The stop-signal reaction-time (SSRT) task measures inhibition of a response that has already been initiated, that is, the ability to stop. Human subjects classified as "impulsive," for example, those with attention deficit and hyperactivity disorder, are slower to respond to the stop signal. Although functional and structural imaging studies in humans have implicated frontal and basal ganglia circuitry in the mediation of this form of response control, the precise roles of the cortex and basal ganglia in SSRT performance are far from understood. We describe effects of excitotoxic fiber-sparing lesions of the orbitofrontal cortex (OF), infralimbic cortex (IL), and subthalamic nucleus (STN) in rats performing a SSRT task. Lesions to the OF slowed SSRT, whereas lesions to the IL or the STN had no effect. On the go-signal trials, neither cortical lesion affected go-trial reaction time (GoRT), but STN lesions speeded such latencies. The STN lesion also significantly reduced accuracy of stopping at all stop-signal delays, indicative of a generalized stopping impairment that was independent of the SSRT itself.

The cholinergic basal forebrain has been implicated in aspects of cognitive function including memory and attention, but the precise contribution of its major components, the basalocortical and the septohippocampal systems, remains unclear. Rats were subjected to lesions of either the nucleus basalis magnocellularis (Basalis), the medial septum/vertical limb of the diagonal band of Broca (Septum), or both nuclei (Basalis + Septum), using the selective cholinotoxin 192 IgG-saporin. Cognitive performance was evaluated in tasks taxing attention (the five-choice serial reaction time task, 5-CSRTT) and spatial working memory (radial arm maze, RAM). Nucleus basalis lesions disrupted performance of the 5-CSRTT, as demonstrated by decreased choice accuracy, increased incidence of missed trials, increased latencies to respond correctly, and a disrupted pattern of response control. Combined lesions of the Basalis and Septum resulted in qualitatively similar deficits to Basalis lesions alone, although interestingly, these rats were unimpaired on measures of response speed, and showed weaker deficits on accuracy and omissions. Decreasing the attentional load by lengthening stimulus duration reversed some of the deficits in Basalis and Basalis + Septum rats, suggesting an attentional deficit rather than motivation or motor perturbations. Performance in rats with septal lesions was only affected when task difficulty was increased. In the RAM an opposing pattern of effects was observed, with Septum and Basalis + Septum rats showing dramatic impairments, and Basalis rats performing normally. Taken together, these data provide clear evidence for a functional dissociation between septohippocampal and basalocortical cholinergic systems in aspects of cognitive function.

Central serotonin (5-HT) function is thought to be a critical component of behavioral inhibition and impulse control. However, in recent clinical studies, 5-HT manipulations failed to affect stop-signal reaction time (SSRT), which is a fundamental process in behavioral inhibition. We investigated the effect of central 5-HT depletion (intracerebroventricular 5,7-dihydroxytryptamine) in rats on two aspects of behavioral inhibition, SSRT and 'waiting', using the stop-signal task. 5-HT depletion had no effects on SSRT or any other primary measure on the stop-signal task. However, within the same task, there was a deficit in 'waiting' in 5-HT-depleted rats when they were required to withhold from responding in the terminal element of the stop-signal task for an extended period. D-Amphetamine had dosedependent, but not 5-HT-dependent effects on SSRT. Conversely, the dose that tended to improve, or decrease, SSRT (0.3 mg/kg) impaired the ability to wait, again independently of 5-HT manipulation. These findings suggest that SSRT and 'waiting' are distinct measures of behavioral inhibition, and show that 5-HT is critical for some forms of behavioral inhibition but not others. This has significant implications for the treatment of conditions such as attention deficit and hyperactivity disorder, substance abuse, and affective disorders, in which inhibitory and impulse-control deficits are common.

Rationale-Previous data indicate that depletion of cortical noradrenaline (NA) impairs performance of an attentional five-choice serial reaction time task (5CSRT) under certain conditions. This study employed a novel immunotoxin, anti-dopamine-beta hydroylase (DβH)-saporin, to make relatively selective lesions of the noradrenergic projections to the prefrontal cortex (PFC) in rats trained to perform the 5CSRT.Objectives-The aim of this work is to examine (1) the effect of cortical noradrenaline depletion on sustained attentional performance in the 5CSRT under a variety of test conditions and (2) the effects of guanfacine, a selective α-2 adrenoceptor agonist on attentional performance in sham and NA-depleted rats.Materials and methods-Animals received either intramedial prefrontal anti-DβH-saporin or vehicle and were tested on the baseline task with a variety of additional manipulations including (1) decreasing target duration, (2) increasing rate and (3) temporal unpredictability of target presentation and (4) systemic guanfacine.Results-Anti-DβH-saporin infused into the PFC produced a substantial loss of DβH-positive fibers in that region and in other adjacent cortical areas. There was no significant depletion of DA or 5-HT. NA-depleted animals were not impaired on the baseline task, but were slower to respond correctly under high event rate conditions, and their discriminative accuracy was reduced when stimulus predictability decreased. Guanfacine significantly reduced discriminative accuracy in NA-depleted animals only.Conclusion-Selective cortical NA depletion produced deficits on the 5CSRT test of sustained attention, especially when the attentional load was increased and in response to systemic guanfacine. These results are consistent with a role of coeruleo-cortical NA in the regulation of effortful attentional processes.

This study assessed behavioural and neurochemical effects of i.c.v. injections of both the cholinergic toxin 192 IgG-saporin (2 microgram) and the serotonergic toxin 5,7-dihydroxytryptamine (5,7-DHT; 150 microgram) in Long-Evans female rats. Dependent behavioural variables were locomotor activity, forced T-maze alternation, beam walking, Morris water-maze (working and reference memory) and radial-maze performances. After killing by microwave irradiation, the concentrations of acetylcholine, monoamines and 5-hydroxyindoleacetic acid (5-HIAA) were measured in the hippocampus, frontoparietal cortex and striatum. 192 IgG-saporin reduced the concentration of acetylcholine by approximately 40% in the frontoparietal cortex and hippocampus, but had no effect in the striatum. 5,7-DHT lesions reduced the concentration of serotonin by 60% in the frontoparietal cortex and 80% in the hippocampus and striatum. Noradrenaline was unchanged in all structures except the ventral hippocampus where it was slightly increased in rats given 192 IgG-saporin. Cholinergic lesions induced severe motor deficits but had no other effect. Serotonergic lesions produced diurnal and nocturnal hyperactivity but had no other effect. Rats with combined lesions were more active than those with only serotonergic lesions, showed motor dysfunctions similar to those found in rats with cholinergic lesions alone, and exhibited impaired performances in the T-maze alternation test, the water-maze working memory test and the radial-maze. Taken together and although cholinergic lesions were not maximal, these data show that 192 IgG-saporin and 5,7-DHT lesions can be combined to selectively damage cholinergic and serotonergic neurons, and confirm that cholinergic-serotonergic interactions play an important role in some aspects of memory, particularly in spatial working memory.