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Biomedical subjects

D J Sanger

Publications and source records attributed to D J Sanger.

At least 109 records · Page 6Linked to original sources
PubMed1986

Response decrement patterns after neuroleptic and non-neuroleptic drugs.

Previous work has shown that administration of pimozide and other neuroleptic drugs can produce within-session response decrement patterns of appetitively-reinforced behaviour. This phenomenon has been described as an extinction-like pattern of responding and used as evidence for the hypothesis that these drugs attenuate the rewarding properties of food, water and electrical stimulation of the brain. The present study was carried out to investigate within-session patterns of responding maintained by food presentation or shock avoidance after administration of a variety of neuroleptic and non-neuroleptic drugs. Haloperidol, metoclopramide, pimozide and butaclamol produced within-session response decrements of both food-reinforced lever pressing and one-way shock avoidance. The atypical antipsychotic drug clozapine did not consistently produce similar effects nor did the alpha-adrenoceptor agonist clonidine, the opiate agonist morphine, the benzodiazepine anxiolytic chlordiazepoxide and the muscle relaxant methocarbamol, although all these drugs were tested up to doses which markedly disrupted responding. Thus, within-session response decrement patterns are a characteristic effect of dopamine-blocking neuroleptic drugs. However, because of the generally similar effects of these drugs on appetitively- and aversively-motivated behaviour, these effects are probably best interpreted as actions on motor, rather than motivational, mechanisms.

Animals↗
PubMed1986

Effects of zolpidem, a new imidazopyridine hypnotic, on the acquisition of conditioned fear in mice. Comparison with triazolam and CL 218,872.

Benzodiazepines and other compounds which act at benzodiazepine binding sites have been shown previously to attenuate the acquisition of conditioned fear in rodents when administered before the acquisition session, an effect which may parallel the disruption of human memory produced by anxiolytics and sedatives. Such an action is usually, but not invariably, produced by doses which have direct behavioural depressant effects. The present study was carried out to extend previous work by investigating the effects of the hypnotic benzodiazepine triazolam and the nonbenzodiazepines zolpidem and CL 218,872 on the acquisition of learned fear in mice. All these drugs reduced locomotor activity shortly after injection. They also produced disruptions of the acquisition of learned fear. Triazolam exerted behavioural effects similar to those found previously with other benzodiazepines, the does which disrupted the acquisition of conditioned fear being similar to, or lower than, the doses which depressed locomotion. In contrast, the results indicated that zolpidem was more potent at reducing locomotion than at interfering with fear conditioning, a result which may reflect the preferential sedative action of zolpidem.

Animals↗
PubMed1986

Investigation of the actions of the benzodiazepine antagonists Ro 15-1788 and CGS 8216 using the schedule-controlled behavior of rats.

Ro 15-1788 and CGS 8216 antagonise many of the pharmacological effects of benzodiazepines but both of these compounds have also been shown to exert behavioral effects when administered alone. In the present study the effects of Ro 15-1788 and CGS 8216, alone and in combination with diazepam and with the benzodiazepine receptor ligand zolpidem, were investigated. Diazepam and zolpidem produced dose-related decreases in rates of food-reinforced lever-pressing maintained by a fixed-ratio (FR 10) schedule. CGS 8216 also reduced response rates although Ro 15-1788, at several doses, produced small, but statistically significant, increases in responding. When the diazepam and zolpidem dose-response curves were re-established in the presence of a dose of Ro 15-1788 or CGS 8216 the depressant effects of the higher doses were antagonised. However, neither diazepam nor zolpidem blocked the rate reducing effect of CGS 8216 which may not therefore be due to an action at benzodiazepine receptors.

Animals↗
PubMed1986

The effects of fluoxetine and zimeldine on the behavior of olfactory bulbectomized rats.

Previous work has shown that subchronic administration of antidepressant drugs can reverse the behavioral and physiological changes produced by removal of the olfactory bulbs of rats. It has also been reported that acute administration of drugs believed to enhance serotonergic transmission can improve passive avoidance performance in bulbectomized rats. In order to follow up this observation the effects of the serotonin reuptake inhibitor, fluoxetine, were studied in bulbectomized and control rats. Fluoxetine produced a dose-related improvement in the passive avoidance behavior of bulbectomized rats in a step-down task and in a Y-maze. The effect of fluoxetine on step-down avoidance was blocked by metergoline and was also shown by zimeldine, another inhibitor of serotonin reuptake. However, in tests of active avoidance responding in a shuttle box and exploratory locomotion, fluoxetine produced similar disruptions of behavior in both bulbectomized and control animals. Thus, the effects of fluoxetine on the behavior of bulbectomized rats are dependent upon the behavioral test.

Animals↗
PubMed1986

Zimelidine does not antagonise the effects of alcohol or diazepam on the acquisition of conditioned fear in mice.

Recent work has suggested that, in man, the specific inhibitor of serotonin reuptake, zimelidine, can block the effects of ethanol on memory processes without affecting psychomotor performance decrements produced by ethanol. The present study was carried out to investigate whether a similar interaction between ethanol and zimelidine could be observed in mice. Using a 2-trial conditioned fear test known to be sensitive to the effects of benzodiazepines and similar drugs, it was found that ethanol, administered before the first trial, produced a dose-related disruption of fear conditioning as shown on the second trial. In a second experiment several doses of zimelidine were administered at the same time as a dose of either ethanol or diazepam. No evidence was obtained for a zimelidine-induced antagonism of the effects of either ethanol or diazepam.

Animals↗
PubMed1986

Zolpidem, a novel nonbenzodiazepine hypnotic. I. Neuropharmacological and behavioral effects.

Zolpidem [N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide hemitartrate] is reported to be a rapid onset, short duration hypnotic that interacts at the benzodiazepine recognition site. The present report establishes the neuropsychopharmacological profile of zolpidem and compares it with those of benzodiazepine hypnotics. Although in mice the effects of zolpidem are qualitatively similar to those of midazolam, triazolam and flunitrazepam, sedation with zolpidem occurs at doses 10 and 20 times lower than those inducing anticonvulsant and myorelaxant effects, respectively. In contrast, the benzodiazepines studied induce sedation at doses causing myorelaxation and which are 2 to 6 times superior to those antagonizing pentetrazole-induced convulsions. In the rat, zolpidem induces sleep (as indicated behaviorally and electrocorticographically) and displays anticonflict activity in a punished drinking paradigm, as do the benzodiazepines. However, whereas benzodiazepine hypnotics induce EEG sleep patterns in curarized rats at doses similar or inferior to those active in the conflict test (in freely moving animals), the hypnotic effect of zolpidem is seen at doses 10 times lower than those producing an anticonflict effect. Moreover, a qualitative difference between the effects of zolpidem and benzodiazepines is observed in electrocorticographic recordings obtained in curarized rats: electrocorticographic hypersynchronization induced by zolpidem is dominated by the energy increase within the 2 to 4 Hz band whereas the benzodiazepines increase predominantly energy levels within the 12 to 14 Hz band. Studies of the sleep-wakefulness cycle in the rat and the cat revealed that hypnotic doses of zolpidem do not alter the pattern of physiological sleep, although elevated doses of the drug decrease paradoxical sleep and increase slow wave sleep. In rats trained to discriminate chlordiazepoxide, zolpidem fails to generalize with the chlordiazepoxide-associated lever indicating that the compound and benzodiazepines do not share the same discriminative stimulus properties. Nevertheless, the anticonvulsant, hypnotic, myorelaxant and anticonflict effects of zolpidem are antagonized by benzodiazepine receptor antagonist Ro 15-1788 and CGS 8216 indicating an involvement of the benzodiazepine recognition site in the action of this drug. The highly selective sedative effect of zolpidem (as compared to myorelaxant and anticonvulsant effects) suggests that it may possess a specificity for certain subtypes of benzodiazepine receptors.

Animals↗
PubMed1985

GABA and the behavioral effects of anxiolytic drugs.

Much recent research has shown that benzodiazepine binding sites in the central nervous system are associated with GABA receptors. It is therefore possible that the pharmacological and therapeutic effects of benzodiazepines and drugs with similar profiles are mediated through GABAergic mechanisms. In this paper the evidence is considered for a possible involvement of GABA in the behavioral effects of anxiolytic drugs. There are a number of reports that the behavioral actions of anxiolytics can be antagonised by GABA antagonists such as bicuculline or picrotoxin but there are many contradictory findings and these drugs are difficult to use effectively in behavioral studies. In general, GABA agonists do not exert anxiolytic-like behavioral effects after systemic injection but intracerebral administration of muscimol has been shown to produce benzodiazepine-like actions. Although a number of questions remain unanswered, current evidence does not provide strong support for a role for GABA in the behavioral effects of anxiolytic drugs.

Animals↗
PubMed1985

Anxiolytic drugs and the acquisition of conditioned fear in mice.

Previous studies have shown that, in rodents, chlordiazepoxide and other benzodiazepines can interfere with learning in passive avoidance or conditioned suppression procedures. The most consistent effects are observed when the drugs are administered before the acquisition trial and subjects are re-tested in the non-drugged state. It is not clear, however, whether this effect on learning is associated with the behavioural depressant actions of these drugs. In the present study mice were injected with chloridiazepoxide, diazepam, zopiclone, or CGS 9896 and locomotor activity measured in a two-compartment box. The animals were then enclosed in one of the compartments and received a series of footshocks. On a second trial, 24 h after the first, the mice were returned to the box without injection and locomotion and time spent in each compartment were measured. During trial 1 chlordiazepoxide, diazepam, and zopiclone produced dose-related decreases in locomotor activity. The same doses disrupted fear conditioning. CGS 9896 also interfered with the conditioning of fear but did not reduce exploratory activity during the first trial at any of a wide range of doses, showing that learning can be affected without direct behavioural depressant activity. In a further experiment, chlordiazepoxide and CGS 9896 disrupted fear conditioning when injected before trial 1 but not when injected immediately after this trial. Mice drugged with chlordiazepoxide or CGS 9896 before both trials 1 and 2 also showed disrupted conditioning, demonstrating that the drug effects cannot be interpreted in terms of state dependent learning.

Animals↗
PubMed1985

Effects of d-amphetamine and of beta-phenylethylamine on fixed interval responding maintained by self-regulated lateral hypothalamic stimulation in rats.

d-Amphetamine sulphate (0.25-4.0 mg/kg) and beta-phenylethylamine hydrochloride (1.25-50 mg/kg) respectively were administered IP to two groups of rats (R1-R4 and R5-R8 respectively) responding on a fixed interval (FI) schedule (R1-R4 FI 60 sec, R5-R8 FI 30 sec) of electrical hypothalamic stimulation. The duration of each train of stimulation was controlled by the duration of each lever press that initiated stimulation. Under these conditions administration of d-amphetamine resulted in a marked increase in overall response rates on the FI 60 sec schedule. This effect was significant at 1, 2 and 4 mg/kg. d-Amphetamine had not significant effect on the duration of hypothalamic stimulation or on the duration of responses occurring during the FI. Administration of beta-phenylethylamine resulted in a decrease in overall response rates on the FI 30 sec schedule. This effect was significant at 50 mg/kg. beta-Phenylethylamine increased the duration of responses occurring during the FI, this effect being significant at 25 and 50 mg/kg, but had no significant effect on the duration of hypothalamic stimulation. These results indicate that the systemic effects of d-amphetamine on response rate, and of beta-phenylethylamine on both response rate and response duration, are dissociable from changes in the self-regulated duration of lateral hypothalamic stimulation.

Animals↗
PubMed1985

The effects of clozapine on shuttle-box avoidance responding in rats: comparisons with haloperidol and chlordiazepoxide.

Previous studies have shown that clozapine produces effects different from those of other antipsychotic drugs on positively reinforced responding but may give rise to similar disruptions of avoidance behavior. To investigate the actions of clozapine on avoidance responding in more detail the effects of this drug were compared with those of haloperidol and chlordiazepoxide in rats trained to avoid shock in a shuttle-box. Acute administration of all three drugs reduced avoidance responses and increased escape failures although clozapine produced this latter effect only at a high dose. With repeated administration of each drug over 4 days tolerance developed rapidly to the effect of clozapine, the effect of haloperidol increased and there was no systematic change in the action of chlordiazepoxide. Disrupted avoidance responding after acute administration of clozapine does not reflect the clinical antipsychotic action of this drug.

Animals↗
PubMed1985

Behavioral effects of nonbenzodiazepine anxiolytic drugs: a comparison of CGS 9896 and zopiclone with chlordiazepoxide.

Zopiclone and CGS 9896 are two nonbenzodiazepine compounds which have been shown to displace benzodiazepines from their binding sites. The present study compared the behavioral effects of these two compounds in rats with those of chlordiazepoxide. The three drugs produced dose-related increases in punished drinking as did pentobarbital and meprobamate but not PK 9084, which also acts at benzodiazepine binding sites, or buspirone. Rates of lever pressing suppressed by punishment were also increased by chlordiazepoxide and zopiclone. CGS 9896 exerted a similar although less marked effect. Lever pressing maintained by a differential reinforcement of low rate 18-sec schedule of milk presentation was increased by low doses of chlordiazepoxide and zopiclone and decreased by higher doses leading to dose-related reductions in numbers of reinforcers obtained. CGS 9896 also reduced number of reinforcers but without affecting rate of responding. In rats trained to discriminate a dose of chlordiazepoxide from saline, chlordiazepoxide, zopiclone, pentobarbital and meprobamate produced chlordiazepoxide-appropriate responding. CGS 9896 also produced chlordiazepoxide-appropriate responding at a wide range of doses although the stimulus properties of this compound appeared to be weaker than those of the other active drugs. Chlordiazepoxide and zopiclone produced dose-related increases in food intake in food-deprived rats. CGS 9896 had similar effects at low doses but its effects were less consistent at higher doses. Thus, zopiclone has a behavioral profile very similar to that of chlordiazepoxide. Although many of the effects of CGS 9896 were similar to those of chlordiazepoxide, a number of differences were also observed.

Animals↗
PubMed1984

Chlordiazepoxide-induced hyperphagia in rats: lack of effect of GABA agonists and antagonists.

Because of the evidence that benzodiazepine binding sites are associated with GABA receptors in the central nervous system, it has been suggested that the behavioural effects of benzodiazepines may be mediated by GABAergic mechanisms. In order to investigate this hypothesis in relation to the hyperphagia produced by benzodiazepines, the effects of chlordiazepoxide were compared with those of the GABA agonists progabide and muscimol and the GABA antagonists picrotoxin and bicuculline. In rats adapted to a 22 h/day food deprivation schedule chlordiazepoxide produced a dose-related increase in food intake. Neither progabide nor muscimol produced a similar effect after IP injection, nor did these drugs potentiate the effects of a dose of chlordiazepoxide. Picrotoxin and bicuculline, each given at a sub-convulsant dose, did not affect quantities of food consumed and also did not antagonise the effect of chlordiazepoxide. These results provide no evidence for the hypothesis that chlordiazepoxide-induced hyperphagia in rats is mediated by GABAergic mechanisms.

Animals↗
PubMed1983

Effects of chlordiazepoxide on the self-regulated duration of lateral hypothalamic stimulation in rats.

Rats were exposed to a fixed-interval 60-s schedule under which responding was maintained by electrical stimulation of the lateral hypothalamus. The duration of stimulation was controlled by the duration of each lever press that initiated reinforcement. The effects of variation in current intensity and administration of several chlordiazepoxide (CDP) doses (2.5--20 mg/kg IP) were investigated. The duration of stimulation was inversely related to current intensity. Administration of CDP resulted in increases in response rate and the durations of reinforced and non-reinforced responses. CDP increased the response duration reliably more with non-reinforced responses than with responses that served to regulate the duration of stimulation. Thus CDP-induced increases in the duration of brain stimulation with the single lever self-regulation procedure may not be attributed to a specific effect of this compound on neural processes underlying reinforcement. The present results indicate the utility of intermittent schedules in establishing the specificity of drug effects on self-regulated duration of brain stimulation in the single-lever condition.

Animals↗
PubMed1983

An analysis of the effects of systemically administered clonidine on the food and water intake of rats.

1 It is known that intracerebral injections of clonidine can induce eating in rats but it has not been clear whether systemic administration can produce similar effects. 2 Subcutaneous injections of clonidine (0.01, 0.03, 0.1 mg/kg) increased food and water intake during the 6 h period following injection in non-deprived male rats. 3 Pretreatment with a dose of yohimbine (1.0 mg/kg) shifted the clonidine dose-response curves to the right, suggesting competitive antagonism. 4 A dose of naloxone (0.1 mg/kg) produced a lowering of the clonidine dose-response curve but statistical analysis suggested that the opiate antagonist did not produce a competitive antagonism of the effect of clonidine. 5 The results are consistent with a role for alpha 2-adrenoceptors in appetite regulation.

Animals↗
PubMed1982

The anorectic action of naloxone is attenuated by adaptation to a food-deprivation schedule.

Recent studies have shown that naloxone and other opiate antagonists can reduce the amounts of food and water consumed by laboratory animals, a finding consistent with a role for endogenous opioids in the control of appetite. Because there have also been some failures to observe an anorectic action of naloxone, a study was carried out in which the effects of the drug on food intake were investigated using two different experimental procedures. In naive rats deprived of food for 24 h, both naloxone (0.1, 1.0 and 10.0 mg/kg) and fenfluramine (1.0, 3.0 and 10.0 mg/kg) produced dose-related decreases in food and water intake. In rats which had been adapted to receiving food for only 6h each day, fenfluoramine produced a similar effect whereas naloxone had no effect on food intake and reduced water consumption only at the highest dose. A second experiment showed that the different actions of a 1.0 mg/kg dose of naloxone in the two procedures were not due to differences in the duration of the immediately preceding period of food deprivation or in the time during which the rats were handled. These results show that the anorectic action of naloxone can be attenuated by adaptation to a schedule of repeated food deprivation.

Adaptation, Physiological↗
PubMed1982

A comparison of the effects of opiate antagonists on operant and ingestive behavior.

Previous studies have found that naloxone and other opiate antagonists will decrease the food and water intake of experimental animals. The present study investigated the possibility that these effects may be due to a generalized action of opiate antagonists to block an endogenous reward system. A direct comparison was made between the effects of naloxone and naltrexone on FR responding maintained by small quantities of milk and on the consumption of milk when it was freely available. Both drugs reduced milk consumption at all doses (0.3-30 mg/kg) but produced only small decreases in FR response rates at the highest doses. These results do not support the view that the actions of opiate antagonists on eating and drinking represent an inhibitory action on central reward mechanisms.

Animals↗
PubMed1981

Increased food and water intake produced in rats by opiate receptor agonists.

It has been suggested that endogenous opiate mechanisms may be involved in the physiological control of food and water intake. Support for this hypothesis has been obtained from studies of the effects of narcotic antagonists which reduce feeding and drinking, but it is also necessary to show that food and water intake can be facilitated by opiate agonists. In the present study the food intake of freely-feeding rats was increased by subcutaneous injections of morphine, a stabilised enkephalin and analogue (RX 783030), and ethylketocyclazocine. Water intake was also increased but this effect was more variable than the increased eating. The increased food intake produced by the putative mu receptor agonists morphine and RX 783030 was blocked by a dose of naloxone which did not affect the facilitation of eating produced by ethylketocyclazocine, which may act at a separate population of receptors known as kappa receptors. These data are consistent with the possibility that opiate receptors are involved in the control of feeding and drinking.

Animals↗