Biomedical subjects

D J Sanger

Publications and source records attributed to D J Sanger.

At least 91 records · Page 5Linked to original sources

PubMed1990

Pharmacological and behavioral profile of alpidem as an anxiolytic.

Pharmacological and behavioral studies in mice and rats have shown that the imidazopyridine alpidem possesses anxiolytic activity with a profile which is substantially different from that of benzodiazepines. Thus, in mice, alpidem inhibited marble-burying behavior and enhanced feeding under stressful conditions, as did benzodiazepines; in contrast to these drugs, however, alpidem was inactive against shock-induced fighting and shock-suppressed exploration. In rats, alpidem exerted anticonflict activity in the punished drinking test, but failed to antagonize punishment-induced inhibition of operant behavior. Moreover, in rats trained to discriminate chlordiazepoxide from saline, alpidem did not produce a benzodiazepine-like interoceptive stimulus. Alpidem also produced anticonvulsant effects in a variety of tests sensitive to benzodiazepines. However, the order of potencies against convulsions induced by different convulsive agents was different from that of the benzodiazepines. Alpidem decreased motor performance in the rotarod test and only produced a deficit in muscle strength at doses which were more than 20 times higher than the doses active in anxiolytic tests. Moreover, alpidem did not interfere with the acquisition of conditioned fear, except at very high doses, indicating a weak potential to impair memory. The effects of alpidem were antagonized by flumazenil, indicating that central omega receptors are involved in the action of this drug. The weak sedative effects of alpidem may be attributed to its low intrinsic activity, as demonstrated by its low efficacy in increasing latency to isoniazid-induced convulsions.

Animals↗

PubMed1990

Effects of buspirone and related compounds on suppressed operant responding in rats.

The novel anxiolytic drug buspirone and its analogues, gepirone and ipsapirone, have behavioral effects that differ substantially from those of other anxiolytics such as benzodiazepines and barbiturates. In particular, buspirone does not consistently produce large increases in rates of responding suppressed by punishment in rodents or primates. To study the effects of buspirone and other compounds on suppressed operant responding in rats, two procedures were used. In the first, food-reinforced responding was suppressed during a stimulus associated with response-produced electric shocks (punishment). Chlordiazepoxide produced large increases in rates of punished responding, but neither buspirone nor ipsapirone gave rise to a similar effect. In a second experiment, food-reinforced responding was suppressed during a stimulus that terminated with an unavoidable shock (conditioned emotional response). Chlorodiazepoxide and clorazepate increased suppressed response rates at low doses and decreased nonsuppressed responding at higher doses, giving rise to dose-related increases in suppression ratios. The effects of buspirone, gepirone and ipsapirone were similar to those of the benzodiazepines with ipsapirone producing particularly marked increases in responding during the pre-shock stimulus. 8-Hydroxy-2-(di-n-propylamino)tetralin did not consistently give rise to the same effect. In addition, similar effects were not produced by haloperidol, imipramine, morphine or idazoxan. Haloperidol and morphine decreased nonsuppressed responding without changing rates of suppressed responding or suppression ratios. Imipramine decreased rates of both nonsuppressed and suppressed responding and idazoxan decreased suppression ratios. The conditioned emotional response procedure may be more sensitive for assessing the behavioral effects of buspirone and similar anxiolytic drugs in rats than are punishment procedures.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗

PubMed1989

Discriminative stimulus effects of the alpha 2-adrenoceptor antagonist idazoxan.

Rats were trained to discriminate a dose of the alpha 2-adrenoceptor antagonist idazoxan (10 mg/kg IP) from saline. The discriminative stimulus produced by idazoxan was dose related and generalised to yohimbine. However, generalisation did not occur with a variety of compounds from other pharmacological categories including the alpha 1-adrenoceptor agonist cirazoline, the alpha 1-adrenoceptor antagonist prazosin, and the alpha 2-adrenoceptor agonist clonidine. The idazoxan stimulus was not antagonised by either prazosin or clonidine, although it was clear that idazoxan antagonised the reductions in response rate produced by clonidine. Dose-related responding on the idazoxan-associated lever was produced by the anxiolytics buspirone and ipsapirone and by their metabolite MJ 13653 (1-PP), which has previously been shown to be an alpha 2-adrenoceptor antagonist. In general, however, high levels of generalisation occurred with these three compounds only at doses which substantially reduced response rates. These results demonstrate that idazoxan can give rise to a discriminative stimulus which is probably mediated through antagonism at alpha 2-adrenoceptors although the failure of clonidine to block the idazoxan stimulus is difficult to explain.

Adrenergic alpha-Antagonists↗

PubMed1989

Conditioned taste aversions induced by phencyclidine and other antagonists of N-methyl-D-aspartate.

Taste aversions can be conditioned in rats by a variety of psychoactive drugs, including those with reinforcing properties. Previous research, however, has not established clearly whether phencyclidine and related drugs are active in such procedures. The present study was carried out to investigate whether phencyclidine would induce a conditioned taste aversion and whether several other compounds (MK-801, the stereoisomers of NANM and ifenprodil) which, like phencyclidine, are known to antagonise the actions of N-methyl-D-aspartate (NMDA), would produce similar effects. When rats received injections of these compounds, after consuming a novel solution of saccharin, their subsequent consumption of the same solution decreased. The smallest doses of the different drugs which induced clear taste aversions were: phencyclidine 3 mg/kg, MK-801 0.3 mg/kg, (+)-NANM 10 mg/kg, (-)-NANM 3 mg/kg and ifenprodil 10 mg/kg. Thus, all the drugs were active. However, as neither the potencies nor the efficacies of the different compounds in inducing taste aversions correlated with their other behavioural effects or with their relative potencies in antagonising the effects of NMDA or in displacing phencyclidine from its binding sites, the mechanisms involved are unclear.

Adrenergic alpha-Antagonists↗

PubMed1989

Effects of phencyclidine and other N-methyl-D-aspartate antagonists on the schedule-controlled behavior of rats.

The behavioral effects of phencyclidine (PCP) were compared with those of several compounds known to antagonize the actions of N-methyl-D-aspartate using two patterns of schedule-controlled responding in rats. Rates of variable interval responding suppressed by punishment were increased greatly by the benzodiazepine chlorodiazepoxide and showed small increases after MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine] . However, no consistent increases in response rates were produced by PCP, by the stereoisomers of N-allylnormetazocine (NANM: SKF 10,047) or by the anti-ischemic drug, ifenprodil. Small doses of PCP did increase rates of unpublished variable interval responding, as did a low dose of MK-801. Timing behavior maintained by a differential reinforcement of low rate schedule was disrupted by all the compounds studied. Response rates were increased by at least one dose of PCP, MK-801, (+)-NANM and 3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid. The effect of MK-801, however, was considerably greater than that of the other compounds. Ifenprodil and (-)-NANM did not increase rates of responding but, at high doses, produced decreases in reinforcement frequency indicating that efficient timing behavior had been disrupted. These results show that although PCP, MK-801 and (+)-NANM produce generally similar behavioral effects, there may also be some differences between the compounds, notably a more consistent effect of MK-801 on punished responding. These behavioral effects may be related to antagonism of N-methyl-D-aspartate but ifenprodil, which is also an N-methyl-D-aspartate antagonist, does not show a similar behavioral profile.

Animals↗

PubMed1988

The interaction between zolpidem and beta-CMC: a clue to the identification of receptor sites involved in the sedative effect of zolpidem.

The interaction of beta-CMC, an amino beta-carboline recently described as a selective antagonist of the sedative effect of diazepam, with zolpidem, an imidazopyridine hypnotic, which like beta-CMC binds preferentially to the omega 1 (BZ-1) site of the GABA benzodiazepine chloride channel receptor complex, was investigated. In mice, beta-CMC antagonized the effect of zolpidem against isoniazid-induced convulsions without affecting its activity against convulsions induced by pentylenetetrazole or electroshock. beta-CMC also antagonized the decrease in locomotor activity and the impairment in muscle strength provoked by zolpidem. In rats trained to discriminate zolpidem, beta-CMC antagonized both the interoceptive stimulus and the decrease in the rate of lever pressing produced by zolpidem. This selective antagonism, inhibition of effects of zolpidem exerted by low doses (locomotor activity and isoniazid-induced convulsions) as well as effects produced by high doses (muscle strength) but not those provoked by intermediate doses (pentylenetetrazole and electroshock-induced convulsions), could not be explained by a receptor occupancy hypothesis. These results suggest that the anticonvulsant and sedative effects of zolpidem do not involve the same receptor subtype and that the hypnoselective properties of zolpidem may be linked to its selectivity for the omega 1 (BZ-1) site of the GABAA receptor.

Animals↗

PubMed1988

Discriminative stimulus properties of anxiolytic and sedative drugs: pharmacological specificity.

In the first set of experiments rats were trained to discriminate a dose of 5 mg/kg chlordiazepoxide from saline. The chlordiazepoxide cue was antagonized by flumazepil (Ro 15-1788) and by CGS 8216, and generalized to a variety of anxiolytic and sedative drugs including the benzodiazepine receptor ligands zopiclone, suriclone, CL 218,872, CGS 9896, and ZK 91296. The novel imidazopyridine hypnotic, zolpidem, which also displaces benzodiazepines from their binding sites, failed to produce high levels of responding on the chlordiazepoxide-associated level except at a dose which greatly reduced rates of lever pressing. In further experiments rats were trained to discriminate a dose of 2 mg/kg zolpidem from saline. This dose produced reductions in response rates but an attempt to establish a lower dose of zolpidem as a discriminative stimulus was largely unsuccessful. Zolpidem-appropriate responding was produced by pentobarbital, chlordiazepoxide, triazolam, CL 218,872, clorazepate, lorazepam, quazepam, and zopiclone but only at doses which reduced response rates. The zolpidem cue was antagonized by flumazepil, CGS 9896, and ZK 91296. While the discriminative stimulus produced by chlordiazepoxide may be related to its anxiolytic action, the zolpidem stimulus is probably more closely associated with sedation. It was also tentatively concluded that the stimulus properties of chlordiazepoxide and zolpidem are produced by activity at different subtypes of benzodiazepine receptors.

Animals↗

PubMed1988

Behavioural effects of the alpha 2-adrenoceptor antagonists idazoxan and yohimbine in rats: comparisons with amphetamine.

Although yohimbine has long been known to increase arousal, reactivity and anxiety in animals and humans, little is known about the behavioural effects of more selective alpha 2-adrenoceptor antagonists such as idazoxan. In a recent experiment, however, it was found that in rats both yohimbine and idazoxan increased low rates of lever pressing, an effect also produced by amphetamine. The purpose of the present study was to investigate further the effects of yohimbine and idazoxan in comparison with those of d-amphetamine on the operant behaviour of rats. In rats trained to press a lever on a FI 60s schedule to obtain food both yohimbine and idazoxan increased response rates, although the effect of yohimbine was considerably greater than that of idazoxan. Lower doses of d-amphetamine had no consistent effect on overall rates of responding whereas a higher dose suppressed responding. Characteristically, d-amphetamine increased responding during early portions of the intervals and decreased responding during the final portions. Idazoxan and yohimbine tended to increase responding throughout the intervals except immediately after reinforcement. When idazoxan was administered in combination with prazosin FI response rates were markedly decreased. Administration of DSP4 did not alter the response rate-increasing effects of either yohimbine or idazoxan. In rats trained to discriminate d-amphetamine from saline both idazoxan and yohimbine gave rise to responding on the saline associated lever. Combination of idazoxan with d-amphetamine did not antagonise the amphetamine cue but produced substantial reductions in response rates, probably due to toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗

PubMed1988

The alpha 2-adrenoceptor antagonists idazoxan and yohimbine increase rates of DRL responding in rats.

Previous studies have reported that antidepressant drugs exert specific effects on responding maintained by DRL schedules of reinforcement, giving rise to increased frequencies of reinforcement. In order to investigate whether the alpha 2-adrenoceptor antagonist idazoxan would produce similar effects, the actions of this compound were compared with those of yohimbine, imipramine, mianserin and d-amphetamine in rats trained to lever press for food reinforcement on a DRL 60-s schedule. Neither imipramine nor mianserin produced any effects on response rate or reinforcement frequency, except at the highest doses. In contrast, both idazoxan and yohimbine gave rise to dose-related increases in rates of responding and consequent decreases in reinforcement frequencies. Amphetamine also increased responding, but higher doses of this drug produced marked hyperactivity and stereotyped movements which were not observed after idazoxan and yohimbine. Although the present behavioural baseline was not sensitive to antidepressants, it demonstrated an unexpected activity of two alpha 2-adrenoceptor antagonists which deserves further investigation.

Adrenergic alpha-Agonists↗

PubMed1988

Is the discriminative stimulus produced by phencyclidine due to an interaction with N-methyl-D-aspartate receptors?

Rats were trained to discriminate phencyclidine (PCP) from saline at doses of 2 and 4 mg/kg, using a two-lever food reinforced operant technique. +/- N-allylnormetazocine (+/- SKF 10047), +5-methyl-10,11-dihydro-5H-dibenzo[A,D]cyclohepten-5,10-imine MK 801), 3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP) and ifenprodil, which have been shown to antagonise the effects of N-methyl-D-aspartate (NMDA), were tested for their ability to give rise to PCP-appropriate responding. In rats trained at both doses of PCP, +/- SKF 10047 (2-12 mg/kg) and MK 801 (0.0125-0.2 mg/kg) produced dose-related responding on the lever associated with PCP injection. The relative potency of these two compounds was the same in the two groups of animals, but their absolute potencies to produce a PCP-like discriminative stimulus were dependent on the training dose of PCP. In contrast, neither the competitive NMDA antagonist CPP (4-20 mg/kg) nor the non-competitive antagonist ifenprodil (2-12 mg/kg) produced PCP-appropriate responding and ifenprodil (4 mg/kg) neither potentiated nor antagonised PCP. These findings are discussed in the light of the hypothesis that the behavioural effects of PCP are mediated via a reduction of neurotransmission at the NMDA-subtype of glutamate receptors.

Adrenergic beta-Antagonists↗

PubMed1988

Further behavioural evidence for the selective sedative action of zolpidem.

Small doses of benzodiazepines stimulate behavioural output in experimental animals in a variety of situations. Zolpidem, which displaces benzodiazepines from their binding sites, however, has been shown to exert preferential sedative activity. In order to investigate whether small doses of zolpidem would also have stimulant effects, the actions of zolpidem and chlordiazepoxide were compared in three procedures which are sensitive to the behavioural-facilitating effects of benzodiazepines in rats. A small dose of chlordiazepoxide (3.0 mg/kg) increased locomotion in an open field whereas a large dose (30 mg/kg) suppressed this behaviour. Zolpidem (0.3-3.0 mg/kg) only decreased locomotion. The effects of both chlordiazepoxide and zolpidem were antagonised by flumazenil. Chlordiazepoxide (2.5-10 mg/kg) increased the intake of food in rats habituated to a daily feeding schedule but similar doses of zolpidem neither increased nor decreased the intake of food. Rates of punished operant responding were increased by chlordiazepoxide (3.0-30 mg/kg) but zolpidem (1.0-4.0 mg/kg) produced no such anti-punishment effect and suppressed responding at the large dose. These results show that zolpidem does not increase behavioural output in situations which are sensitive to the stimulant effects of benzodiazepines and further emphasize the selective sedative activity of this drug.

Animals↗

PubMed1987

Further investigation of the stimulus properties of chlordiazepoxide and zolpidem. Agonism and antagonism by two novel benzodiazepines.

The effects of Ro 16-6028 and Ro 17-1812, two novel benzodiazepines with mixed agonist and antagonist properties, were studied in rats trained to discriminate either chlordiazepoxide or the benzodiazepine receptor ligand zolpidem. In rats discriminating 5 mg/kg chlordiazepoxide from saline both Ro 16-6028 and Ro 17-1812 produced responding on the drug lever. At a dose of 10 mg/kg both compounds gave rise to 100% responding on the lever associated with chlordiazepoxide. The dose-response curve produced by Ro 16-6028 was flatter than that for Ro 17-1812, however. The discriminative cue produced by 2 mg/kg zolpidem did not generalise to either Ro 16-6028 or Ro 17-1812. In contrast, both of those compounds antagonised the zolpidem cue and also antagonised the reduction in response rates produced by zolpidem. These results are consistent with previous findings that Ro 16-6028 and Ro 17-1812 may exert anxiolytic-like effects typical of benzodiazepines while antagonising the depressant actions of benzodiazepine receptor ligands. The results are also consistent with the suggestion that the discriminative cues produced by chlordiazepoxide and zolpidem may be mediated, at least partially, by activity at different sub-types of benzodiazepine receptors.

Animals↗

PubMed1987

The benzodiazepine antagonist CGS 8216 decreases both shocked and unshocked drinking in rats.

Previous studies of the benzodiazepine antagonist CGS 8216 have reported that this compound may enhance the punishment-induced suppression of behaviour. In order to investigate this phenomenon further, water-deprived rats were trained to drink from a water spout during a multiple schedule with shocked and unshocked components. During the shocked components a very mild electric footshock was presented after every 20th lick. The shock slightly reduced the rate of licking during these components below that which occurred during periods without shock, although this effect decreased during the experiment. CGS 8216 (0.3-10 mg/kg) produced a dose-related reduction in licking during both schedule components. The overall volumes of water consumed were reduced by CGS 8216 as was the number of licks during the first, unshocked schedule component, before shock was applied, showing that the effect on unshocked licking was not due to a generalisation of suppression between periods with or without shock. In contrast to CGS 8216, a dose of 10 mg/kg pentylenetetrazol selectively reduced shocked licking. In a second group of rats which drank under identical conditions but without shock, CGS 8216 again reduced water intake. These results show that CGS 8216 can reduce water intake in rats regardless of whether drinking results in shock presentation.

Animals↗

PubMed1987

Discriminative stimulus properties of chlordiazepoxide and zolpidem. Agonist and antagonist effects of CGS 9896 and ZK 91296.

In previous studies the effects of CGS 9896, a pyrazoloquinoline ligand at benzodiazepine receptors, in rats trained to discriminate benzodiazepines from vehicle, have been variable. The present experiment confirmed that this compound produced responding on the drug-lever in rats trained to discriminate 5 mg/kg of chlordiazepoxide from saline, and showed that CGS 9896 did not antagonise the effect of chlordiazepoxide in this test. In contrast, CGS 9896 antagonised the stimulus properties of zolpidem (2 mg/kg), a non-benzodiazepine hypnotic, which displaces benzodiazepines from their binding sites. The drug CGS 9896 also antagonised responding on the drug-lever produced by chlordiazepoxide in rats trained with zolpidem. The beta-carboline, ZK 91296, produced effects similar to those of CGS 9896, giving rise to responding on the drug-lever in rats trained with chlordiazepoxide and antagonising the zolpidem cue. These results demonstrate the mixed agonist-antagonist effects of CGS 9896 and ZK 91296 and suggest that the stimulus properties of chlordiazepoxide and zolpidem may be mediated by different sub-types of benzodiazepine receptors.

Animals↗

PubMed1987

Investigation of the development of tolerance to the actions of zolpidem and midazolam.

It is well established that tolerance can develop very rapidly to the behaviour-suppressing effects of benzodiazepines. In previous studies, however, the depressant action of zolpidem, a novel hypnotic acting at the benzodiazepine receptor, on operant behaviour in rats was maintained after many injections. An experiment was carried out, therefore, to compare the effects of acute and chronic administration of zolpidem and midazolam. Rats were trained to press a lever in standard operant test chambers to obtain 45 mg food pellets on an FR 10 schedule. Dose-response curves were then established, before, immediately after and 4 weeks after the daily administration of midazolam (3.0 mg/kg s.c.) or zolpidem (1.0 mg/kg) for 10 days. In confirmation of previous work, marked tolerance developed to the response-rate-decreasing effect of midazolam, the dose-response curve being shifted to the right by a factor of 6 and also flattened. No significant dissipation of this tolerance occurred during a period of 4-6 weeks. In contrast, repeated administration of zolpidem produced only a small degree of tolerance, the dose-response curve being shifted by a factor of two. There was little evidence for cross tolerance between the two drugs, zolpidem-treated rats being sensitive to a dose of midazolam and midazolam-treated rats sensitive to a dose of zolpidem. Although the explanation for the development of tolerance to midazolam is unknown, these results suggest that the mechanisms of action of midazolam and zolpidem in reducing response rates are different.

Animals↗

PubMed1987

The behavioral profile of zolpidem, a novel hypnotic drug of imidazopyridine structure.

The imidazopyridine zolpidem has previously been shown to displace benzodiazepines from their receptors, with a preferential activity at BZ1 sites, and to exert hypnotic activity in man. Zolpidem's pharmacological profile includes anticonvulsant, antipunishment and behavioral depressant actions. However, unlike benzodiazepines, zolpidem exerts sedative actions at relatively low doses. In drug discrimination experiments differences between the internal stimuli produced by chlordiazepoxide and zolpidem were identified. These differences appeared to be qualitative rather than quantitative with the stimulus properties of zolpidem being related to the drug's sedative action. In condition where tolerance developed rapidly to the depressant activity of benzodiazepines little tolerance was seen with zolpidem. The behavioral profile of consistent with the suggestion that this compound may have selective sedative action produced by activity at a sub-type of benzodiazepine receptor.

Animals↗

PubMed1987

The actions of SCH 23390, a D1 receptor antagonist, on operant and avoidance behavior in rats.

Previous studies have shown that dopamine antagonists such as haloperidol, pimozide and metoclopramide will produce gradually increasing decrements of operant and avoidance responding. The present study was carried out to investigate whether the dopamine D1 blocking agent, SCH 23390, would exert a similar effect. In the first experiment, SCH 23390 produced a dose-related (0.03-0.1 mg/kg) reduction in responding maintained by an FR 10 schedule of food reinforcement. However, the compound gave rise to similar reductions of response rate throughout the 15 min session. In a second experiment, higher doses of SCH 23390 (0.1-1.0 mg/kg) disrupted one-way avoidance performance in a shuttle-box. Again, there was no within-session decline in responding after administration of SCH 23390 although injection of a dose of 0.4 mg/kg of haloperidol produced a greater response deficit during the second half of the session. During 4 daily administrations of 0.3 mg/kg of SCH 23390 the degree to which avoidance responding was disrupted neither increased nor decreased. SCH 23390 disrupts operant bar pressing and one-way avoidance responding but its actions in these behavioral tests are not identical to the effects of typical neuroleptics such as haloperidol.

Animals↗

PubMed1986

The discriminative stimulus properties of zolpidem, a novel imidazopyridine hypnotic.

Zolpidem is a non-benzodiazepine hypnotic drug which displaces benzodiazepines from their binding sites in different brain structures. Previous work has demonstrated several differences between zolpidem and benzodiazepines, including differences between the stimulus properties of zolpidem and chlordiazepoxide. In the present study the discriminative stimulus properties of zolpidem were analysed by training rats to discriminate between this drug and saline. It was found that stimulus control developed readily with 2 mg/kg but not with 1 mg/kg zolpidem. The effect was dose-related, had a short duration of action and was antagonised by Ro 15-1788. Furthermore, stimulus control produced by zolpidem was associated with marked reductions in rates of responding. Injections of chlordiazepoxide, triazolam, lorazepam, zopiclone, CL 218,872 and pentobarbital produced dose-related responding on the zolpidem-associated lever but haloperidol did not. However, in general, the doses of those drugs which produced drug-lever responding also reduced response rates. It is possible that the above mentioned differences between the discriminative stimulus produced by zolpidem in rats and those produced by other sedatives may be due to a selective action of zolpidem on a sub-type of benzodiazepine binding site.

Animals↗