Biomedical subjects

S J Cooper

Publications and source records attributed to S J Cooper.

At least 163 records · Page 9Linked to original sources

PubMed1986

Beta-carbolines characterized as benzodiazepine receptor agonists and inverse agonists produce bi-directional changes in palatable food consumption.

Drugs which bind to specific benzodiazepine recognition sites fall into three categories: agonists, antagonists, and inverse agonists. A set of biochemical parameters is available which distinguishes between the three. In addition, actions of the drugs result in physiological and behavioural effects which are distinguishable. beta-Carboline derivatives provide a group of compounds which show high affinity for the benzodiazepine sites, and which contains examples belonging to each of the three categories. Evidence is reviewed which shows that beta-carboline benzodiazepine receptor agonists (ZK 93423, ZK 91296) produce increases in the consumption of a palatable diet by non-deprived rats, that beta-carboline inverse agonists (FG 7142, DMCM) produce an anorectic effect, and that the beta-carboline ZK 93426 acts as a benzodiazepine receptor antagonist. The results support the proposal of bi-directional control of feeding responses through the action of drugs at a common benzodiazepine receptor. Furthermore, benzodiazepine receptor inverse agonists provide a novel class of anorectic agents. Evidence is also reviewed which is suggestive of the modulation of food-related reward by drug actions at benzodiazepine receptors.

Animals↗

PubMed1986

Initial environment influences amphetamine-induced stereotypy: subsequently environment change has little effect.

Saline-treated and amphetamine-treated (7 mg/kg, ip, immediate) male rats from a Sprague-Dawley substrain were observed in two test environments designed to elicit different investigative responses in normal rats. Snout contact with the substrate was generated by placing the rat in a small enclosed cage. Absence of snout contact was induced by placement of the rat on a square elevated platform. Detailed ethological records were kept of locomotion, rearing, sitting, grooming, gnawing, and sleeping throughout the 90-min session. Amphetamine-treated rats incorporated environmentally contingent bodily postures into their forms of stereotyped behavior. The postures were characteristic of those evinced initially by the saline-treated rats in the same test environment. The control rats showed appropriate changes in their investigative behavior when the apparatus was changed at 10 and at 30 min postinjection. The amphetamine-treated rats, however, were completely unresponsive to such changes at 30 min and only partially so at 10 min postinjection. It was concluded that there is a temporal gradient of decreasing readiness to modify repetitive behavior after a single, large dose of amphetamine.

Amphetamine↗

PubMed1986

Monoclonal antibody cure and prophylaxis of lethal Sindbis virus encephalitis in mice.

Neuroadapted Sindbis virus (NSV) causes acute encephalitis and paralyzes and kills adult mice unless they are treated with primary immune serum after infection. To study the nature and specificity of curative antibodies, we gave mice 30 different monoclonal antibodies (MAbs) against Sindbis virus (SV) 24 h after lethal intracerebral inoculation of NSV. By the time of MAb treatment, NSV replication in the brain had been well established (7.5 X 10(7) PFU/g). Seventeen MAbs directed against multiple biological domains on the NSV E1 and E2 envelope glycoproteins prevented paralysis and death. Anticapsid MAbs failed to protect. Altogether, 15 of 17 curative MAbs either neutralized NSV infectivity or lysed NSV-infected cells with complement, but neither ability was necessary or sufficient to guarantee recovery. All 5 protective anti-E2 MAbs neutralized NSV infectivity; 6 of 10 protective anti-E1 MAbs neutralized NSV; 4 did not. Plaque assay or immunohistochemical staining showed that neutralizing and nonneutralizing curative MAbs decreased NSV in the brain, brainstem, and spinal cord. Despite high neutralization titers, hyperimmune anti-SV and anti-NSV mouse sera prevented only 6 and 30% of deaths, respectively, while primary immune sera prevented 50 (SV) and 90% (NSV) of deaths. Secondary intravenous immunization with a live virus apparently diminished, obscured, or failed to boost a class of protective antibodies. When separate mouse groups were given these 30 MAbs 24 h before lethal intracerebral inoculation of NSV, a slightly different set of 17 neutralizing or nonneutralizing anti-E1 and anti-E2 antibodies protected. Two nonneutralizing MAbs and hyperimmune anti-SV serum, which had failed to promote recovery, prophylactically protected 100% of the mice. The antibody requirements or mechanisms of prophylaxis and recovery may differ.

Animals↗

PubMed1985

The anorectic effect of FG 7142, a partial inverse agonist at benzodiazepine recognition sites, is reversed by CGS 8216 and clonazepam but not food deprivation.

The benzodiazepine partial inverse agonist N'-methyl-beta-carboline-3-carboxamide (FG 7142; 5.0 and 10.0 mg/kg, i.p.) produced a dose-dependent reduction in the consumption of a familiar, highly palatable diet by non-food-deprived male rats. At dose levels which exhibited no significant intrinsic effects, the benzodiazepine receptor antagonist 2-phenylpyrazolo-[4,3-c]-quinoline-3(5H)-one (CGS 8216; 1.25-5.0 mg/kg, i.p.) reversed the anorectic effect of FG 7142. When clonazepam and FG 7142 were given in combination, mutual cancelling of their opposite effects occurred. These results are consistent with an action of FG 7142 at benzodiazepine recognition sites to reduce the level of palatable food consumption, and imply that a bidirectional control of food intake via benzodiazepine recognition sites can be achieved. The anorectic effect of FG 7142 was not reversed by 24-h food deprivation, indicating a possible separation from the effects of hunger mechanisms.

Animals↗

PubMed1985

Chlordiazepoxide-induced hyperphagia in non-food-deprived rats: effects of Ro15-1788, CGS 8216 and ZK 93 426.

Chlordiazepoxide (1.25-20.0 mg/kg i.p.) was administered to non-food-deprived male rats given 30 min access to a highly palatable, familiar diet, and produced a potent stimulation of food consumption. At the maximum dose effect, the rats consumed about 24 g food in the 30 min test. The benzodiazepine receptor antagonist, Ro15-1788 (2.5-40.0 mg/kg i.p.) had no effect on food intake when given alone, but did dose-dependently attenuate chlordiazepoxide's hyperphagic effect. The antagonist CGS 8216 (5.0-20.0 mg/kg i.p.) completely abolished the hyperphagic effect, and in doses of 10.0 and 20.0 mg/kg produced significant suppression of feeding when administered by itself. ZK 93 426, in doses (0.625-10.0 mg/kg i.p.) which have previously been shown to antagonize the discriminative cue of chlordiazepoxide produced no significant change in chlordiazepoxide's hyperphagic effect. These data point to an interesting and important distinction between ZK 93426 and the other two benzodiazepine receptor antagonists when given in combination with chlordiazepoxide in the palatable food consumption test.

Animals↗

PubMed1985

Yawning elicited by systemic and intrastriatal injection of piribedil and apomorphine in the rat.

The behavioural effects of systemic and intrastriatal injections of the dopamine agonists piribedil and apomorphine in male rats were examined. Bilateral application of piribedil (50 and 100 micrograms) or apomorphine (5, 10 and 20 micrograms) to the striatum produced yawning and chewing mouth movements accompanied by intermittent stretching and sexual arousal. Low doses of piribedil (1.25 and 2.5 mg/kg) and apomorphine (0.1 and 0.2 mg/kg) injected SC produced an identical yawning syndrome. Previous work has suggested that yawning elicited by systemic dopamine agonist treatment is a consequence of dopamine autoreceptor stimulation. Similarly, the most likely explanation of the present data is that yawning elicited by systemic and central dopamine agonist treatment was due to activation of dopamine autoreceptors. Systemic injection of haloperidol and scopolamine abolished yawning induced by intrastriatal piribedil and these data provide tentative support for the proposal that a dopamine-acetylcholine link may be involved in the expression of yawning.

Animals↗

PubMed1985

Benzodiazepine receptor ligands and the consumption of a highly palatable diet in non-deprived male rats.

Non-deprived rats were familiarized with a highly palatable diet until baseline consumption in a 60-min daily access period had stabilised. The benzodiazepine receptor agonist midazolam (1.25-10.0 mg/kg, IP) produced a large, dose-related increase in food consumption during the first 30 min of access. It also produced significant, short-term hyperphagia in animals which had been partially pre-satiated on the diet before drug administration, an effect which was reversible by the benzodiazepine receptor antagonist Ro15-1788. Administered alone, Ro15-1788 (1.25-10.0 mg/kg, IP) had no intrinsic activity in the food consumption test. In contrast, CGS 8216 (2.5-40.0 mg/kg, IP) produced a marked dose-related suppression of food intake. This anorectic effect was shared by two benzodiazepine receptor inverse agonists, FG 7142 and DMCM, which also produced dose-dependent reductions in consumption. The effects on feeding produced by FG 7142 (20 mg/kg, IP) and DMCM (1.25 mg/kg, IP) were reversed by either Ro15-1788 (2.5 and 5.0 mg/kg) or midazolam (5.0 and 10.0 mg/kg). A matched anorectic effect produced by CGS 8216 (40 mg/kg) was not, however, reversed by either Ro15-1788 or midazolam. This suggests that at a high dose CGS 8216 may act by a mechanism different from that of the two inverse agonists. The feeding test described in the report proved sensitive to both hyperphagic and anorectic effects of drugs active at benzodiazepine receptors, pointing to a possible bi-directional control of palatable food consumption.

Animals↗

PubMed1985

Effects of tifluadom on food consumption compared with chlordiazepoxide and kappa agonists in the rat.

Tifluadom (0.625-10.0 mg kg-1) was administered to non-deprived male rats which had been accustomed to eating a highly palatable diet in a 30 min test period. This compound, an opioid benzodiazepine, produced a significant increase in consumption of food when administered by the subcutaneous route, but not after intraperitoneal injection. Both chlordiazepoxide (1.25-20.0 mg kg-1) and the selective kappa opiate receptor agonist U-50,488 (0.3125-2.5 mg kg-1) also produced significant hyperphagic effects in the same feeding situation. In contrast, the two kappa opiate receptor agonists, ethylketocyclazocine (0.1-3.0 mg kg-1) and bremazocine (0.078-1.25 mg kg-1) brought about a dose-related suppression of food intake. Hence, the effects of kappa opiate receptor agonists in the feeding situation described here were not uniform. Furthermore, tifluadom could be likened either to a benzodiazepine or to a selective kappa receptor agonist. The hyperphagia induced by tifluadom was antagonized by naloxone, suggesting that the effect was mediated by an action at opiate receptors. It was not antagonized however by Ro15-1788 (10.0 and 20.0 mg kg-1), a selective benzodiazepine receptor antagonist, ruling out possible mediation by benzodiazepine receptors. The benzodiazepine receptor antagonist, CGS 8216, exhibited intrinsic activity when administered alone, and significantly reduced food consumption in tifluadom-treated and control animals.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1985

Endorphins and food intake: kappa opioid receptor agonists and hyperphagia.

Evidence from studies which utilise either opiate receptor agonists and antagonists strongly indicate a role for endorphinergic mechanisms in the control of feeding responses. Two means by which these compounds may exert an effect on feeding can be singled-out. Firstly, emerging evidence suggests that the process of achieving satiety (terminating a meal, or choice of a commodity) may be accelerated following treatments with opiate receptor antagonists. Secondly, the preference for highly palatable solutions (sweet solutions have received most attention) in two-bottle tests is blocked after injection of opiate receptor antagonists. This finding has been interpreted in terms of the abolition of the reward or incentive quality associated with the particularly attractive flavour. These two mechanisms of action may represent two aspects of a single, fundamental process. Following an introduction to rat urination model of in vivo kappa agonist activity, the consistent effect of several kappa agonists (including the highly selective U-50,488H) to stimulate food consumption is described. Recognising that members of the dynorphin group of endogenous opioid peptides are kappa receptor ligands, some with a high degree of selectivity, and the evidence the dynorphins and neo-endorphins produce hyperphagia in rats is particularly interesting. Such lines of evidence lead to the hypothesis that peptides of the dynorphin group may act endogenously to promote the expression of normal feeding behaviour.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1985

A microgram dose of diazepam produces specific inhibition of ambulation in the rat.

There is considerable consistency in the experimental literature showing that non-sedating doses of benzodiazepines can enhance the consumption of food, water and salt solutions. It is of great interest, therefore, that in a previous report low dose treatments with diazepam were found to significantly suppress the level of consumption of a palatable 0.005 M sodium saccharin solution in nondeprived male rats. The present study was designed to elucidate the behavioral characteristics of the inhibitory action of low dose diazepam treatments. Food consumption and general activity measures were chosen for analysis to examine the possibilities that low dose diazepam treatments might suppress ingestive behavior in a general way, or that the treatments might affect nonconsummatory responses including components of spontaneous motor activity. The results of two experiments succeeded in locating a highly specific inhibitory effect produced by 100 micrograms/kg diazepam. First, food consumption was not inhibited. Instead, 1.0 mg/kg diazepam produced significant elevations in food intake in both food-deprived and nondeprived animals. Second, vertical activity (rearing) and fine body movements were unaffected over the dose-range 0.1-3.0 mg/kg diazepam. Hence, low dose treatments with diazepam did not produce a generalised nonspecific behavioral depression. However, 100 micrograms/mg diazepam significantly inhibited coarse activity (measured automatically) and the corresponding ambulation measure (recorded by direct observation). The effect was present throughout a 1 hr test period and did not interact with the declining baseline level of activity. The results therefore confirm the presence of low dose diazepam-induced behavioral inhibition in quite a different context from the saccharin solution consumption study.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

Clonazepam-induced hyperphagia in nondeprived rats: tests of pharmacological specificity with Ro5-4864, Ro5-3663, Ro15-1788 and CGS 9896.

Nondeprived male rats were familiarised with daily 60 min access to a highly palatable diet, consisting of powdered rat diet, sweetened condensed milk and water. Clonazepam (0.625-5.0 mg/kg, IP) produced a substantial increase in food consumption within the first 30 min of access. The increase was similar across all dose conditions, suggesting that a maximal effect may have been achieved with a dose as small as 0.625 mg/kg. The hyperphagia induced by clonazepam was reversed by the benzodiazepine receptor antagonist, Ro15-1788 (5.0-20.0 mg/kg), indicating that the effect was benzodiazepine receptor-mediated. Treatments with the peripheral-type benzodiazepine agonist, Ro5-4864, did not induce a hyperphagic response. Instead, food consumption was significantly depressed following the administration of Ro5-4864 at 20 and 40 mg/kg, IP. A comparison of the clonazepam and Ro5-4864 data suggests that benzodiazepine-induced hyperphagia is mediated by central-type benzodiazepine binding sites. The pyrazoloquinoline, CGS 9896, binds with high affinity to benzodiazepine sites and has recently been described as a nonsedating anxiolytic. CGS 9896 (2.5-20.0 mg/kg, administered either IP or PO) did not affect consumption of the highly palatable diet. In consequence, anxiolytic and hyperphagic effects of drug actions at benzodiazepine receptors may be dissociated in the case of this compound. The atypical 1,4-benzodiazepine, Ro5-3663, a GABA antagonist which may act at the picrotoxinin site, produced a dose-related reduction in food consumption. Comparison with the results for Ro5-4864 rules out an interpretation for the anorexia in terms of anxiogenic effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

Benzodiazepine-induced hyperphagia in the nondeprived rat: comparisons with CL 218,872, zopiclone, tracazolate and phenobarbital.

Nondeprived male rats were familiarized with 30 min daily access to a highly palatable diet. Clonazepam, midazolam and chlordiazepoxide each produced significant dose-dependent increases in food consumption. Clonazepam was the most potent, and a significant hyperphagic effect was detected following 0.078 mg/kg (IP). Amongst novel non-benzodiazepine anxiolytics, zopiclone and CL 218,872 also produced significant increases in food intake. The smallest doses to produce significant hyperphagia for these two drugs were 10.0 and 2.5 mg/kg (IP) respectively. In contrast, tracazolate caused only a reduction in feeding, evident at 20 and 40 mg/kg (IP). Previous reports indicate that although benzodiazepines, zopiclone and CL 218,872 displace [3H] flunitrazepam binding in rat cerebral cortex preparations, tracazolate enhances the binding. Our results are consistent with the drug-induced hyperphagia depending upon agonist actions at high-affinity benzodiazepine sites. They also provide pharmacological evidence for a dissociation between hyperphagic and anxiolytic drug effects. Phenobarbital (2.5-40.0 mg/kg), like the benzodiazepines, produced a strong stimulation of food intake, indicating that drug action at an alternative site in the benzodiazepine receptor-GABA receptor-chloride channel complex can also lead to hyperphagia.

Animals↗

PubMed1985

Changes in plasma IgE levels during complicated and uncomplicated measles virus infections.

Plasma IgE levels were measured in 214 samples from 182 Peruvian patients with acute measles virus infections. Plasma IgE levels were significantly elevated early in infection compared to later time points. Plasma levels of IgG from the same patients rose during the same time period, whereas levels of IgA and IgM did not change. In patients with postmeasles encephalomyelitis, IgE remained elevated longer than it did in patients either with uncomplicated measles or measles complicated by pneumonia. It is proposed that the elevation of IgE is another manifestation of the altered immunoregulatory function in patients with measles.

Adolescent↗

PubMed1985

Evidence for opiate receptor involvement in the consumption of a high palatability diet in nondeprived rats.

Nondeprived adult rats were familiarized with a highly palatable diet (powdered small animal diet mixed with sweetened condensed milk and water). The palatability of food was such that it induced vigorous feeding responses, 15-20 g food consumed within the first 30 min of access. In partially-satiated male rats, the kappa receptor agonists EKC and U-50,488 (subcutaneously administered) produced large increases in food consumption in the first 30 min of access, post-injection. In experiments with naloxone and WIN 44,441-3, we found that the effects of naloxone (0.01-10 mg/kg; S.C.) were crucially dependent on the sex and dietary history of the animals. Male, obese rats were most sensitive to naloxone's anorectic effect. Lean females were completely insensitive. WIN 44,441-3 (0.01-10 mg/kg, S.C.) had no effect on food intake in any group of animals.

Animals↗

PubMed1985

Selective attenuation of sweetened milk consumption by opiate receptor antagonists in male and female rats of the Roman strains.

Male and female rats of the three Roman strains (Roman High-, Roman Low-, and Roman Control Avoidance; RHA, RLA and RCA, respectively) were familiarized with a highly palatable sweetened milk in a daily 30 min test. The animals were never food- or water-deprived prior to the test. Daily milk intake stabilised at a high level before drug tests were initiated. Effects of naloxone, diprenorphine, WIN 44,441-3, MR2266, MR2267, and ICI 154129 on milk consumption were investigated. Naloxone, diprenorphine and MR2266 each had comparable anorectic effects across strains and sexes. WIN 44,441-3 was relatively ineffective; MR2267 and ICI 154129 were without effect on milk consumption.

Animals↗

PubMed1985

Benzodiazepines and behavior.

This article sets the background for the following series of articles on the behavioral actions of drugs acting at the GABA-benzodiazepine receptor complex. The articles provide detailed analyses of particular behaviors and emphasise the danger of interpreting all behavioral effects in terms of anxiety. What also emerges clearly from several of the articles is that any agonist/inverse agonist classification is test-dependent and that global categorisation is not possible for many of the novel compounds.

Animals↗

PubMed1985

Behavioural pharmacology of food, water and salt intake in relation to drug actions at benzodiazepine receptors.

Drugs which are agonists at benzodiazepine receptors produce many interesting behavioural effects, and amongst these are the stimulation of food, water and salt intake. This review examines the evidence for benzodiazepine effects on these forms of ingestion, and makes tentative proposals about their modes of action. The recent advent of putative benzodiazepine antagonists and inverse agonists provides important new pharmacological tools for the analysis of factors which control ingestion. Preliminary data on examples of such drugs are considered. Anorectic effects of inverse agonists are described. It is clear, though, that the categorization of a drug in one test situation may not apply to another. For example, the compound Ro15-1788 appears as a specific antagonist in one test, a partial agonist in another, and apparently lacks effect in a third. We are not yet sufficiently forward in our understanding of drug actions at benzodiazepine receptors, and their interactions with particular test circumstances, to predict and account for divergent effects of this kind.

Animals↗

PubMed1985

Analysis of dopamine D1 and D2 receptor involvement in d- and l-amphetamine-induced anorexia in rats.

The concept of dopamine receptor subtypes and the recent development of selective dopamine receptor agonists and antagonists raises the possibility of specific subtype involvement in amphetamine-induced anorexia, and, furthermore, provides the means to evaluate the possibility. Using a test of palatable food consumption by nondeprived male rats, our data confirmed a more potent suppressant effect of d-amphetamine on food intake, compared to l-amphetamine (potency ratio 5.32:1). The test proved sensitive, with ED50s of 0.28 mg/kg and 1.49 mg/kg for d- and l-amphetamine, respectively. The modest anorectic effect of 0.3 mg/kg d-amphetamine was completely reversed by the selective dopamine D1 receptor antagonist, SCH 23390, but was not affected by the selective D2 receptor antagonist, sulpiride. A matched feeding-suppressant effect of 1.0 mg/kg l-amphetamine was reversed at one dose of SCH 23390, but was unaffected by sulpiride. Stronger anorectic effects produced by 1.0 mg/kg d-amphetamine and 3.0 mg/kg l-amphetamine were not antagonized either by SCH 23390 or sulpiride. The selective D1 receptor agonist, SKF 38393, produced a dose-dependent reduction in food consumption, without producing behavioural stereotypy. Unlike amphetamine, SKF 38393 is not self-administered, and therefore may provide an example of a novel pharmacological dissociation between anorectic and reinforcing effects of drug treatments mediated by dopamine receptors. Our data implicate dopamine D1 receptors in the control of feeding responses, and suggest that these receptors may mediate the anorectic effect of small-dose amphetamine treatments.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗