Human Psychopharmacology: Clinical and Experimental, 1993
ABSTRACT This experiment investigated the phenomenon of state-dependent retrieval with midazolam ... more ABSTRACT This experiment investigated the phenomenon of state-dependent retrieval with midazolam by comparing performance after midazolam + placebo with that after reversal with the benzodiazepine antagonist flumazenil, in tests of explicit and semantic memory and judgements of recency. The subjects completed analogue rating scales and psychomotor tests to provide measures of sedation. Midazolam (0.05 mg/kg) impaired recall and recognition of pictures and performance in the digit-symbol substitution task. There were no significant state-dependent effects with this dose. Midazolam (0.075 mg/kg) impaired recall and recognition of words and pictures and recognition of coloured slides of complex scenes. There were significant state-dependent effects on all the recognition tests, i.e. the group tested after reversal with flumazenil (0.5 mg) performed worse than that tested after placebo. Midazolam (0.075 mg/kg) also impaired recency judgements and performance in the number cancellation and digit-symbol substitution tests, but there were no state-dependent effects in these tests. To determine whether subjects had insight into their memory impairments, for each task they were asked to rate on an analogue scale whether they thought their memory would be ‘better or worse than usual’. Those tested with midazolam (0.075 mg/kg) showed no insight into their memory impairments and there were negative correlations between actual and estimated performance. However those reversed with flumazenil were aware their memory was worse than usual and had positive correlations between actual and estimated performance, similar to those shown by subjects tested undrugged.
1st, 2nd, 3rd and 5th year medical students completed a questionnaire with 35 questions relating ... more 1st, 2nd, 3rd and 5th year medical students completed a questionnaire with 35 questions relating to diet, general health, exercise, smoking and drinking. Based on reported 'typical weekly intake' one-third of male non-Asian students in years 1-3, and 59% in year 5 were drinking above safe limits. 12-26% of non-Asian female students were drinking above safe limits. In all years most Asian students were drinking within safe limits. Non-Asians smoked more than Asians and males smoked more than females. A group of non-Asian male students with alcohol intake for the previous week > 35 units was compared with a group of safe drinkers (<25 > 0 units/week). Significantly more of the former group drank > 10 units per occasion, had been hurt as a result of someone's drinking, had caused physical harm and drank at lunch. Although 65% were aware their level of drinking was dangerous, only 7.5% wanted advice on safe drinking and only 5% wanted to drink less. The dangerous level drinkers ate less fruit and smoked more cigarettes than those drinking safely, but there were no other significant differences and there was no evidence for impaired academic performance.
Rats were fed a liquid diet to which an increasing concentration of ethanol was added over a peri... more Rats were fed a liquid diet to which an increasing concentration of ethanol was added over a period of 3 weeks; a concentration of 10% ethanol was then maintained for a further 4 weeks. The rats were then returned to a normal ad libitum diet of rat pellets. In order to assess the long-term effects of this ethanol diet, the performance of different groups of rats was assessed 3 and 5 months after the normal diet was resumed. At both times, the ex-ethanol-treated rats showed significantly impaired between-day habituation of exploratory head-dipping at holes that were empty, but normal between-day habituation of head-dipping at the hole with the same object underneath on all 3 days. The ex-ethanol-treated rats also showed a reduced response to the introduction of an object at a previously empty hole and, following this, a subsequent disruption of between-day habituation of head-dipping at this hole. Within-session habituation of head-dipping was unimpaired. There were no deficits in the acquisition or short-term retention of a passive avoidance response, but on retention testing 24 h after training the ex-ethanol-treated rats showed a decreased latency to enter the shocked compartment. On the trials 24 h and 48 h after training the rats tested 5 months after their ethanol treatment showed impaired extinction of the passive avoidance response.
The number of head-dips, the time spent head-dipping, the number of rears and the locomotor activ... more The number of head-dips, the time spent head-dipping, the number of rears and the locomotor activity of mice placed in a holeboard was reduced by lorazepam (0.25 mg/kg) 1 and 1.5 h after oral administration and these reductions were reversed by the benzodiazepine antagonist flumazenil (1 mg/kg). Activity returned to control levels at 3 and 4.5 h for head-dipping, and between 3 and 12 h for rearing and locomotor activity. However, significant late-appearing reductions were found for the number of head-dips and the time spent head-dipping (6 h) and rearing and locomotor activity (15 h) and these decreases could not be reversed by flumazenil. Similar results were found after oral administration of oxazepam (7 mg/kg). Oxazepam reduced the number of head-dips and time spent head-dipping at 1, 1.5 and 3 h and these reductions were reversed by flumazenil (1 mg/kg). Head-dipping activity returned to normal at 4.5 h. Significant reductions were also found for both measures at 1, 6 and 7.5 h and these late reductions could not be reversed by flumazenil. This suggests that the late-appearing reductions in holeboard behaviours, resulting from lorazepam or oxazepam administration to mice, is not mediated by the benzodiazepine receptor. This conclusion was supported by the results from in vivo binding, which showed no change in the % receptor occupancy 3–15 h after administration of lorazepam or oxazepam. In contrast to the holeboard behaviours, the anticonvulsant effects of the two drugs showed good correlations with receptor occupancy. The anticonvulsant effect of oxazepam (7 mg/kg) significantly decreased 1–3 h after oral administration, but thereafter a steady anticonvulsant effect was retained for up to 24 h. The anticonvulsant effect of lorazepam (0.25 mg/kg) also significantly decreased 1–3 h after administration, and thereafter remained steady for up to 15 h. At all the time-points tested, oxazepam (7 mg/kg) had a significantly greater anticonvulsant effect than lorazepam (0.25 mg/kg). This was mirrored by higher percentage receptor occupancies in cortex, hippocampus and cerebellum, from 3 to 15 h after administration.
Human Psychopharmacology: Clinical and Experimental, 1993
ABSTRACT This experiment investigated the phenomenon of state-dependent retrieval with midazolam ... more ABSTRACT This experiment investigated the phenomenon of state-dependent retrieval with midazolam by comparing performance after midazolam + placebo with that after reversal with the benzodiazepine antagonist flumazenil, in tests of explicit and semantic memory and judgements of recency. The subjects completed analogue rating scales and psychomotor tests to provide measures of sedation. Midazolam (0.05 mg/kg) impaired recall and recognition of pictures and performance in the digit-symbol substitution task. There were no significant state-dependent effects with this dose. Midazolam (0.075 mg/kg) impaired recall and recognition of words and pictures and recognition of coloured slides of complex scenes. There were significant state-dependent effects on all the recognition tests, i.e. the group tested after reversal with flumazenil (0.5 mg) performed worse than that tested after placebo. Midazolam (0.075 mg/kg) also impaired recency judgements and performance in the number cancellation and digit-symbol substitution tests, but there were no state-dependent effects in these tests. To determine whether subjects had insight into their memory impairments, for each task they were asked to rate on an analogue scale whether they thought their memory would be ‘better or worse than usual’. Those tested with midazolam (0.075 mg/kg) showed no insight into their memory impairments and there were negative correlations between actual and estimated performance. However those reversed with flumazenil were aware their memory was worse than usual and had positive correlations between actual and estimated performance, similar to those shown by subjects tested undrugged.
1st, 2nd, 3rd and 5th year medical students completed a questionnaire with 35 questions relating ... more 1st, 2nd, 3rd and 5th year medical students completed a questionnaire with 35 questions relating to diet, general health, exercise, smoking and drinking. Based on reported 'typical weekly intake' one-third of male non-Asian students in years 1-3, and 59% in year 5 were drinking above safe limits. 12-26% of non-Asian female students were drinking above safe limits. In all years most Asian students were drinking within safe limits. Non-Asians smoked more than Asians and males smoked more than females. A group of non-Asian male students with alcohol intake for the previous week > 35 units was compared with a group of safe drinkers (<25 > 0 units/week). Significantly more of the former group drank > 10 units per occasion, had been hurt as a result of someone's drinking, had caused physical harm and drank at lunch. Although 65% were aware their level of drinking was dangerous, only 7.5% wanted advice on safe drinking and only 5% wanted to drink less. The dangerous level drinkers ate less fruit and smoked more cigarettes than those drinking safely, but there were no other significant differences and there was no evidence for impaired academic performance.
Rats were fed a liquid diet to which an increasing concentration of ethanol was added over a peri... more Rats were fed a liquid diet to which an increasing concentration of ethanol was added over a period of 3 weeks; a concentration of 10% ethanol was then maintained for a further 4 weeks. The rats were then returned to a normal ad libitum diet of rat pellets. In order to assess the long-term effects of this ethanol diet, the performance of different groups of rats was assessed 3 and 5 months after the normal diet was resumed. At both times, the ex-ethanol-treated rats showed significantly impaired between-day habituation of exploratory head-dipping at holes that were empty, but normal between-day habituation of head-dipping at the hole with the same object underneath on all 3 days. The ex-ethanol-treated rats also showed a reduced response to the introduction of an object at a previously empty hole and, following this, a subsequent disruption of between-day habituation of head-dipping at this hole. Within-session habituation of head-dipping was unimpaired. There were no deficits in the acquisition or short-term retention of a passive avoidance response, but on retention testing 24 h after training the ex-ethanol-treated rats showed a decreased latency to enter the shocked compartment. On the trials 24 h and 48 h after training the rats tested 5 months after their ethanol treatment showed impaired extinction of the passive avoidance response.
The number of head-dips, the time spent head-dipping, the number of rears and the locomotor activ... more The number of head-dips, the time spent head-dipping, the number of rears and the locomotor activity of mice placed in a holeboard was reduced by lorazepam (0.25 mg/kg) 1 and 1.5 h after oral administration and these reductions were reversed by the benzodiazepine antagonist flumazenil (1 mg/kg). Activity returned to control levels at 3 and 4.5 h for head-dipping, and between 3 and 12 h for rearing and locomotor activity. However, significant late-appearing reductions were found for the number of head-dips and the time spent head-dipping (6 h) and rearing and locomotor activity (15 h) and these decreases could not be reversed by flumazenil. Similar results were found after oral administration of oxazepam (7 mg/kg). Oxazepam reduced the number of head-dips and time spent head-dipping at 1, 1.5 and 3 h and these reductions were reversed by flumazenil (1 mg/kg). Head-dipping activity returned to normal at 4.5 h. Significant reductions were also found for both measures at 1, 6 and 7.5 h and these late reductions could not be reversed by flumazenil. This suggests that the late-appearing reductions in holeboard behaviours, resulting from lorazepam or oxazepam administration to mice, is not mediated by the benzodiazepine receptor. This conclusion was supported by the results from in vivo binding, which showed no change in the % receptor occupancy 3–15 h after administration of lorazepam or oxazepam. In contrast to the holeboard behaviours, the anticonvulsant effects of the two drugs showed good correlations with receptor occupancy. The anticonvulsant effect of oxazepam (7 mg/kg) significantly decreased 1–3 h after oral administration, but thereafter a steady anticonvulsant effect was retained for up to 24 h. The anticonvulsant effect of lorazepam (0.25 mg/kg) also significantly decreased 1–3 h after administration, and thereafter remained steady for up to 15 h. At all the time-points tested, oxazepam (7 mg/kg) had a significantly greater anticonvulsant effect than lorazepam (0.25 mg/kg). This was mirrored by higher percentage receptor occupancies in cortex, hippocampus and cerebellum, from 3 to 15 h after administration.
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