Suritozole

Benzodiazepine receptor (BZR) ligands have been demonstrated to affect the performance in tasks measuring attentional abilities. In such tasks, subjects typically are required to discriminate visual and/or auditory stimuli. The possibility that the effects of BZR ligands on the performance in tasks measuring attention are primarily due to effects on discriminative processes has not been tested systematically. Rats were trained to discriminate between simultaneously presented pairs of visual stimuli flashing either at 5 Hz versus 4.17, 3.75, 2.5, 1.67 or 1.25 Hz (group 1; FAST), or at 1.25, 1.46, 1.67, 2.5 or 3.33 Hz versus 5 Hz (group 2; SLOW) for 4.8 s (20 trials per discrimination type; sequence of pairs was randomized). In both groups, response accuracy depended significantly on the discriminability of the stimuli, with near perfect accuracy in response to most different pairs of stimuli and near chance-level accuracy in response to least different pairs of stimuli. Administration of the BZR full agonist chlordiazepoxide (1.56, 6.25, 9.38 mg/kg; i.p.) potently increased the number of errors of omission which, following the higher doses, confounded the effects on absolute numbers of correct and incorrect responses. However, the available data do not suggest that the agonist affected the animals' abilities to discriminate between the stimuli. Similarly, administration of the BZR ligands ZK 93 426 and MDL 26,479 (which negatively modulate GABAergic transmission) produced no systematic effects. These data suggest that the effects of BZR ligands on the performance in tasks measuring attentional abilities are not primarily due to effects on the animals' ability to discriminate sensory stimuli.

The effects of ibotenic acid-induced basal forebrain lesions and treatment with the triazole MDL 26,479 on the acquisition of an operant visual conditional discrimination task and on [3H]hemicholinium-3 and [3H]vesamicol binding were examined. Lesioned animals required more training sessions to acquire the stimulus-response rules of this task. They also showed longer response latencies throughout the experiment. The effects of the treatment with MDL 26,479 (5 mg/kg; i.p. 60 min before each training session) interacted with the effects of the lesion, producing a decrease in the number of sessions required to perform above chance-level in lesioned but not in control animals. MDL 26,479 did not seem to produce immediate performance effects but interacted with the learning process. The lesions destroyed the cell bodies in the area of the substantia innominata, basal nucleus of Meynert, and the globus pallidus. The number of frontocortical cholinergic terminals as primarily indicated by hemicholinium-3 binding was reduced in lesioned animals; however, another measure of cholinergic terminals, vesamicol binding, was unchanged. Behavioral performance of animals correlated significantly with hemicholinium binding in the frontal cortex of the right hemisphere. The fact that the lesion delayed but did not block the acquisition of the task may have been a result of compensatory mechanisms in remaining cholinergic terminals as indicated by stable vesamicol binding. These data allow assumptions about the conditions for the demonstration of beneficial behavioral effects of MDL 26,479. They also suggest that the long-term effects of basal forebrain lesions on cortical cholinergic transmission remain unsettled.