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  • 1
    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
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 118 (1995), S. 57-64 
    ISSN: 1432-2072
    Keywords: CCKB antagonists ; L-365, 260 Benzodiazepines ; Chlordiazepoxide ; Withdrawal Anxiety ; Food Intake ; Hypophagia ; Rats
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effect of the selective CCKB antagonist L-365, 260 on chlordiazepoxide (CDP) withdrawal-induced hypophagia was assessed in two related studies in rats pretreated for 21 days with CDP at doses escalated from 10 to 30 mg/kg per day (b.i.d.). L-365, 260 was studied at doses from 0.001 to 10 mg/kg (b.i.d.). There was no evidence that L-365, 260 at any dose alleviated CDP withdrawal-induced hypophagia. These data contrast with reports that CCKB antagonists alleviate behavioural benzodiazepine (BZ) withdrawal symptoms considered to be indicative of “anxiogenesis”. Presumably, such positive effects of CCKB antagonists are due to “functional antagonism”, with enhanced anxiety during BZ withdrawal being attenuated by anxiolytic actions of CCKB antagonists. Collectively, studies with CCKB antagonists and other agents involving a number of different BZ withdrawal signs suggest that BZ withdrawal is a heterogeneous syndrome, with various different underlying mechanisms. CCKB antagonists appear to alleviate only a subset of possible BZ withdrawal signs.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 35 (1974), S. 1-12 
    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
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 35 (1974), S. 13-17 
    ISSN: 1432-2072
    Keywords: Anorexia ; Time Sampling ; Fenfluramine ; SE 780
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The behavioural and anorexic effects of the fenfluramine derivative “SE 780” in rats were studied after chronic administration over 35 days. Behavioural effects of the compound were assessed by “time sampling” behavioural categorisation, on days 1, 14 and 28 of administration. An initial sedative effect observed after acute administration was absent on days 14 and 28 of observation, when the drug had no behavioural effects at all. The anorexic properties of the drug were investigated in two ways. Firstly, by measuring daily body weights; and secondly by measuring intake of food over a 2 h period on observation days. The drug appeared to be a highly potent anorexiant in that tolerance to its effects built up very slowly. It is suggested that SE 780 may be an anorexic agent which is superior to Fenfluramine in two ways; firstly, it lacks stimulant properties after chronic administration, and secondly it is active over longer periods of time; as such it merits further study in humans.
    Type of Medium: Electronic Resource
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