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G Perrault

Publications and source records attributed to G Perrault.

At least 55 records · Page 3Linked to original sources
PubMed1997

Discriminative stimulus effects of apomorphine and 7-OH-DPAT: a potential role for dopamine D3 receptors.

Previous studies have reported that the non-selective dopamine agonist, apomorphine, can serve effectively as a discriminative stimulus in experimental animals, and evidence has been presented that this effect is mediated by dopamine D2 receptors. More recently, it has been found that another dopamine agonist, 7-OH-DPAT, which has some selectivity for D3 receptors, also produces a discriminative cue in rats. The present study set out to make a direct comparison of the discriminative stimulus effects of these two compounds. Rats were trained to discriminate either apomorphine (0.05 mg/kg, SC) or 7-OH-DPAT (0.1 mg/kg, IP) from saline. Both discriminations were acquired but extended training was necessary. Cross generalisation occurred between the two compounds and both cues generalised to the dopamine agonists, quinpirole, quinelorane, PD 128207, and bromocriptine. When the potencies of these compounds to produce the apomorphine or 7-OH-DPAT cues were correlated with their potencies to produce D2 or D3 functional responses in vitro (mitogenesis in transfected cells-results taken from the literature) stronger correlations with D3 than with D2 responses were observed. Both the cueing and the response rate-decreasing effects of apomorphine and 7-OH-DPAT were antagonised by the autoreceptor selective dopamine antagonist amisulpride, and sulpiride also antagonised the cues but without affecting response rates. In contrast, haloperidol blocked the cues but potentiated the response rate decreases. These results suggest that, at the doses used, apomorphine and 7-OH-DPAT produce similar discriminative stimuli, which may be mediated by presynaptically located dopamine D3 receptors.

Animals↗
PubMed1997

Behavioural profiles of the reversible monoamine-oxidase-A inhibitors befloxatone and moclobemide in an experimental model for screening anxiolytic and anti-panic drugs.

The present study compared the behavioural effects of acute and chronic (one daily i.p. injection for 14 days) treatments with the reversible monoamine oxidase-A inhibitors (RIMAs) moclobemide (3 and 10 mg/kg) and befloxatone (0.3 and 1 mg/kg) in the Mouse Defence Test Battery (MDTB) which has been designed for screening anxiolytic and anti-panic drugs. In the MDTB, Swiss mice were 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 (RA) and defensive threat and attack. After acute administration of both compounds, no modification of defensive behaviours were observed. This was in contrast to chronic treatments, where moclobemide (3 and 10 mg/kg) and befloxatone (1 mg/kg) produced a significant reduction in one flight measure (avoidance distance when the rat was approaching). In addition, befloxatone (0.3 and 1 mg/kg), but not moclobemide, increased RA responses when mice were constrained in one part of the apparatus facing the rat, which remained at a constant distance. No other drug effects were observed with either compound. Although these behavioural profiles are consistent with an anxiolytic-like effect, the finding of an action upon a limited number of defence responses suggests a weaker anxiolytic-like potential compared to that of classical anxiolytics. However, in view of previous data with panic-modulating compounds on flight behaviours in the MDTB, the present results are in line with clinical results showing that moclobemide is effective in panic disorders and suggest that befloxatone may have some efficacy in the clinical management of panic.

Animals↗
PubMed1997

Potentiation of prepulse inhibition of the startle reflex in rats: pharmacological evaluation of the procedure as a model for detecting antipsychotic activity.

Prepulse inhibition (PPI) of the startle reflex-whereby presentation of a weak prepulse preceding a startling pulse diminishes the amplitude of the startle reflex-is disrupted by dopamine (DA) agonists; this disruption can be reversed by antipsychotics. There are also some indications in the literature that a few antipsychotics (most notably clozapine and haloperidol) may, on their own, have effects opposite to those of DA agonists, i.e. may enhance PPI. In order to explore these antipsychotic-induced potentiations of PPI more thoroughly, we assessed, in Sprague-Dawley rats, the effects of IP administration of various clinically effective antipsychotics in a PPI procedure with levels of PPI (ranging from 5 to about 40%) low enough to facilitate detection of PPI-potentiating effects of drugs. Both clozapine (5-20 mg/kg) and haloperidol (0.25-1 mg/kg) robustly and dose-dependently potentiated PPI. A similar effect was not seen with risperidone (0.1-1 mg/kg) or with the three substituted benzamides amisulpride (10-60 mg/kg), raclopride (0.1-3 mg/kg) and remoxipride (1-10 mg/kg). As risperidone is known to have prominent 5-HT2 antagonistic activity, these results do not indicate a role for 5-HT2 receptors in the clozapine and haloperidol PPI-enhancing effects. The absence of effects with the benzamides and with risperidone, at doses with known anti-dopaminergic activity, suggests that DA antagonist activity is not involved. The demonstration that prazosin (3-20 mg/kg), a non-antipsychotic with alpha 1 adrenoceptor antagonistic properties, dose-dependently potentiated PPI indicates that alpha 1 receptors might mediate the clozapine and haloperidol PPI-enhancing activity. Additionally, the finding that diazepam (1-10 mg/kg) did not enhance, but on the contrary reduced PPI, argues against a sedation- or general depressant-mediated effect of clozapine, haloperidol and prazosin. The negative results with four clinically active antipsychotics (risperidone and the benzamides), and the positive result with the non-antipsychotic prazosin indicate that this PPI-enhancing procedure has poor predictive validity as a screening tool for potential antipsychotics.

Animals↗
PubMed1997

A comparative study of the effects of selective and non-selective 5-HT2 receptor subtype antagonists in rat and mouse models of anxiety.

Although there is some evidence that compounds acting at 5-HT2 receptors show anxiolytic activity, little is known about the specific involvement of the different 5-HT2 receptor subtypes in the modulation of anxiety-related responses. In the present study, the behavioural effects of mianserin, a non-selective 5-HT2 receptor antagonist, MDL 100,907, a selective 5-HT2A receptor antagonist, and SB 206553, a selective 5-HT2B/2C receptor antagonist, were investigated in two rat (the Vogel drinking conflict and the elevated plus-maze tests) and two mouse (i.e. the mouse defense test battery (MDTB) and the light/dark choice test) models of anxiety. Diazepam was used as a positive control. In the Vogel drinking test, mianserin (10 mg/kg) and SB 206553 (3-30 mg/kg), but not MDL 100,907, increased punished responding. Similarly, mianserin (1 mg/kg) and SB 206553 (3-10 mg/kg), but not MDL 100,907, increased entries into the open arms of the elevated plus-maze. These effects are consistent with anxiolytic-like actions of mianserin and SB 206553, although the magnitude of the effects of these two compounds was less than those of diazepam. In addition, in the MDTB, the 5-HT2 antagonists did not clearly affect the defensive reactions of mice exposed to a rat stimulus and they failed to reverse the avoidance of the illuminated box in the light/dark choice test. These results indicate a lack of anxiolytic-like action of the compounds in mice. These behavioural profiles suggest that blockade of the 5-HT2A receptor may not reduce anxiety and demonstrate that 5-HT2B and/or 5-HT2C receptor subtypes may be primarily involved in the anxiolytic-like effects of mianserin and SB 206553 in rats.

Animals↗
PubMed1997

Evidence for the involvement of dopamine receptors in ethanol-induced hyperactivity in mice.

Based on the hypothesis that drugs of abuse increase locomotor activity through mechanisms related to reinforcement, i.e. the mesolimbic dopamine (DA) system, ethanol-induced hyperactivity might provide a screening model to investigate the effect of ethanol on reward pathways. In the present study, ethanol had bidirectional effects on locomotion in mice: hyperactivity at low doses (2-3 g/kg) and sedation at high doses (4-5 g/kg). Such high doses induced a loss of righting reflex (LRR). The stimulant effect of ethanol was blocked by the D2/D3 antagonists, haloperidol (0.2 mg/kg) and tiapride (30-60 mg/kg), and by the D1 antagonist, SCH 23390 (0.03 mg/kg) whereas the non selective DA antagonist, clozapine decreased ethanol-induced hyperactivity at a dose (1 mg/kg) which also decreased activity in control animals. Unlike haloperidol and clozapine which potentiated LRR induced by ethanol, the selective DA antagonists, tiapride and SCH 23390, had no effect. Pretreatment with the D2/D3 agonist, quinpirole (0.1-0.3 mg/kg), reduced hyperactivity induced by ethanol presumably by stimulation of pre-synaptic receptors but did not change LRR. The D1 full agonist, SKF 81297 which produced hyperactivity by itself and the D1 partial agonist, SKF 38393, did not specifically affect ethanol-induced activities. The results indicate that activation of D1 and D2/D3 DA receptors is implicated in ethanol-induced hyperactivity whereas other mechanisms might mediate the sedative effects of ethanol. Tiapride and haloperidol, both used in the management of alcohol dependence, might exert beneficial effects by counteracting the reinforcing effects of ethanol. Tiapride's lack of interaction with the depressant effects of ethanol may account for its better tolerance in alcoholic patients.

Animals↗
PubMed1997

Risk assessment behaviour: evaluation of utility in the study of 5-HT-related drugs in the rat elevated plus-maze test.

The present study compared the effects of a wide range of 5-hydroxytryptamine (5-HT)-modulating and potential anxiolytic agents in the rat elevated plus-maze using spatiotemporal (i.e., open arm time and entries) and ethologically derived measures (i.e., risk assessment activities and directed exploration). The drugs used were 5-HT1A receptor partial (buspirone and ipsapirone) and full (8-OH-DPAT and flesinoxan) agonists, mixed 5-HT2A/2C receptor antagonists (ritanserin, ketanserin, mianserin, and pirenperone), selective 5-HT3 receptor antagonists (ICS 205-930, MDL 72222, ondansetron, and (RS)-zacopride), and selective (fluoxetine, fluvoxamine, and zimelidine) and nonselective (imipramine) 5-HT reuptake inhibitors. Only buspirone and mianserin produced effects indicative of an anxiolytic-like action on the spatiotemporal measures. However, all 5-HT1A receptor ligands, as well as mianserin, ketanserin, ondansetron, and zacopride, decreased the number of aborted attempts at entry into open arms (risk assessment). In addition, buspirone, mianserin, and zacopride increased head-dipping (directed exploration). Among the 5-HT reuptake inhibitors, zimelidine reduced head-dipping and total entries. The present findings demonstrate that risk assessment responses are sensitive to the action of 5-HT1A receptor ligands, but their modulation by drugs targetting 5-HT2A, 5-HT2C, and 5-HT3 receptors was not convincingly established.

Animals↗
PubMed1997

Amisulpride: from animal pharmacology to therapeutic action.

Amisulpride is a benzamide derivative with a unique neurochemical and psychopharmacological profile. This compound has selective affinity for human dopamine D3 and D2 receptor subtypes in vitro (binding constant, K approximately 3 nmol/l) and blocks functional responses mediated by these receptors. In ex vivo binding studies, amisulpride is twice as selective for D3 as for D2 receptors. At low doses, it preferentially blocks presynaptic dopamine autoreceptors (increase in dopamine release in vivo in the rat olfactory tubercle, 50% effective dose, ED50 3.7 mg/kg), while postsynaptic dopamine receptor antagonism is apparent at higher doses (decrease in striatal acetylcholine levels, ED50 approximately 60 mg/kg). Anisulpride preferentially stimulates dopamine synthesis and displaces 3H-raclopride binding in vivo in the limbic system rather than the striatum. It antagonizes apomorphine-induced hypothermia in mice and amphetamine-induced hypermotility in rats at low doses (ED50 2-3 mg/kg), blocks apomorphine-induced climbing and spontaneous grooming in mice, blocks apomorphine-induced gnawing in rats at higher doses (ED50 19-115 mg/kg) and does not induce catalepsy at 100 mg/kg. The preferential antagonism by amisulpride of presynaptic D2/D3 receptors is reflected behaviourally in the potent blockade of apomorphine-induced effects mediated by dopamine autoreceptors (yawning and hypomotility: ED50 0.2 and 0.3 mg/kg, respectively) compared with those medicated by postsynaptic D2 receptors (e.g. gnawing: ED50 115 mg/kg). Moreover, low doses of amisulpride induce prohedonic (potentiation of food-induced place preference) effects in rats. The atypical neurochemical and psychopharmacological profiles of amisulpride may explain its therapeutic efficacy on both positive and negative symptoms of schizophrenia.

Amisulpride↗
PubMed1997

Some, but not all, antipsychotic drugs potentiate a low level of prepulse inhibition shown by rats of the Wistar strain.

In a previous study using Sprague-Dawley rats, we showed that in a prepulse inhibition (PPI) procedure with levels of PPI ranging from approximately 10 to 40% (for prepulse intensities 2, 9 and 15 dB above background noise), the antipsychotics clozapine and haloperidol, but also the alpha 1 adrenoceptor antagonist prazosin, robustly and dose-dependently potentiated PPI. In contrast, the antipsychotics risperidone, amisulpride, raclopride and remoxipride did not potentiate PPI. The false positive (prazosin) and the four false negatives led us to conclude that this PPI-enhancing procedure had poor predictive validity as a screening tool for potential antipsychotics. In the present study, we used Wistar rats, which under the same protocol as that used for Sprague-Dawley rats show a very low level of PPI. We examined the ability of six antipsychotics, given intraperitoneally (i.p.), to reverse this PPI deficit. It was found that clozapine (5-20 mg/kg), olanzapine (5-20 mg/kg) and sertindole (1-10 mg/kg) reversed this deficiency of PPI (i.e. potentiated the low level of PPI). In contrast, risperidone (0.1-1 mg/kg), remoxipride (1-10 mg/kg) and haloperidol (0.1-1 mg/kg) were inactive. The negative results with three clinically active antipsychotics (risperidone, remoxipride and haloperidol) indicate that reversal of this PPI deficit in Wistar rats has poor predictive validity to screen for potential antipsychotic activity. In an attempt to investigate the mechanism that might underlie the reversing effect of clozapine, olanzapine and sertindole, we tested the ability of the alpha 1 adrenoceptor antagonist prazosin (3-20 mg/kg), the dopamine D1 receptor antagonist SCH 23390 (0.01-0.1 mg/kg) and the 5-HT2 antagonist ritanserin (0.3-3 mg/kg) to reverse the PPI deficit. Negative results with these three drugs did not allow us to characterize the receptor(s) that might be implicated in the reversal of this type of PPI deficit.

Adrenergic alpha-Antagonists↗
PubMed1997

CCK receptor antagonists in animal models of anxiety: comparison between exploration tests, conflict procedures and a model based on defensive behaviours.

The present experiments compared the behavioural effects of one cholecystokininA (CCKA; lorglumide) and two CCKB (PD 135,158 and LY 288513) receptor antagonists in classical animal models of anxiety, including conflict tests (punished lever pressing and Vogel 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 both anti-panic and classical anxiolytic (i.e. benzodiazepines) drugs. Diazepam was used as a positive control. Results showed that all three CCK receptor antagonists were inactive in both conflict tests. Furthermore, despite the incorporation of more ethologically-derived measures (i.e. risk assessment activities or directed exploration, or both) no effects were observed in the elevated plus-maze and in the light/dark tests. These profiles contrast with that of diazepam which displayed clear anxiolytic-like effects in these models. In the MDTB, the CCK receptor antagonists failed to modify parameters (i.e. risk assessment, defensive threat/attack and escape attempts), which have been shown to be particularly sensitive to drugs effective in the treatment of generalized anxiety. By contrast, the CCKB receptor antagnoists PD 135,158 (0.001-0.01, 1 mg/kg, i.p.) and LY 288513 (1 and 3 mg/kg, i.p.) significantly decreased avoidance distance when the rat was first placed in the test apparatus, an effect which is consistent with an anti-panic-like action. Overall, these findings support the idea that classical animal models of anxiety may not be suitable for evaluation of the behavioural effects of CCK receptor antagonists, whereas tests which may model certain aspects of human panic such as the MDTB appear to be more reliable tools when screening such compounds.

Aggression↗
PubMed1997

Assessment of the antidepressant-like effects of L-type voltage-dependent channel modulators.

L-type voltage-dependent calcium channel blockers acting at different sites were tested in animal models of depression. Their effects on locomotion were studied in separate experiments. Nifedipine, a drug which interacts selectively with dihydropyridine (DHP) binding sites, reduced immobility time in the mouse forced swimming test and tail suspension test, but lacked activity in the differential-reinforcement-of-low-rate schedule in rats (DRL 72 s). The effects of nifedipine in the tail suspension test was partly antagonized by Bay K 8644, a DHP channel activator, indicating that its effect involved L-type calcium channel. Several other DHP drugs (nicardipine, nitrendipine, isradipine, felodipine and nimodipine) also showed antidepressant-like properties in the tail suspension test, whereas amlodipine, a less selective compound, lacked activity. In contrast to the DHP drugs, verapamil and (-)emopamil (which act at the phenylalkylamine binding sites), diltiazem and clentiazem (benzothiazepine binding sites), and the non-selective drug, flunarizine, were inactive in the tail suspension test. Negative results were also obtained with verapamil, diltiazem and flunarizine in the forced swimming test and with flunarizine on DRL 72 s responding. The present results show that DHP channel blockers displayed 'antidepressant-like' properties in mice. There was little dissociation, however, between the doses that produced antidepressant effects and those that decreased locomotor activity.

Animals↗
PubMed1997

Psychopharmacological profile of amisulpride: an antipsychotic drug with presynaptic D2/D3 dopamine receptor antagonist activity and limbic selectivity.

Amisulpride, a benzamide derivative, is an antipsychotic drug with a pharmacological profile distinct from that of classical neuroleptics such as haloperidol and from that of another benzamide, remoxipride. In mice, amisulpride antagonized hypothermia induced by apomorphine, quinpirole or (+/-) 7-hydroxy-2-(di-n-propylamino)-tetralin, an effect involving D2/D3 receptors, at similar doses (ED50 approximately 2 mg/kg i.p.), which were much lower than doses that blocked apomorphine-induced climbing, an effect involving postsynaptic D2 and D1 receptor activation (ED50 = 21 mg/kg i.p.). Much higher doses (ED50 = 54 mg/kg i.p.) of amisulpride were needed to block grooming behavior observed after a short period in water, a D1 receptor-mediated behavior. In rats, amisulpride preferentially inhibited effects produced by low doses of apomorphine (hypomotility and yawning), related to stimulation of presynaptic D2/D3 dopamine autoreceptors (ED50 = 0.3 and 0.19 mg/kg i.p.). By contrast, amisulpride antagonized apomorphine-induced hypermotility, a postsynaptic dopamine receptor-mediated effect, at a much higher dose (ED50 = 30 mg/kg i.p.). Amisulpride (100 mg/kg i.p.) only partially inhibited apomorphine-induced stereotypies (gnawing) and had no effect on stereotypies induced by d-amphetamine. However, d-amphetamine-induced hyperactivity was antagonized by doses of amisulpride as low as 3 mg/kg i.p., which may indicate selectivity of this drug for limbic dopaminergic mechanisms. In addition, in contrast to haloperidol or remoxipride, which produced catalepsy at doses 2 or 3 times higher than those that antagonized stereotypies induced by apomorphine, amisulpride did not induce catalepsy up to a dose of 100 mg/kg i.p., which occupies 80% of striatal D2 receptors. This pharmacological profile of amisulpride, characterized by a preferential blockade of effects involving presynaptic mechanisms and limbic structures, may explain the clinical efficacy of this drug against both negative and positive symptoms of schizophrenia and its low propensity to produce extrapyramidal side effects.

Amisulpride↗
PubMed1997

Characterization of the discriminative stimulus produced by the dopamine antagonist tiapride.

The ability of tiapride, a selective D2/D3 dopamine receptor antagonist, to exert discriminative stimulus control of responding was investigated by training rats to discriminate this drug (30 mg/kg) from saline in a two-lever, food-reinforcement procedure. Acquisition of tiapride discrimination required a relatively lengthy training period (mean of 76 sessions) but stable performance was maintained throughout the 18- month study. The dose of tiapride eliciting 50% tiapride-lever choice (ED50) was 2.2 mg/kg. After determination of the dose-effect curve with tiapride, substitution tests with several dopamine antagonists and other reference compounds were performed. All dopamine antagonists, including amisulpride (ED50 4 mg/kg), sulpiride (18 mg/kg), sultopride (1.5 mg/kg), clebopride (0.13 mg/kg), raclopride (0.16 mg/kg), metoclopramide (1.4 mg/kg), remoxipride (4.8 mg/kg), pimozide (2.7 mg/kg), thioridazine (3.4 mg/kg), olanzapine (0.97 mg/kg), chlorpromazine (1.9 mg/kg), risperidone (0.22 mg/kg) and haloperidol (0.14 mg/kg), except clozapine (>10 mg/kg), produced dose-dependent substitution for tiapride. Tiapride-like stimulus effects were observed at doses that decreased response rates. However, ED50 values for substitution by tiapride, amisulpride, sulpiride, sultopride, pimozide, clebopride and thioridazine were lower than ED50 values for decreasing responding. Additional studies were conducted to evaluate the ability of direct and indirect dopamine agonists to attenuate the tiapride discriminative stimulus. Pretreatment with d-amphetamine and nomifensine antagonized the discriminative stimulus effects of tiapride. Quinpirole, 7-OH-DPAT, bromocriptine and apomorphine partially blocked the stimulus effects of tiapride whereas SKF 38393 did not affect the discrimination. These results from substitution and antagonism tests indicated that the discriminative effects of tiapride are mediated by activity at D2/D3 dopamine receptors.

Animals↗
PubMed1996

Comparison of the pharmacological profiles of the hypnotic drugs, zaleplon and zolpidem.

The BZ1 (omega 1)-selective compound, zolpidem, is a clinically effective hypnotic drug with a pharmacological profile which differs from those of benzodiazepine anxiolytics and hypnotics. Zaleplon (CL 284,846) has recently been described as a hypnotic agent which also has BZ1 (omega 1) receptor selectivity. The pharmacological effects of zolpidem and zaleplon were therefore compared in mice and rats. Both drugs blocked tonic convulsions induced in mice by pentylenetetrazole and electroconvulsive shock and clonic convulsions induced by isoniazid. Zaleplon was more potent than zolpidem but the maximal effect of zolpidem for increasing the latency to isoniazid-induced convulsions was greater than that of zaleplon. Little tolerance developed to the anticonvulsant effect of zaleplon against isoniazid-induced seizures following twice daily administration of 10 or 30 mg/kg for 10 days. Both compounds reduced locomotor activity and produced motor deficits in the rotarod and loaded grid tests in mice. However, while zaleplon produced all three effects at similar doses, zolpidem showed the greatest potency for reducing locomotion. Zaleplon and zolpidem also decreased locomotion and produced a rotarod deficit in rats. Again, the difference between the doses giving rise to these two effects was greater for zolpidem than for zaleplon. In a drug discrimination procedure using rats trained to discriminate a dose (5 mg/kg) of chlordiazepoxide, zaleplon produced partial substitution for chlordiazepoxide at doses which greatly reduced response rates. These results show that zaleplon and zolpidem have similar pharmacological profiles, presumably related to their BZ1 (omega 1) receptor selectivity. However, the difference between doses producing motor deficits (rotarod, loaded grid) and those giving rise to other effects (anticonvulsant, decreased locomotion) was greater for zolpidem than for zaleplon. This difference may be related to a greater in vivo intrinsic activity of zolpidem as indicated by the different efficacies of the two drugs to antagonise isoniazid-induced convulsions.

Acetamides↗
PubMed1996

Behavioural effects in the rat of the putative dopamine D3 receptor agonist 7-OH-DPAT: comparison with quinpirole and apomorphine.

This study assessed the effects of IP injections of (+/-) 7-hydroxy-2(N,N-di-n-propylamino)tetralin (7-OH-DPAT), a dopamine agonist that has been reported to have preferential affinity for the dopamine D3 sub-type of receptor, on four behavioural procedures in the rat: 1) spontaneous locomotion, 2) electrical self-stimulation of the ventral tegmental area (VTA), using the curve-shift procedure 3) operant responding for food under a progressive-ratio (PR) schedule and 4) induction of stereotypies. The effects of (+/-) 7-OH-DPAT were compared to the effects of apomorphine, a non-specific DA agonist, and quinpirole, a selective D2/D3 agonist. All three dopamine agonists decreased locomotor activity at low doses (0.01-0.3 mg/kg), and only apomorphine had clear locomotor stimulant effects at the highest dose tested (3 mg/kg). The three drugs dose-dependently depressed VTA self-stimulation in a similar way, with low doses inducing a fairly parallel rightward shift of the frequency/rate curves and higher doses flattening the curves. In contrast, responding for food under the PR schedule appeared to be differentially affected by the three agonists: 7-OH-DPAT induced a biphasic effect, with a maximal decrease in lever-pressing at 0.1 mg/kg, followed by a return to baseline levels with increasing doses (0.3-3 mg/kg); quinpirole showed a tendency to decrease responding over the whole dose-range tested with a maximal effect of about 50% of baseline between 0.25 and 1 mg/kg, and apomorphine dose-dependently decreased responding, with rats ceasing to respond at 0.3 mg/kg. All three DA agonists induced stereotypies, but there was a difference in the maximal stereotypy score induced by each of the ligands: 7-OH-DPAT produced a lower maximal effect than quinpirole or apomorphine. This indicates that each of the three dopamine agonists preferentially induced different types of stereotypies. Together, these data suggest that the putative dopamine D3 agonist 7-OH-DPAT, at low doses, has depressant effects similar to those induced by low doses of the other two DA agonists. Differences in the behavioural effects of higher doses were, however, mostly observed in two procedures, PR responding and induction of stereotypies.

Animals↗
PubMed1996

The use of the rat elevated plus-maze to discriminate between non-selective and BZ-1 (omega 1) selective, benzodiazepine receptor ligands.

The behavioral effects of a wide range of BZ (omega) receptor ligands, including non-selective full (alprazolam, clorazepate, chlordiazepoxide and diazepam) and partial (bretazenil, imidazenil and Ro 19-8022) agonists, and selective BZ-1 (omega 1) (abecarnil, CL 218,872, CL 284,846 and zolpidem) receptor ligands, were compared in the rat elevated plus-maze test. Behaviors recorded comprised the traditional indices of anxiety as well as a number of ethologically derived measures. In addition, the specificity of drug effects was evaluated by measuring spontaneous locomotor activity in activity cages in separate groups of animals. Results showed that all compounds tested not only increased the proportion of time spent and proportion of entries into the open arms of the maze (considered as traditional indices of anxiety) but also affected head-dippings and attempts at entry into open arms, which can be considered as indices of risk assessment responses. However, the magnitude of these effects was generally smaller with the BZ-1 (omega 1) selective agents. Moreover, additional differences were apparent on the total number of arm entries measure, which was significantly increased by most full and all partial agonists, but was unaffected by the selective BZ-1 (omega 1) compounds. If it is assumed that total arm entries are contaminated by anxiety, the latter finding indicates a weaker anxiety-reducing potential of selective BZ-1 (omega 1) ligands. Importantly, the increase in total arm entries induced by the non-selective agents was not associated with a similar effect on locomotion as revealed in the actimeter. Finally, anxiolysis produced by the BZ-1 (omega 1) ligands was invariably observed at doses which reduced locomotor activity, suggesting that the anxiolytic-like effects of these compounds are confounded by decreases in locomotor activity.

Alprazolam↗
PubMed1996

Further evidence for differences between non-selective and BZ-1 (omega 1) selective, benzodiazepine receptor ligands in murine models of "state" and "trait" anxiety.

The behavioural effects of several BZ (omega) receptor ligands were compared in mice using the light/dark choice task, an animal model of "state" anxiety, and the free-exploration test, which has been proposed as an experimental model of "trait" anxiety. The drugs used included non-selective full (alprazolam, clorazepate, chlordiazepoxide and diazepam), partial agonists (bretazenil, imidazenil and Ro 19-8022) and BZ-1 (omega 1) selective receptor ligands (abecarnil, CL 218,872 and zolpidem). In the light/dark choice task, non-selective full agonists elicited clear anxiolytic-like effects increasing time spent in the lit box and simultaneously reducing attempts at entry into the illuminated cage followed by withdrawal responses, a measure of risk assessment. With the exception of abecarnil, both non-selective partial agonists and BZ-1 (omega 1) selective receptor ligands displayed reduced efficacy compared to the full agonists as they decreased risk assessment responses without altering time in the lit box. In addition, the weak anxiolytic-like actions displayed by selective BZ-1 (omega 1) agents were evident only at doses which reduced locomotor activity, indicating that this effect may be non-specific. In the free-exploration test, non-selective BZ (omega) receptor agonists markedly increased the percentage of time spent in the novel compartment and reduced the number of attempts to enter whereas selective BZ-1 (omega 1) receptor ligands displayed a weaker neophobia-reducing effect as they reduced risk assessment responses only. As was the case in the light/dark choice task, this latter effect was observed at locomotor depressant doses. These findings indicate that while both full and partial BZ (omega) receptor agonists are equally effective against "trait" anxiety, full agonists may be superior in reducing "state" anxiety. In addition, the lack of specific effects of selective BZ-1 (omega 1) receptor ligands in reducing both types of anxiety suggests that the BZ-1 (omega 1) receptor subtype cannot be considered as the primary target mediating the anxiolytic action of drugs interacting with the GABAA benzodiazepine receptor complex.

Animals↗
PubMed1996

Retention of asbestos fibres in lungs of workers with asbestosis, asbestosis and lung cancer, and mesothelioma in Asbestos township.

OBJECTIVE: To conduct a mineralogical study on the particles retained in the necropsied lungs of a homogenous group of asbestos miners and millers from Asbestos township (and a local reference population) and to consider the hypothesis that there is a difference in size between fibres retained in the lungs of patients with asbestosis with and without lung cancer. METHODS: Samples of lung tissue were obtained from 38 patients with asbestosis without lung cancer, 25 with asbestosis and lung cancer, and 12 with mesothelioma, from necropsied Quebec chrysotile miners and millers from Asbestos township. Fibre concentrations in the lungs of these patients were compared with those in tissue from necropsies carried out on a local reference population: men who had died of either accidental death or acute myocardial infarction between 1990 and 1992. 23 were born before 1940 and 26 after 1940. RESULTS: Geometric mean (GM) concentrations were higher in cases than in the controls for chrysotile fibres 5 to 10 microns long in patients with asbestosis with or without lung cancer; for tremolite fibres 5 to 10 microns long in all patients; for crocidolite, talc, or anthophyllite fibres 5 to 10 microns long in patients with mesothelioma; for chrysotile and tremolite fibres > or = 10 microns long in patients with asbestosis; and crocidolite, talc, or anthophyllite fibres > or = 10 microns long in patients with mesothelioma. However, median concentrations of each type of fibre in the lungs did not show any significant differences between the three disease groups. Average length to diameter ratios of the fibres were calculated to be larger in patients with asbestosis and lung cancer than in those without lung cancer for crocidolite fibres > or = 10 microns long, for chrysotile, amosite, and tremolite fibres 5 to 10 microns long, and for chrysotile and crocidolite fibres < 5 microns long. However, there was no statistical difference in the median length to diameter ratios for any type of fibres across the disease groups when they were calculated in each patient. Cumulative smoking index (pack-years) was higher in the group with asbestosis and lung cancer but was not statistically different from the two other disease groups. CONCLUSION: Lung cancers occurred in workers with asbestosis from Asbestos township who had an equal concentration of retained fibres but a tendency to a higher length to diameter ratio of amphiboles. These workers had a 29% higher average cumulative smoking index.

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