The effects of a benzodiazepine receptor antagonist β-carboline ZK-93426 on scopolamine-induced impairment on attention, memory and psychomotor skills

Abstract

The effects of a single dose of scopolamine alone and in combination with ZK 93426 (a beta-carboline antagonist at the GABAA/BZ receptor complex with weak inverse agonist activity) were tested in two studies. In one study (study 1) the emphasis of enquiry was on different stages of information processing measured by a psychometric battery; in the second study (study 2) performance at different stages of memory and psychomotor abilities was tested and electroencephalogram recordings and video-tracking were also performed. Each study consisted of two parts, part I in which scopolamine (0.5 mg; 1 ml) or placebo were administered subcutaneously, and part II in which scopolamine (0.5 mg; 1 ml) was administered subcutaneously followed by an intravenous injection of ZK 93426 (0.04 mg; 0.04 ml/kg) or placebo. Thirty-six volunteers, who were randomly allocated to receive one of the two treatments (n = 18 per treatment), participated in each part. In study 1 attention was measured by a continuous attention task and a rapid information processing task, vigilance was measured by a visual vigilance task, and working memory and reasoning were evaluated by a logical reasoning task. A visual memory task was also included to measure acquisition and retention. In study 2 acquisition and short term storage and retrieval were measured by a word lists-Buschke restricted reminding procedure, and retention was tested by delayed recall and recognition. Psychomotor performance was assessed by measuring tapping speed (related to gross motoric abilities) and a pegboard task (related to fine motoric abilities). A task to measure working memory, the Pauli test, was also included. In study 1 scopolamine significantly impaired performance in the attentional and vigilance tasks (P < 0.05), but there was no effect in the logical reasoning task main measurements of time and accuracy. In study 2, scopolamine also impaired performance in the psychomotor tasks (P < 0.05) and the Pauli test. ZK 93426 partially antagonised most of the effects of scopolamine on memory and attention, suggesting that an interaction between the GABA-ergic and cholinergic systems is reflected in measurements of both attention and memory. In general a dissociation was found in the effects of scopolamine on memory, i.e. scopolamine impaired performance during all acquisition measurements but left retention unaffected.

The scopolamine-reversal paradigm in rats and monkeys: the importance of computer-assisted operant-conditioning memory tasks for screening drug candidates

“…Asterisk, significantly different from respective mean values in the vehicle (0 μg/kg) group, P<0.05. d The effect of donepezil in scopolamine-treated monkeys on shortdelay trial accuracies plotted as a function of donepezil dose 10 μg/kg dose range used in healthy human volunteers (Preston et al 1988;Molchan et al 1990;Ray et al 1992;Lines et al 1993;Snyder et al 2005). Scopolamine-induced impairment in task acquisition in the spatial memory task and in the proximate stages of memory formation, i.e., attention and vigilance, in the operant-conditioning tasks is also in keeping with similar effects reported in human subjects (Wesnes and Warburton 1984;Dunne and Hartley 1985;Preston et al 1989;Sunderland et al 1989;Duka et al 1996). In monkeys (and possibly in the rats performing the DSDT task), the memory retention curve (Fig.…”

“…We also noted that scopolamine slightly but significantly increased swim speed in the water maze task, although it is not clear whether this effect of scopolamine is mechanistically related to the shortened latencies produced in the DSDT. The increase in motor speed noted in rats after scopolamine treatment might be species specific because in the monkeys, scopolamine tended to increase median choice latencies, a response more in keeping with that reported for human studies with the drug (Duka et al 1996).…”

“…3, scopolamine produced a significant dose-dependent decrease in choice latencies. This result was surprising in view of the known ability of scopolamine to slow psychomotor speed in monkeys (Taffe et al 1999) and in humans (Duka et al 1996). One explanation pertains to our unpublished observation that oftentimes, choice latencies Fig.…”

PWZ-029, a compound with moderate inverse agonist functional selectivity at GABAA receptors containing α5 subunits, improves passive, but not active, avoidance learning in rats

“…Venault et al, 1986;Jensen et al, 1987), as well as in human volunteers (e.g. Dorow et al, 1983;Duka et al, 1996). However, this desirable effect is confounded by different concomitant psychomotor effects (increased vigilance, anxiogenic and/or proconvulsant state), some of which have been described in memory studies with nonselective inverse agonists in humans, urging their early termination (Dorow et al, 1983).…”

Pharmacokinetic–pharmacodynamic relationships of central nervous system effects of scopolamine in healthy subjects

“…The 30-word learning test avoids ceiling effects in healthy students, and has shown CNS effects, e.g. for benzodiazepines [32,38,45], cannabinoids [33] and antipsychotics [46]. For each study period, a different 30-word learning list was used to avoid learning effects over time.…”