Figure 4. Log–log plot of average Lomb–Scargill power spectrum estimates, for response times sequences following GABAA agonist (blue line) and GABAA agonist (orange line) injections. Frequency f is cycles-per-block. doi:10.1371/journal.pone.0005208.g004 spectrum (Figure 4) c. In contrast, the power of RTs oscillations following the GABAA antagonist injections are more similar to white noise power spectrum traduced by an overall increase the power spectrum distribution (Figure 4). Again, these results are consistent with the noticeable noise and the smaller lag observed in serial correlations for GABAA antagonist sequences as shown in Figures 1 and 3 (see also Figure S5). Functionally, the presence of white noise within the sequences of RTs following GABAA antagonist injections is also consistent with the view that these sequences were generated by a more unstable and more chaotic process in which short or long term memory are less or not expressed. Discussion It is well established that simply instructing human or non- human primate subjects to focus attention is not sufficient to prevent them from distractibility [1,2]. In the primate brain, the dlPFC is a frontal cortical region known to be engaged in these attentional, memory and high level executive functions [15,16]. Our results show here that focal pharmacological perturbations of the dlPFC are also capable to impair a basic motor task with a low cognitive load [15–17]. These results are important for at least two reasons. First, they indicate that the classical boundaries delimitating the highest cognitive processes and the levels of motor encoding stages is less tight than previously thought. Second, these results open a novel route to explore long-term pharmacological treatments for the numerous patients suffering from attentional disorders. In human, recent studies comparing TDC with ADHD children has shown increased of intraindividual variability at all parts of the spectrum of RTs, even in tasks with the lowest cognitive loads [1,2,10]. These measures of variability appeared to be so robust that intraindividual variability in RTs is now viewed as a valid endophenotype with the potential ability to index genetic vulnerability to ADHD reflecting attentional lapses on some but not all responses [2]. Before these recent findings, poorer performances in neuropsychological tasks of Frontal Cortex and Variability ADHD children were typically interpreted as evidence for high level executive function deficits. This interpretation was partially supported by the fact that ADHD children produce on average slower and less accurate responses than TDC. However, it has subsequently been shown that intraindividual variability of these RT sequences often correlates better with the behavioural symptoms of ADHD than the mean values. Consistent with the possibility that the dlPFC is implicated in the pathology of ADHD, we show here that minimal local micro-injections of GABAA antagonist but not GABAA agonist in the dlPFC exert a profound effect on intraindividual variability during sequences of a simple response task. This variability was observed in the RTs as well as the direction and the amplitude of the movement. In our study, only Bicuculline (GABAA antagonist) affected the monkey’s behavior. This result may be considered as circum- stantial to our simple response task but is not trivial. In V1, micro-injection of GABAA antagonist (bicuculline) was found to exert a much weaker effect on neuronal responses compared to GABAA agonist (muscimol) [18]. However, and importantly, it was noticed that both administrations of GABAA antogonist and GABAA agonist in visual cortex resulted in improved visual function [19,20]. In other subcortical and cortical regions implicated in visual target selection and saccade programming, it has been shown that the application of GABAA (bicuculline) greatly facilitates saccade production, whereas injection of GABAA agonist (muscimol) inhibits saccade generation [18– 21]. The increased intrasubject variability observed in the present study appears therefore to be specifically related to dlPFC dysfunction. Altogether these results let us speculate that, rather than the absolute activity of the GABA-mediated circuits in dlPFC, what might be more crucial to the behavioural expression depends on the fragile balance between activation or inhibition of the GABA-mediated circuits. Depending on the task, on the environmental constraints and/or the level of activity of other GABAergic circuits, a modest variation can lead to dramatic behavioural changes. In our experiment, using a simple saccadic reflexive task, a GABAA antagonist action appeared to be the solely route to affect the balance and the subsequent behaviour. The reaction time variability is one of the strongest findings that recently emerge in cognitive-experimental research on ADHD. However, it is important to notice that the symptoms of ADHD are heterogeneous and often accompanied by multiple comorbid psychiatric disorders. If our finding among others offer a new route for potential pharmacotherapies capable to influence the activity of GABAA receptors, further researches would be needed in order to understand better the principles and rules that govern the variations of the most simple of our behavioural responses. Materials and Methods Two adult male green monkeys (Caercopitheca aethiops) were used. The maintenance of the monkeys, all surgical procedures and the experimental protocols were carried out in strict accordance with the National Institutes of Health (NIH) guidelines (1996) and the recommendations of the EEC (86/ 609) and the French National Committee (87/848). Before training, each monkey underwent a surgical procedure for the implantation of a scleral search coil on each eye and an acrylic head holder. At the end of the training period, a recording chamber was implanted above the principal sulcus (PS), on each side. Heart rate and body temperature were monitored during PLoS ONE | www.plosone.org 3 April 2009 | Volume 4 | Issue 4 | e5208