Biomedical subjects
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The interaction between lorazepam (1.0 mg) and low doses of alcohol (1/6 or 1/2 gill of vodka, equal to 6.5 or 19.6 g, respectively) was investigated in a variety of performance tests using a double-blind crossover design. The effects on mood ratings and bodily symptoms were also studied. The subjects were normal student volunteers. Lorazepam significantly impaired performance in a digit symbol substitution test and in number and verbal learning tasks. In the latter, long term recall was also impaired. Alcohol increased subjects' simple reaction time. Self-ratings of sedation were significantly increased by both lorazepam and alcohol alone, and these sedative effects were additive when the drugs were combined. Both lorazepam and alcohol had anxiolytic effects when taken alone, but when combined they made subjects more anxious than they were on placebo. This anxiogenic action of the drug combination was found on two occasions under test conditions where significantly different levels of state-anxiety were observed. These results suggest that benzodiazepine treatment should not be combined with even small quantities of alcohol because of the risk of both psychomotor impairment and possible anxiogenic effects.
RO 15-1788 (4-20 mg/kg), both alone and in combination with chlordiazepoxide (5 mg/kg), increased exploratory head-dipping in an holeboard above control levels. This intrinsic action of a benzodiazepine antagonist is not reversed, and is even augmented, by chlordiazepoxide. RO 15-1788 alone had no effect on locomotor activity, but antagonized the sedative effects of chlordiazepoxide. beta-CCE (1 and 2 mg/kg) was without effect on locomotor activity, but the higher dose reduced head-dipping.
Groups of rats were pretreated for 5 days with chlordiazepoxide (5 to 50 mg/kg) or with control water injections. On the sixth day the rats were given a test dose of chlordiazepoxide (10 mg/kg), or water. The rats that had received 5 days of pretreatment with chlordiazepoxide were significantly less sedated by the test dose than were those given chlordiazepoxide for the first time, i.e. they had developed tolerance. There were no significant differences between the two pretreatment groups in the extent of tolerance. A second experiment examined the effects of associating drug injections with apparatus cues. This had no effect on the development of tolerance, but had a significant effect on its retention: rats pretreated and replaced in their home cages showed complete recovery from tolerance after two drug-free days, whereas those placed in the apparatus after each day's injection retained some tolerance even after two drug-free weeks.
After 3 days of dosing rats with lorazepam (0.25 mg/kg), tolerance developed to its sedative effects. Recovery from this tolerance was rapid. No differences could be detected in undrugged behaviour 24 h after the last dose and no differences in response to a probe injection could be found when 2 drug-free days intervened between the chronic treatment and test dose. RO 15-1788 (1-4 mg/kg) antagonised the sedative effects of acute lorazepam (0.5 and 0.25 mg/kg), but chronic treatment with these doses concomitantly with lorazepam did not prevent the development of tolerance. However, 4 mg/kg RO 15-1788 administered for 5 days at the same time as lorazepam (0.5 mg/kg) and again 45 min later attenuated the development of tolerance. Plasma concentrations after acute and chronic treatment did not differ for 0.25 mg/kg lorazepam, but they were lower following chronic treatment with 0.5 mg/kg. Therefore the development of behavioural tolerance in rats to the sedative effects of benzodiazepines probably involves changes in benzodiazepine receptors, in addition to a pharmacokinetic contribution after treatment with high doses.
Two benzodiazepine antagonists were tested in an animal model of anxiety, the social interaction test. Ethyl beta-carboline-3-carboxylate (1 and 2 mg/kg) had a potent anxiogenic action; the imidazodiazepine RO 15-1788 (4-10 mg/kg) had a weak anxiogenic effect that with a larger dose (20 mg/kg) disappeared and RO 15-1788 (10 mg/kg) significantly counteracted the anxiogenic effect of the beta-carboline (1 mg/kg). The implications of these results for the understanding of the pharmacological basis of anxiety and for the existence and nature of an endogenous ligand for the benzodiazepine binding site are discussed.
Intravenous injection of ethyl beta-carboline-3-carboxylate (beta-CCE, 2 mg/kg) significantly reduced exploratory behaviour in a holeboard and 1 & 2 mg/kg markedly reduced the number of rears made. These effects were similar to those found with chlordiazepoxide (5 mg/kg). When they were given together the two drugs neither counteracted each other's effects, nor were their combined effects additive. We suggest that beta-CCE and the benzodiazepines might both act at one class of benzodiazepine receptor, as agonists to produce the same behavioural effects. The results are also discussed with reference to other intrinsic actions of these compounds.
The rat plasma corticosterone response was measured in 3 novel situations that differed in the extent to which the rat's own behavior determined its sampling of novel stimuli. All 3 tests induced a significant rise in corticosterone concentrations and on repeated exposures the corticosterone significantly decreased. Acute administration of chlordiazepoxide (5 mg/kg) significantly reduced the corticosterone response to novelty and after 5 days of drug pretreatment chlordiazepoxide was even more effective at reducing the corticosterone response to novel situations. The corticosterone response to the stress of cold and restraint was reduced by an acute dose of 50 mg/kg chlordiazepoxide, and after 5 days of pretreatment by doses of 10 and 50 mg/kg. In all but one test tolerance developed to the corticosterone-blocking action of chlordiazepoxide after 10 days of drug treatment.
Chlordiazepoxide-induced ataxia was potentiated by muscimol (0.5 mg/kg) and antagonised by picrotoxin (2 and 4 mg/kg) and by naloxone (2 and 4 mg/kg). The muscle-relaxant effects of chlordiazepoxide were not significantly altered by any of these three drugs and nor was the chlordiazepoxide-induced decrease in exploratory head-dipping. However, the sedative effects of chlordiazepoxide, measured by a reduction in spontaneous motor activity, were antagonised by picrotoxin.
Bilateral microinjection of 5,7-dihydroxytryptamine into the lateral septum resulted in a behavioural profile in the Social Interaction test of anxiety similar to that seen after chronically-administered benzodiazepines. In contrast, bilateral microinjection of 6-hydroxydopamine into this locus did not alter the profile of rats tested in this model. In a colony-intruder model of aggression, the 5,7-dihydroxytryptamine lesioned rats showed decreased dominance, while the 6-hydroxydopamine lesioned rats showed increased dominance and reduced subordination. The results suggest that lateral septal 5-hydroxytryptamine, but not catecholamines, is important in the control of anxiety, whereas both lateral septal 5-hydroxytryptamine and catecholamines are involved in the control of aggression.
1. The effects of drugs has been studied on escape behaviour of rats following electrical stimulation of the periaqueductal grey, in order to assess the feasibility of using the latency to escape as a measure of experimental anxiety. 2. Escape latencies were decreased by methysergide and cyproheptadine, whilst lorazepam and chlordiazepoxide (CDP) increased the latencies. 3. ACTH marginally decreased escape latencies, and did not alter the response to lorazepam. 4. Difficulties associated with using this paradigm to detect anxiolytic or anxiogenic effects of drugs are discussed.
1 The effects of 1.0 mg and 2.5 mg lorazepam on learning performance were examined in a double-blind cross-over study using student volunteers. 2 Test conditions were manipulated to prevent rehearsal and to vary the subjects' motivation to perform well. Self-ratings of alertness, motivation to perform well and state anxiety were obtained prior to each test. 3 Performance in arithmetic tasks of varying difficulty was also studied. 4 Lorazepam produced dose-related deficits in verbal and nonsense-syllable learning tasks. A greater proportion of errors in the number of problems attempted in the arithmetic tests reflected an impairment in cognitive function. Lorazepam reduced the number of arithmetic problems that were correctly solved as well as increasing the percentage of errors in the problems attempted. 5 Lorazepam did not significantly decrease motivation to perform well and the lorazepam impairment was found even when the test conditions were manipulated so as to prevent rehearsal. Therefore the learning deficits cannot be explained solely by changes in motivation or impairments in rehearsal. 6 Performance in the learning tasks correlated with ratings of alertness and therefore the deficits observed after administration of lorazepam seem likely to result from the non-specific sedative effect of the drug.
In 18 normal volunteers, lorazepam (2.5 mg) compared with placebo significantly impaired performance in a verbal learning task, in the digit-symbol substitution test, and in symbol copying and number cancellation tasks. These impairments were found equally in subjects with high and low state anxiety and in subjects with high and low trait anxiety. Caffeine citrate (125 to 500 mg) significantly improved performance on the digit-symbol substitution test when given alone and reduced the lorazepam impairment. In the symbol copying test caffeine counteracted the lorazepam impairment. Lorazepam produced a significant loss of appetite and made the subjects feel significantly more dizzy, physically and mentally tired, withdrawn and tranquil, and significantly less anxious. Caffeine citrate (500 mg) counteracted the lorazepam effect of reducing anxiety and making the subjects feel more relaxed.
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Acute administration of lorazepam (0.25 and 0.5 mg/kg) and triazolam (0.075-0.25 mg/kg) significantly reduced the locomotor activity of rats placed in a holeboard for 10 min. Acute injections of lorazepam (0.25 and 0.5 mg/kg) and triazolam (0.05-0.25 mg/kg) also significantly reduced exploration, measured by the number of head-dips and the time spent head-dipping. After 3 days of pretreatment, tolerance developed to the sedative effects of these drugs: lorazepam (0.25 mg/kg) and triazolam (0.05 and 1 mg/kg) were without significant effect, and lorazepam (0.5 mg/kg) had only the effect of half that dose given acutely. Some of this behavioural tolerance could be attributed to changes in drug metabolism, and the development of tolerance did not require continuous presence of drug in brain and plasma.
The effects of single intravenous doses of naloxone (0.8 and 1.6 mg) in a variety of performance tasks and on subjective ratings of mood and bodily symptoms were investigated in 12 student volunteers. Naloxone was without effect on any of the performance measures. However, 5 min after naloxone (1.6 mg) the subjects felt significantly more troubled, mentally slow, incompetent, withdrawn and physically tired, and less irritable. These effects appeared to be dose-related since 0.8 mg produced similar, but not statistically significant changes. Sixty-five minutes after the higher dose subjects felt significantly more muzzy and incompetent; in contrast to the effects at 5 min they now felt significantly more irritable. These results are difficult to explain solely in terms of opiate receptor blockade.
5,7-Dihydroxytryptamine (10 and 20 microgram) was microinjected bilaterally into the amygdaloid complex of rats and resulted in 55% and 80% depletion in 5-hydroxytryptamine concentration, respectively. The lesioned animals exhibited fewer dominance behaviours and submitted more often to an intruder into their home-cages than did the vehicle-injected controls. The lesioned rats were also more submissive than were the controls when they were intruding into another rat's territory. Only the higher dose of toxin altered social investigatory behaviour when this was measured in an arena in which neither rat had established territory. The lesioned rats displayed less social interaction and had reduced levels of motor activity. The results are compared with those of other studies in which there has been regional or general depletion of brain 5-hydroxytryptamine concentration.
Intraventricular injection of morphine (5 microgram) and ACTH (2.5 microgram) reduced the time spent head-dipping and the number of head-dips made by rats during a 10-min trial in a holeboard. These effects were reversed by naloxone (2.0 mg/kg, i.p.), in spite of the fact that naloxone alone also reduced these measures of exploration. None of the drugs or drug combinations tested significantly reduced locomotor activity. The results are discussed in relation to the action of ACTH on opiate receptors.