which has been validated for the screening of anxiolytic drugs. Results from both conflict procedures showed that zopiclone (0.3-10 mg/kg) produced anxiolytic-like effects comparable to those of triazolam (0.1-3 mg/kg), whereas the selective omega1-BZD receptor hypnotics zolpidem (0.3-3 mg/kg), zaleplon (0.1-3 mg/kg) and SX-3228 (0.1-1 mg/kg) displayed weaker and/or non-specific anxiolytic-like effects. Similarly, in the light/dark test in mice, zolpidem (0.1-1 mg/kg), zaleplon (0.3-10 mg/kg) and SX-3228 (0.03-0.3 mg/kg) showed a reduced potential to produce anxiolytic-like effects as compared to the non-selective omega-BZD receptor hypnotics triazolam (0.03-1 mg/kg) and zopiclone (1-30 mg/kg). In the elevated plus-maze test, zopiclone (1-10 mg/kg), zolpidem (0.1-1 mg/kg), zaleplon (0.3-3 mg/kg) and SX-3228 (0.1-1 mg/kg) displayed anxiolytic-like activity at doses close to those producing behavioural impairment, whereas triazolam (0.03-1 mg/kg) exhibited anxiolytic-like effects over a wide dose range in the absence of decreases in general activity. In the MDTB, zaleplon (0.3-10 mg/kg) decreased all defensive responses, a profile which was similar to that of triazolam (0.03-1 mg/kg), while zopiclone (1-30 mg/kg), zolpidem (0.3-10 mg/kg) and SX-3228 (0.03-1 mg/kg) had fewer effects on defensive behaviours with several effects occurring only at motor-impairing doses. Taken together, these results demonstrate that, although selective omega1-BZD receptor hypnotics display anxiolytic-like activity, the effects are generally weaker than those observed with non-selective omega-BZD receptor selective hypnotics such as triazolam or zopiclone. In particular, the anxiety-reducing potential of the omega1-BZD receptor selective compounds is limited to certain anxiety measures and may be confounded and/or masked by behavioural suppression.

Acetamides↗

PubMed1997

Angular and fibrous particles in lung are markers of job categories.

INTRODUCTION: The lung concentration of angular and fibrous particles has been measured when cases are stratified into their job categories; 21 miners (metallic mines such as gold, zinc and copper), 18 iron foundrymen, 22 non-iron foundrymen, four welders, three sand-blast workers, four construction workers, three technicians and professionals, seven workers in other trades excluding welding. Twelve asbestos miners representing a positive exposure to asbestos and 20 people representing a background population were added to the previous groups. MATERIAL AND METHODS: Particles, both angular and fibrous, were extracted from lung parenchyma by a bleach digestion method, mounted on copper microscopic grids by a carbon replica technique and analyzed by transmission electron microscopy (TEM) and energy dispersive spectroscopy (EDS). Quartz concentration was also determined by X-ray diffraction (XRD) on a silver membrane filter after the extraction from the lung parenchyma. RESULTS: (1) The highest concentrations of quartz were found in mines (metallic mines), iron foundrymen and sand-blast workers. Notable amounts quartz were found in welders and professionals. (2) The highest concentrations of short fibres were found in non-iron foundrymen, asbestos miners and construction workers. (3) The highest concentrations of long fibres were found in non-iron foundry men and asbestos miners. (4) The highest concentrations of ferruginous bodies were found in non-iron foundrymen and asbestos miners. (5) The non-iron foundrymen were exposed to ceramic fibres and asbestos fibres. CONCLUSION: The results of the study may not be representative of the broad spectrum of workers in the industrial activities in which they have been involved. However, the detailed composition of the retained particles of our workers is explained both qualitatively and quantitatively by their work histories. Finally, the broad range of particle types identified in the lungs of these workers illustrate the complexity or trying to determine disease origins in these occupational settings.

Biological Availability↗

PubMed1997

Effects of dihydropyridine Ca2+ channel blockers on the discriminative stimulus and the motor impairing effects of (+/-)-Bay K 8644.

Functional interactions between the dihydropyridine Ca2+ channel activator, (+/-)-Bay K 8644 (methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethyphenyl )-pyridine-5-carboxylate), and several dihydropyridine L-type Ca2+ channel blockers were investigated on rotarod performance in mice and in rats trained to discriminate between (+/-)Bay K 8644 and saline. When administered alone, (+/-)-Bay K 8644 produced dose-dependent impairments of rotarod activity with an ED50 of 1.3 mg/kg. Pretreatment with nifedipine (10-30 mg/kg) produced dose-dependent rightward shifts of the (+/-)-Bay K 8644 dose-response curve. In contrast, pretreatment with several other dihydropyridine L-type Ca2+ channel blockers, including nicardipine, nimodipine, isradipine and nitrendipine, did not modify the (+/-)-Bay K 8644 dose-effect function. Rats learned to discriminate between (+/-)-Bay K 8644 (0.5 mg/kg) and saline in an average of 65 training sessions. In substitution tests, the Ca2+ channel activator engendered dose-related increases in the percentage of rats selecting the drug-associated lever with an ED50 of 0.19 mg/kg. Pretreatment with nifedipine (10 mg/kg) produced a rightward shift of the (+/-)-Bay K 8644 dose-response function. Pretreatment with nicardipine (2.5 mg/kg) only partially antagonised the training dose of (+/-)-Bay K 8644 whereas nimodipine (0.6-10 mg/kg) did not affect the (+/-)-Bay K 8644 discriminative stimulus. The results of the present study show that the behavioural effects of the dihydropyridine Ca2+ channel activator are differentially modified by dihydropyridine L-type Ca2+ channel blockers. These results may suggest that dihydropyridine blockers possess different intrinsic activities or act at different binding sites.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗