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  • 1
    Electronic Resource
    Electronic Resource
    Analysis of the role of drug-predictive environmental stimuli in tolerance to the hypothermic effects of the benzodiazepine midazolam (1986)
    Springer
    Psychopharmacology 90 (1986), S. 513-521 
    Details
    ISSN: 1432-2072
    Keywords: Benzodiazepines ; Midazolam ; Tolerance ; Classical conditioning ; Rats ; Body temperature
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The role of classical conditioning processes in the development of tolerance to the hypothermic effects of the short-acting benzodiazepine midazolam was studied in three experiments in rats. The experiments were all designed so that one set of environmental stimuli reliably predicted drug treatments whilst another set of stimuli predicted control (vehicle) treatment. According to the classical conditioning account of tolerance, the degree of tolerance observed should be greater in the presence of drug-predictive stimuli than in their absence, i.e. tolerance should show environmental (context) specificity. A preliminary study was conducted to determine the dose- and time-effect curves for midazolam-induced hypothermia. The results of this study provided essential background data for the design of all the subsequent tolerance studies. In the first tolerance study, it was found that virtually complete tolerance developed to the hypothermic effects of 4 mg/kg (IP) midazolam given on alternate days. However, the observed tolerance was clearly not environmentally specific. Since there is evidence that conditioned tolerance to some drug effects develops most readily if drugs are given at low doses with long inter-injection intervals, a second study was conducted with a lower (1.6 mg/kg IP) dose of midazolam, which was given every 5th day. Despite these procedural changes, the second study indicated that the observed tolerance again did not show context specificity, even though tolerance developed rapidly with the lower dose of a short acting drug which was given infrequently. In a final study, the experimental procedure was changed again so that the environmental stimuli which predicted drug treatment were only present during the onset of drug-induced hypothermia, in contrast to the procedure adopted in the two previous studies in which the drug-predictive stimuli were present during the onset and the offset of the drug's hypothermic effect. This procedural change was introduced because it was considered possible that the presence of stimuli associated with recovery from the drug's effects might have prevented the development of conditioned tolerance in the first two studies. However, no evidence was obtained for context specific tolerance, even after this further procedural manipulation. These data indicate clearly that it is difficult to demonstrate context specificity of midazolam hypothermic tolerance. A number of possible reasons for these results are considered.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00174071
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  • 2
    Electronic Resource
    Electronic Resource
    Effects of drug experience on drug induced conditioned taste aversions: Studies with amphetamine and fenfluramine (1975)
    Springer
    Psychopharmacology 44 (1975), S. 77-82 
    Details
    ISSN: 1432-2072
    Keywords: Conditioned Taste Aversions ; Amphetamine ; Fenfluramine ; Tolerance ; Cross-Tolerance ; Drug Abuse ; Animal Models
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Conditioned taste aversions (C.T.As) established in rats to 0.1% sodium saccharin by intra-peritoneal injections of dl-fenfluramine hydrochloride (6 mg per kg) or d-amphetamine sulphate (2.0 mg per kg) were found to be significantly attenuated, but not abolished altogether, by chronic pretreatment (over 9 days) with the specific drug. Prior treatment with fenfluramine attenuated the aversive effects of amphetamine, but the converse was found not to be the case. These results are considered to refute the “Unnatural need state” and “Novelty” hypotheses of the effects of prior drug experience on the establishment of C.T.As. An alternative explanation of such effects in terms of tolerance is considered, and the possible relevance of the results to studies of drug abuse in humans discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00421187
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  • 3
    Electronic Resource
    Electronic Resource
    Acute sedative properties of SKF 525 A in rats: Implications for its use as a metabolism inhibitor in the study of psychoactive drugs (1975)
    Springer
    Psychopharmacology 41 (1975), S. 291-294 
    Details
    ISSN: 1432-2072
    Keywords: SKF 525 A ; Activity Analysis ; Drug Metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract SKF 525 A was found possess sedative properties in rats at doses of 25 and 50 mg per kg, when injected intraperitoneally. The behavioural effects of the drug were assessed in two ways. Firstly, by “Time Sampling Behavioural Categorisation” of exploratory behaviour; and secondly by activity measurements obtained with an ultrasonic motion recorder. The results clearly demonstrate that SKF 525A has sedative properties in rats at doses which are conventionally used to inhibit metabolism of a wide range of drugs. The implications of these results for the use of SKF 525 A in the study of the actions of psychotropic drugs are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00428939
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  • 4
    Electronic Resource
    Electronic Resource
    Time sampling of rat exploratory behaviour: A reliable screening test for the C.N.S. effects of anorexic agents (1974)
    Springer
    Psychopharmacology 35 (1974), S. 1-12 
    Details
    ISSN: 1432-2072
    Keywords: Anorexiants ; Activity Analysis ; Time Sampling ; Screening Tests ; Phenylethylamines ; Serotonin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A series of eight experiments were conducted on the acute effects of a number of anorexic agents on rat exploratory behaviour, as assessed by a “time sampling” procedure of behavioural categorisation. Compounds studied were of three types. Firstly, some well known anorexiants (Amphetamine, Diethylpropion, Fenfluramine); secondly, a series of fenfluramine derivatives (Norfenfluramine, SE 780, SE 1513 and SKF 1-39728); and thirdly, an indole derivative (U 22-394A). All the compounds except the latter are based upon a phenylethylamine configuration. The results indicate that amphetamine and diethylpropion are stimulants whilst fenfluramine is a sedative, in accord with the clinical reports of the effects of acute administration of these compounds. All the other phenylethylamines and U 22-394A were found to be sedatives. The technique of activity analysis described here is a useful screening test for psychotropic agents which affect C.N.S. excitability in humans, which is probably superior to other measures of activity in its predictive value. However, it is noted that the effects of acute administration do not always provide a reliable index of chronic effects. The compounds SE 780 and SKF 1-39728 would seem to merit further study. It is suggested that all the fenfluramine derivatives, except SKF 1-39728, have a similar mode of anorexic action to U 22-394A.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00421560
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  • 5
    Electronic Resource
    Electronic Resource
    Chronic anorexic and behavioural effects of the fenfluramine metabolite, norfenfluramine: An evaluation of its role in the actions of fenfluramine (1974)
    Springer
    Psychopharmacology 38 (1974), S. 67-74 
    Details
    ISSN: 1432-2072
    Keywords: Fenfluramine ; Norfenfluramine ; Anorexia ; Activity Analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The anorexic and behavioural effects of Norfenfluramine were studied in rats. Two separate experiments were conducted involving administration by intra-peritoneal and sub-cutaneous routes respectively. Behavioural effects were assessed by time sampling categorisation on Days 1 and 14 of a 20 day chronic study and anorexic effects by daily weighing. Norfenfluramine was found to be a potent anorexiant, to which tolerance is established fairly quickly. It was also found to possess sedative properties after acute administration, but marked stimulant properties after 14 days chronic administration. These results are similar to those previously reported in a study of Fenfluramine, although the behavioural effects of Norfenfluramine are more marked. The results implicate Norfenfluramine in the anorexic and behavioural effects of Fenfluramine, and provide indirect confirmation of the suggestion made in an earlier paper that Fenfluramine may have chronic stimulant properties.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00421288
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  • 6
    Electronic Resource
    Electronic Resource
    The effects of chronic fenfluramine administration on behaviour and body weight (1973)
    Springer
    Psychopharmacology 31 (1973), S. 63-76 
    Details
    ISSN: 1432-2072
    Keywords: Fenfluramine ; Anorexia ; Activity Analysis ; C.N.S. Stimulation ; Stereotyped Behaviour
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Two experiments were conducted on the effects of chronic administration of fenfluramine on behaviour and body weight in rats. In Experiment One the effects of 28 day chronic administration were studied. A dose related rapid weight loss was observed in treated subjects, with development of tolerance to the effects of the drug on body weight after 14 days administration. Observations of behaviour were made on days 1, 14 and 28 of chronic administration according to a “time sampling” procedure of behavioural categorisation. The incidence of some behavioural patterns varied significantly between observation days, although observations of control subjects were never significantly different. By the 28th day of administration tolerance to the behavioural effects of the drug had developed, no dose/response eifects being noted in contrast to the results for prior observation days. In Experiment Two confirmation of the development of behavioural tolerance was obtained. Abnormal, “stereotyped” behaviour induced by a very high dose of fenfluramine showed a much lower incidence in subjects that hadr eceived fenfluramine for 30 days than in saline controls. Attention is drawn to the difficulties inherent in describing psychotropic agents as either sedatives or stimulants. It is suggested that although fenfluramine is generally considered to be a sedative, stimulant effects may be observed after chronic administration of anorexic doses. Similarities between the effects of high doses of fenfluramine and amphetamine are described.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00429299
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  • 7
    Electronic Resource
    Electronic Resource
    Behavioural tolerance to amphetamine and other psychostimulants: The case for considering behavioural mechanisms (1983)
    Springer
    Psychopharmacology 80 (1983), S. 287-307 
    Details
    ISSN: 1432-2072
    Keywords: Tolerance ; Sensitization ; Amphetamine ; Cocaine ; Anorexia ; Stimulant ; Operant conditioning ; Classical conditioning ; Animal studies ; Synaptic mechanisms ; Functional tolerance ; Dispositional tolerance ; Behavioural tolerance ; Reinforcement
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract An hypothesis is presented about the nature of behavioural tolerance in animals to stimulant drugs. It is suggested that, in many behavioural procedures, tolerance is due to behavioural adaptation to those drug effects which cause disruption of ongoing rewarded behaviour. This unitary hypothesis accounts for the available data on tolerance and cross-tolerance to stimulants more effectively than all of the other more conventional explanations which are based upon dispositional or functional concepts, the most common of which are described, evaluated, and found to be inadequate. Furthermore, it is suggested that attempts to explain tolerance in terms of changes in synaptic functioning are subject to very considerable problems of interpretation and that an analysis of behavioural mechanisms may be of greater value in understanding the process of behavioural tolerance. Evidence for the basic behavioural hypothesis is outlined in some detail, and a theoretical justification presented for its major assumptions. Operant studies of chronic stimulant effects on behaviour have often produced very complex patterns of data, considerable differences being reported both between subjects and between studies. A speculative model is presented which attempts to account for this pattern of data in tolerance studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00432109
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