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D.J. Sanger

Publications and source records attributed to D.J. Sanger.

13 recordsLinked to original sources
PubMed1996

Evidence for a role for dopamine D3 receptors in the effects of dopamine agonists on operant behaviour in rats.

Several dopamine (DA) agonists have been reported to show some D3 versus D2 selectivity but the extent of this selectivity depends on experimental conditions, and the behavioural effects of these compounds seem to differ little from those of non-selective agonists such as apomorphine. However, some recent studies have reported stronger correlations between several behavioural responses and D3 affinities than between the same responses and affinities for D2 receptors. In the present study rats were trained to lever press for food on a fixed-ratio (FR10) schedule during daily 15min sessions. The DA agonists apomorphine; quinelorane; quinpirole; 7-hydroxy-2-(di-n-propylamino)-tetralin [(+/-)7-OH-DPAT]; (+)-(4aR, 10bR)-4-propyl-3, 4,4a, 10b-tetrahydro-2H,5H-1-benzopyrano [4,3-b], 4(oxazin-9-ol); bromocriptine; and (3-hydroxyphenyl)-N-propylpiperidine produced dose-related decreases in these response rates. The potencies of these compounds correlated significantly with their published potencies to produce a functional D3 but not a functional D2 response (stimulation of mitogenesis in transfected cells). The rate-decreasing effects of 7-OH-DPAT were antagonised by the benzamide antipsychotic agent amisulpride, at low doses (1 and 3mg/kg) which have been shown to exert preferential activity at presynaptic DA receptors. Haloperidol and remoxipride produced only small antagonist effects. These results are consistent with the view that D3 DA receptors may play an important role in mediating the behavioural effects of DA agonists and that these receptors have a presynaptic location.

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PubMed1996

The mouse defense test battery: evaluation of the effects of non-selective and BZ-1 (omega1) selective, benzodiazepine receptor ligands.

The behavioral effects of several benzodiazepine (BZ) (omega) receptor ligands were compared using the Mouse Defense Test Battery which 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. The drugs used included non-selective BZ (omega) full (clonazepam, clorazepate, chlordiazepoxide and diazepam) and partial (bretazenil and imidazenil) agonists, and BZ-1 (omega1) selective (abecarnil, CL 218,872 and zolpidem) receptor ligands. With the exception of clonazepam, non-selective BZ (omega) receptor compounds only partially affected flight behaviors. The drugs reduced some but not all flight measures in response to the approaching rat, whereas clonazepam attenuated all flight reactions. In contrast to their mild and inconsistent actions on flight, the non-selective BZ (omega) receptor agonists displayed clear effects on risk assessment when subjects were chased by the rat. When contact was forced between the subject and the rat, the non-selective BZ (omega) receptor full agonists reduced defensive threat and attack reactions, while the partial agonists imidazenil and bretazenil only weakly attenuated defensive attack behavior. Similarly, after the rat had been removed from the test area, the non-selective BZ (omega) receptor full agonists displayed greater efficacy than the partial agonists in reducing escape attempts. Overall, results obtained with the selective BZ-1 (omega1) receptor ligands demonstrated either no clear effects or no specific action on defensive reactions. Taken together, these data demonstrate that: (1) non-selective BZ (omega) agonists displaying high intrinsic activity affect a wider range of defensive behaviors than non-selective BZ (omega) receptor partial agonists; (2) the defense system does not involve primarily BZ (omega) receptors containing the alpha1-subunit.

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PubMed1995

Behavioural effects of novel benzodiazepine (omega) receptor agonists and partial agonists: increases in punished responding and antagonism of the pentylenetetrazole cue.

In recent years a number of novel compounds have been described with affinity and specificity for BZ (omega) receptors. While some of these agents appear to act, like benzodiazepines themselves, as full agonists at different receptor subtypes (e.g. suriclone), several non-selective partial agonists (e.g. bretazenil) have been described, as have a number of BZ(1) (omega(1)) selective drugs (e.g. zolpidem). Previous work has reported a number of differences between the behavioural effects of some of these drugs and those of benzodiazepines; however, very few studies have attempted systematic comparisons of a large number of drugs in different procedures. In the present study a wide range of BZ (omega) receptor ligands was studied using two behavioural methods in rats: unpunished and punished food-reinforced operant responding and the discriminative stimulus effects of pentylenetetrazole. Punished operant responding showed increases with the benzodiazepines, chlordiazepoxide and clorazepate, the non-benzodiazepines, saripidem, CL 273,547 and F 2692 (limited effect at a single dose) and the partial agonists bretazenil and Ro 19-8022, but the BZ(1) selective agents, alpidem, abecarnil and CL 284,846, did not increase rates of punished operant responding. Rates of unpunished responding were decreased by higher doses of all drugs except bretazenil and Ro 19-8022. Dose-related antagonism of the pentylenetetrazole (18mg/kg) discriminative stimulus was produced by several benzodiazepines, by the partial agonists bretazenil, Ro 19-8022 and divaplon, and by suriclone, saripidem and CL 273,547. The BZ(1) (omega(1)) selective drugs abecarnil, CL 284,846, zolpidem, CL 218,872 and alpidem were also active in blocking pentylenetetrazole but produced only partial antagonism which was not clearly dose-related. The results show that novel BZ (omega) receptor ligands do not always produce a behavioural profile identical to that shown by benzodiazepines. In particular, BZ(1) (omega(1)) selective drugs do not give rise to clear increases in punished operant responding and have only limited efficacy in blocking the pentylenetetrazole cue. These effects may be due to the marked propensity of BZ(1) (omega(1)) selective drugs to decrease operant response rates.

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PubMed1995

The anti-ischaemic drug, eliprodil, blocks hyperactivity induced by intra-accumbens injection of spermine.

NMDA receptor mechanisms in the nucleus accumbens play an important role in the control of locomotor activity. Among the several binding sites associated with these receptors, the polyamine-sensitive sites have received relatively little attention. It has recently been shown, however, that the anti-ischaemic drug eliprodil NMDA antagonist effects probably mediated by activity at this polyamine site. In the present series of experiments the effects of injections of spermine and eliprodil into the nucleus accumbens of rats were investigated. Locomotor hyperactivity was produced by intra-accumbens injection of spermine, phencyclidine and AP7. Phencyclidine, but not AP7, produced a similar effect after systemic injection. Eliprodil did not increase locomotion after either intra-accumbens or i.p. administration. However, systemic injection of eliprodil (5, 10, 20mg/kg) produced a dose-related antagonism of hyperactivity induced by intra-accumbens spermine, but not by systemic or intra-accumbens injection of d-amphetamine. These results provide the first behavioural demonstration of the polyamine antagonist properties of eliprodil, and further emphasise the differences between the pharmacological profile of eliprodil and those of other NMDA antagonists.

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PubMed1993

Substitution by NMDA antagonists and other drugs in rats trained to discriminate ethanol.

It has been reported that, in animals trained to discriminate ethanol, stimulus control generalized to the non-competitive NMDA antagonists phencyclidine, ketamine and dizocilpine. In the present study, rats were trained to discriminate a dose of ethanol (1g/kg, i.p.) and substitution tests were carried out with phencyclidine, dizocilpine, CGS 19755, eliprodil, triazolam, chlordiazepoxide, abecarnil, alpidem and d-amphetamine. Phencyclidine and dizocilpine produce dose-related substitution for ethanol as did the competitive NMDA antagonist, CGS 19755, and the benzodiazepines, triazolam and chlordiazepoxide. Eliprodil, an NMDA antagonist acting through the polyamine modulatory site, neither substituted for ethanol nor modified the ethanol dose-response curve. d-Amphetamine, and the non-benzodiazepine anxiolytics, alpidem and abecarnil, did not substitute for ethanol. The results show that both NMDA antagonists and compounds acting through (GABA receptors (benzodiazepines) can substitute for ethanol, emphasizing that the ethanol cue may involve several mechanisms. As all the drugs substituting for ethanol, like ethanol itself, are known to produce ataxia and muscle relaxation, it is proposed that this property may be an important aspect of the ethanol cue.

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PubMed1992

Social competition in dominant rats can be attenuated by anxiogenic drugs.

In a previous study it was found that, in groups of three male Wistar rats competing for access to sweetened milk, access to the milk by subordinate animals was increased after administration of anxiolytic drugs. This result was consistent with the hypothesis that levels of social competition were associated with different levels of fear. The present study involved the administration of anxiogenic drugs to rats found to be dominant during similar social competition tests. Dose-related decreases in access to the milk during competition sessions were produced by FG 7142 (0.3-5.0mg/kg), pentylenetetrazole (0.6-10mg/kg) and yohimbine (1.0-4.0mg/kg). These three compounds were also investigated on the milk intake of the same animals tested singly. It was found that there was a wide separation between doses active in the two conditions with FG 7142 and pentylenetetrazole, but a much less wide separation with yohimbine. These results are further evidence that tests of social competition provide sensitive behavioural baselines for assessing the effects of drugs which modulate anxiety levels.

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PubMed1992

Memantine has phencyclidine-like but not cocaine-like discriminative stimulus effects in rats.

It has recently been reported that the amantadine derivative, memantine, which is used in the treatment of Parkinsonism, has N-methyl-D-aspartate (NMDA) antagonist properties. In order to investigate whether the behavioural effects of memantine could also be mediated through this mechanism the drug was administered to rats trained to discriminate phencyclidine (3mg/kg) from saline. Memantine produced a dose-related (2.5-10mg/kg) substitution for phencyclidine. Neither amantadine nor cocaine substituted for phencyclidine. In rats trained to discriminate cocaine (10mg/kg) memantine did not substitute. These results show that memantine has phencyclidine-like but not cocaine-like discriminative stimulus effects indicating that the behavioural actions of memantine, like those of phencyclidine, are probably produced by a non-competitive inhibition of NMDA receptors.

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PubMed1992

NMDA antagonists disrupt timing behaviour in rats.

The behavioural effects of six compounds with N-methyl-D-aspartate (NMDA) antagonist properties were compared on the responding of rats maintained by a differential reinforcement of low rate 15s (DRL-15s) schedule. This schedule requires that responses be temporally spaced in order to be reinforced (timing behaviour). The number of reinforcers obtained was decreased by the non-competitive NMDA antagonists phencyclidine, dizocilpine and memantine, by the competitive NMDA antagonist CGS 19755, by the antitussive drug dextromethorphan, but not by the polyamine site antagonist eliprodil (SL 82.0715). Small increases in response rates were produced by phencyclidine and memantine, and dizocilpine gave rise to very marked increases in rates. CGS 19755, eliprodil and dextromethorphan only decreased rates of responding at high doses. Analysis of drug action in terms of inter-response times (IRT) showed that, except for eliprodil, all compounds shifted the peaks of the IRT distributions to the left. The percentage of short IRTs (response bursts) showed statistically significant increases after administration of dizocilpine, phencyclidine, memantine and CGS 19755. These results show that timing behaviour in rats is disturbed by several NMDA antagonists, although eliprodil, while decreasing responding at high doses, did not disrupt efficient timing.

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PubMed1991

The effects of NMDA antagonists on punished exploration in mice.

Previous studies have reported that several NMDA antagonists show anxiolytic-like activity in behavioural tests. To follow up the observation that AP7 increased the punished exploration of mice in the four plate test, several NMDA antagonists were tested in this procedure in shocked and non-shocked conditions. AP7 increased shocked exploration without increasing non-shocked exploration. However, another competitive NMDA antagonist, CGS 19755, produced no increases in exploration in either condition. The non-competitive antagonists, phencyclidine, MK-801 and dextromethorphan, produced dose-related increases in activity in both the non-shocked and shocked conditions. This effect is probably best considered a psychomotor stimulant action rather than an anxiolytic-like activity. The non-competitive NMDA antagonist, SL 82.0715, which acts at the polyamine site, and the ethyl ester of 7-chlorokynurenic acid, which acts at the glycine modulatory site, produced only decreases in exploration indicating that they lack both stimulant and anxiolytic activity. Although providing little evidence for anxiolytic action the present results further demonstrate that compounds acting at different sites within the NMDA receptor complex can give rise to very different pharmacological and behavioural effects.

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PubMed1991

Social competition in rats: a test sensitive to acutely administered anxiolytics.

Male Wistar rats were housed in groups of three (triads) and given brief sessions during which sweetened milk was available in a drinking bottle. The rats showed intense competition to obtain access to the milk and in many groups a stable rank order was formed of a dominant, an intermediate and a subordinate rat, when assessed as the amount of access to the drinking tube. When the subordinate rats were injected with the anxiolytic drugs chlordiazepoxide (1.25-20mg/kg), buspirone (0.3-5.0mg/kg) and alpidem (2.5-20mg/kg) and low doses of the hypnotic, zolpidem (0.125-2.0mg/kg) they increased their access to the milk. These increases were generally at the expense of the dominant rats whose access decreased. The effect of alpidem (5mg/kg) was antagonized by flumazenil (10mg/kg). Increases in access in subordinate rats were not seen after haloperidol (0.025-0.2mg/kg), imipramine (5, 10mg/kg) or morphine (2.5-10mg/kg). As the anxiolytic drugs were active at relatively low doses this test of social competition may provide a particularly sensitive and selective procedure for detecting and evaluating the actions of drugs from this class.

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PubMed1989

Buspirone, gepirone and ipsapirone disrupt both active and passive avoidance responding in rats.

The anxiolytic drug buspirone and its structural analogues gepirone and ipsapirone produce behavioural effects which differ from those seen with benzodiazepines and barbiturates. Buspirone has been reported to disrupt active avoidance responding without interfering with the ability to escape the aversive stimuli, an effect usually associated with antipsychotic drugs. In the present study, buspirone, gepirone and ipsapirone produced dose-related decreases in one-way, active avoidance responding of rats. However, these drugs did not consistently give rise to a within-session decline in avoidance responding as was seen with the dopamine antagonist metoclopramide. In a second experiment, buspirone, gepirone and ipsapirone disrupted the performance of a passive avoidance response. Rats previously conditioned to remain on a raised platform to avoid shock stepped off the platform after injection of these drugs. A similar effect on the passive avoidance response was not produced by chlordiazepoxide; diazepam, CL 218, 872, haloperidol, imipramine or d-amphetamine. These disruptions of the performance of both active and passive avoidance indicate a unique pharmacological profile for buspirone and similar drugs.

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PubMed1989

Performance of a passive avoidance response is disrupted by compounds acting at 5HT(1A) receptors.

In a previous study it was found that the anxiolytic drug buspirone and the related compounds gepirone and ipsapirone disrupted the performance of a passive avoidance response by rats. A similar effect was not produced by several other drugs including chlordiazepoxide, imipramine and haloperidol. In the present study the same procedure was used to investigate whether other compounds known to interact with serotonergic mechanisms would produce a similar effect. The 5HT(1A) agonists 8-OH-DPAT and MDL-72832 produced similar disruptions in the performance of a step-down passive avoidance response (i.e. decreased latencies), with 8-OH-DPAT giving rise to a bell-shaped dose-response curve. Neither ritanserin, a 5HT(2) antagonist, nor 1-PP, a metabolite of buspirone known to have alpha(2)-adrenoceptor antagonist properties, was active. Odansetron (GR38032F), a 5HT(3) antagonist, was active, although the magnitude of the effect was smaller than that seen with the 5HT(1A) agonists and was not clearly dose-related. In drug interaction experiments the effect of 8-OH-DPAT was completely eliminated after treatment with NAN-190 although NAN-190 itself increased step-down latencies. The effect of 8-OH-DPAT was also partially blocked by prazosin. Thus the performance of a step-down passive avoidance response is disrupted by a range of compounds known to be 5HT(1A) agonists but by few other drugs.

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