Differential changes in glutamate concentration in the primate prefrontal cortex during spatial delayed alternation and sensory-guided tasks

Glutamate is a major neurotransmitter in the mammalian brain and glutamatergic neurotransmission in the frontal cortex is indicated to play important roles in cognitive operations. We previously examined changes in extracellular dopamine in the primate frontal cortex in cognitive tasks, and in this paper we extend this to glutamate. We employed, as cognitive tasks, a delayed alternation task where the animal must retain information in working memory, and a sensory-guided task in which there is no working memory requirement but there may be more sensory processing requirements. Using the in vivo microdialysis method, we examined changes in extracellular glutamate concentration in the dorsolateral, arcuate, orbitofrontal, and premotor areas of the primate frontal cortex. Compared to basal rest levels, we observed significant increases in glutamate concentration in dorsolateral and arcuate areas of the prefrontal cortex during the sensory-guided task, but did not find significant changes in any of the frontal areas examined during the delayed alternation task. When glutamate concentration was compared between the delayed alternation and sensory-guided tasks, difference was observed only in the dorsolateral prefrontal cortex, especially in the ventral lip area of the principal sulcus. The results indicate the importance of glutamate in processing sensory information but not in retaining information in working memory in the primate dorsolateral and arcuate prefrontal cortex. We also compared the concentration of glutamate and dopamine in the tasks. We found a double dissociation in the concentration of glutamate and dopamine in the dorsolateral area: there was an increase in glutamate but no change in dopamine during the sensory-guided task, whereas there was an increase in dopamine but no change in glutamate during the delayed alternation task. It is thus suggested that in the primate dorsolateral prefrontal cortex, increased glutamate tone without dopamine increase facilitates sensory-guided task performance, while increased dopamine tone without glutamate increase is beneficial for working memory task performance.     

Levodopa ameliorates learning and memory deficits in a murine model of Alzheimer's disease

Dopamine plays an important role in learning and memory processes. A deficit of this neurotransmitter as it is apparent in Alzheimer's disease (AD) may contribute to cognitive decline, a major symptom of AD patients. The aim of this study was to elucidate whether or not stimulation of the dopaminergic system leads to an improvement of cognitive function and reduction of non-cognitive behavioral alterations in a murine model of AD. Transgenic and wild type male mice of the TgCRND8 line were treated either with the dopamine precursor levodopa or vehicle and tested in two learning tasks, the object-recognition task and the Barnes maze test. Additionally 24 h spontaneous behavior in the home cage was analyzed. In both memory tasks wild type mice performed significantly better than transgenics. However, transgenics treated with levodopa showed a significant object recognition memory and improved acquisition of spatial memory in the Barnes maze compared to vehicle treated transgenics. Concerning spontaneous behavior transgenic mice performed much more stereotypies than wild types. However, there was a trend for reduced stereotypies in the levodopa group in the time the drug was active. Neurochemical analysis revealed elevated levels of dopamine in the neostriata and frontal cortices and reduced levels in the hippocampi of transgenic mice compared to wild types. Thus cognitive deficits and stereotypies may be due to changes in the dopaminergic system as they could be ameliorated by levodopa treatment, that might also have a therapeutic significance for AD.     

Immunohistochemical assessment of mesotelencephalic dopamine activity during the acquisition and expression of Pavlovian versus instrumental behaviours

Dopaminergic activity during Pavlovian or instrumental learning in key target regions of the mesotelencephalic dopamine system was investigated immunohistochemically using antibodies raised against glutaraldehyde-conjugated dopamine. Experiment 1 examined dopamine immunoreactivity during acquisition of a Pavlovian conditioned-approach response. Observations were taken at three stages of learning: initial, intermediate and asymptotic; each with a conditioned stimulus+ (CS+) group for whom visual or auditory stimuli immediately preceded an unconditioned stimulus (sucrose), and a conditioned stimulus- (CS-) group for whom stimuli and the unconditioned stimulus were unpaired. Animals learned to approach the alcove during CS+ presentations, whilst approach behaviour of the CS- group remained low. In general, target regions exhibiting a dopaminergic reaction responded maximally during the intermediate stage of acquisition, and were less responsive initially, and not responsive at all at asymptote. Specifically, the pattern of dopaminergic response was: shell more than core of the nucleus accumbens; prefrontal cortex, central and basolateral nuclei of the amygdala also significantly responsive. Mediodorsal and laterodorsal striatal regions were reactive only very early in training. Experiment 2 examined dopaminergic reaction following acquisition of a novel conditioned instrumental response. The conditioned response+ (CR+) group responded at a much higher rate on the lever for which unconditioned stimulus-associated stimuli were presented, than on the control lever. The conditioned response- (CR-) group responded at a low rate on both levers. In contrast with experiment 1, the most responsive regions were the core of the nucleus accumbens, medial prefrontal cortex and basolateral area of the amygdala. Thus, the acquisition, but not expression of Pavlovian associations activated dopamine within several key target regions of the mesotelencephalic dopamine system, and preferentially within the shell rather than core of the nucleus accumbens. By contrast, acquisition of a novel instrumental response preferentially activated the core of the nucleus accumbens, and basolateral area of the amygdala. These data carry significant implications for the potential role of these regions in learning and memory.     

Dopaminergic neurons can influence heat-box place learning in Drosophila

Abstract

Dopamine provides crucial neuromodulatory functions in several insect and rodent learning and memory paradigms. However, an early study suggested that dopamine may be dispensable for aversive place memory in Drosophila. Here we tested the involvement of particular dopaminergic neurons in place learning and memory. We used the thermogenetic tool Gr28bD to activate protocerebral anterior medial (PAM) cluster and non-PAM dopaminergic neurons in an operant way in heat-box place learning. We show that activation of PAM neurons influences performance during place learning, but not during memory testing. These findings provide a gateway to explore how dopamine influences place learning.     

Progesterone enhances performance of aged mice in cortical or hippocampal tasks

Ovarian steroids alter cognitive performance of young individuals. Whether progesterone enhances learning and memory in tasks involving the prefrontal cortex and/or hippocampus in aged mice was investigated. Aged mice received progesterone (10 mg/kg, SC) or vehicle and were tested for cortical and/or hippocampal learning and memory. Progesterone increased spontaneous alterations in the T-maze and time spent exploring novel objects in the object recognition task. Progesterone increased the time mice spent in the quadrant of the water maze where the hidden platform had been during training, increased latencies to crossover to the shock-associated side of the inhibitory avoidance chamber, and increased freezing in the contextual fear conditioning task. Progesterone did not enhance performance in tasks mediated by the amygdala (cued conditioning), striatum (conditioned place preference), or cerebellum (rotarod) in these aged mice. Thus, progesterone improved learning and memory in tasks mediated by the prefrontal cortex and/or hippocampus of aged mice.     

Dissociating the long-term effects of fetal/neonatal iron deficiency on three types of learning in the rat

Iron deficiency (ID) is a common nutrient deficiency worldwide. This condition is linked to changes in myelin formation, dopaminergic function, and energy metabolism. Early ID results in persistent long-term cognitive and behavioral disturbances in children, despite a return to normal iron status. The present study assesses formerly ID adult rats on maze learning tasks that depend on specific brain regions related to learning, specifically the hippocampus, striatum, and amygdala. Rat dams were fed ID chow starting on gestational Day 2 through postnatal Day 7, and behavioral testing began at postnatal Day 65--following a return to normal iron status. Formerly ID rats exhibited delayed acquisition of the hippocampus-dependant task and no differences from controls on the striatum- and amygdala-dependent tasks. These findings likely reflect long-term reduction in but not abolition of hippocampus-dependent learning and preserved function in other brain structures (e.g., striatum and amygdala).     

A mechanistic account of striatal dopamine function in human cognition: psychopharmacological studies with cabergoline and haloperidol

The authors test a neurocomputational model of dopamine function in cognition by administering to healthy participants low doses of D-sub-2 agents cabergoline and haloperidol. The model suggests that DA dynamically modulates the balance of Go and No-Go basal ganglia pathways during cognitive learning and performance. Cabergoline impaired, while haloperidol enhanced, Go learning from positive reinforcement, consistent with presynaptic drug effects. Cabergoline also caused an overall bias toward Go responding, consistent with postsynaptic action. These same effects extended to working memory and attentional domains, supporting the idea that the basal ganglia/dopamine system modulates the updating of prefrontal representations. Drug effects interacted with baseline working memory span in all tasks. Taken together, the results support a unified account of the role of dopamine in modulating cognitive processes that depend on the basal ganglia. ((c) 2006 APA, all rights reserved).     

Heart rate variability and cognitive function: Effects of physical effort

This study investigated alterations in heart rate variability (HRV) and cognitive performance before and after physical effort, for 30 high-level track and field athletes (23 males and 7 females). Interbeat intervals were assessed at the baseline and during each task of a CogState cognitive battery (simple reaction time, choice reaction time, working memory, short-term memory and sustained attention). Time and frequency domain measures of HRV were compared between conditions and between tasks. The results indicated differences in HRV between executive and non-executive tasks. There was a significant increase in sympathetic-modulation-related indices after physical effort. The differences between executive and non-executive tasks were the same in post-test. Correlations were found between HRV and cognitive performance, which differed by speed and accuracy. We conclude that HRV is related to cognitive demand and that the correlation between HRV and cognitive performance seems to be stronger after physical exercise. The results raise questions about the psychophysiological meaning of different HRV signals and this has implications for future research about the relationship between HRV and cognition.     

Are the effects of psychomotor stimulant drugs on hyperactive children really paradoxical?

The improved “attention” exhibited by hyperactive children treated with amphetamine-like compounds is postulated to be related to a normal action of these drugs in producing stereotyped behaviour. Such activity can be conceptualised as an increased “focusing” of attention, which would be expected to aid performance in tasks involving sustained concentration of attention, but impair performance on tasks involving reversals in cognitive strategy. These behavioural actions of the drugs can be linked to the functioning of central dopaminergic mechanisms.     

Dissociation in the involvement of dopaminergic neurons innervating the core and shell subregions of the nucleus accumbens in latent inhibition and affective perception

Mesencephalic dopaminergic neurons have been found to be involved in affective processes. Their implication in cognitive processes appears less well understood. The use of latent inhibition paradigms is a means of studying these kinds of processes. In this study, we investigated the involvement of dopaminergic projections in the core, the dorsomedial shell and the ventromedial shell of the nucleus accumbens, in latent inhibition in olfactory aversive learning. Variations in extracellular dopamine levels induced by an aversively conditioned olfactory stimulus were monitored in the three parts of the nucleus accumbens in the left hemisphere, after pre-exposure to the olfactory stimulus using in vivo voltammetry in freely moving rats. The parallel between dopamine changes and place preference or aversion toward the stimulus were analyzed in pre-exposed and non-pre-exposed animals. Results showed that dopaminergic neurons innervating the nucleus accumbens are differentially involved in the latent inhibition phenomenon. Dopaminergic neurons innervating the core and the dorsomedial shell subregions of the nucleus accumbens appeared to be involved in latent inhibition processes, unlike those reaching the ventromedial shell. Nonetheless dopamine in the ventromedial shell was found to be involved in affective perception of the stimulus.The present data suggest that dopaminergic neurons innervating the three nucleus accumbens subregions are functionally related to networks involved in parallel processing of the cognitive and affective values of environmental information, and that interaction between these systems, at some levels, may lead to a given behavioral output. These data may provide new insights into the pathophysiology of schizophrenic psychoses.     

Mesolimbic dopaminergic pathways in fear conditioning

One of the most common paradigms used to study the biological basis of emotion, as well as of learning and memory, is Pavlovian fear conditioning. In the acquisition phase of a fear conditioning experiment, an emotionally neutral conditioned stimulus (CS)--which can either be a discrete stimulus, such as a tone, or a contextual stimulus, such as a specific environment--is paired with an aversive unconditioned stimulus (US), for example a foot shock. As a result, the CS elicits conditioned fear responses when subsequently presented alone during the expression phase of the experiment. While considerable work has been done in relating specific circuits of the brain to fear conditioning, less is known about its regulation by neuromodulators; the understanding of which would be of therapeutic relevance for fear related diseases such as phobia, panic attacks, post traumatic stress disorder, obsessive compulsive disorder, or generalized anxiety disorder. Dopamine is one of the neuromodulators most potently acting on the mechanisms underlying states of fear and anxiety. Recently, a growing body of evidence has suggested that dopaminergic mechanisms are significant for different aspects of affective memory, namely its formation, expression, retrieval, and extinction. The aim of this review is to clarify the complex actions of dopamine in fear conditioning with respect to the wide-spread distribution of dopaminergic innervation over structures constituting the fear related circuitry. A particular effort is made to understand how dopamine in the amygdala, medial prefrontal cortex and nucleus accumbens--target structures of the mesolimbic dopamine system originating from the ventral tegmental area--could relate to different aspects of fear conditioning.     

Specificity of amygdalostriatal interactions in the involvement of mesencephalic dopaminergic neurons in affective perception

We have recently shown that dopaminergic responses to an attractive or an aversive stimulus were respectively increased and decreased in the core part of the nucleus accumbens and the ventromedial dorsal striatum. By contrast, increases in dopaminergic responses were obtained in the shell part of the nucleus accumbens with stimuli of both affective values. In addition, the involvement of the basolateral amygdala in affective processes has been reported by several authors. Anatomo-functional relationships between the basolateral amygdala and striatal structures have also been described. Thus, in the present work we studied the regulation by the basolateral amygdala of affective dopaminergic responses in the two parts of the nucleus accumbens (core and shell) and the ventromedial dorsal striatum. More precisely, variations in extracellular levels of dopamine induced by an attractive or an aversive olfactory stimulus were studied using in vivo voltammetry in freely moving rats. Changes in dopamine levels in the three left striatal regions were measured after functional blockade of the ipsilateral basolateral amygdala with tetrodotoxin. Changes in place attraction or aversion toward the stimulus were studied in parallel to dopamine variations.The results obtained suggest a specific regulation of affective dopaminergic responses in the two parts of the nucleus accumbens by the basolateral amygdala and a lack of influence of the basolateral amygdala on the ventromedial dorsal striatum. The results suggest that attraction or aversion toward a stimulus are correlated with dopamine variations in the core of the nucleus accumbens and that the basolateral amygdala controls affective behavioural responses. These data may provide new insights into the pathophysiology of schizophrenic psychoses.     

Dopamine-mediated stabilization of delay-period activity in a network model of prefrontal cortex

The prefrontal cortex (PFC) is critically involved in working memory, which underlies memory-guided, goal-directed behavior. During working-memory tasks, PFC neurons exhibit sustained elevated activity, which may reflect the active holding of goal-related information or the preparation of forthcoming actions. Dopamine via the D1 receptor strongly modulates both this sustained (delay-period) activity and behavioral performance in working-memory tasks. However, the function of dopamine during delay-period activity and the underlying neural mechanisms are only poorly understood. Recently we proposed that dopamine might stabilize active neural representations in PFC circuits during tasks involving working memory and render them robust against interfering stimuli and noise. To further test this idea and to examine the dopamine-modulated ionic currents that could give rise to increased stability of neural representations, we developed a network model of the PFC consisting of multicompartment neurons equipped with Hodgkin-Huxley-like channel kinetics that could reproduce in vitro whole cell and in vivo recordings from PFC neurons. Dopaminergic effects on intrinsic ionic and synaptic conductances were implemented in the model based on in vitro data. Simulated dopamine strongly enhanced high, delay-type activity but not low, spontaneous activity in the model network. Furthermore the strength of an afferent stimulation needed to disrupt delay-type activity increased with the magnitude of the dopamine-induced shifts in network parameters, making the currently active representation much more stable. Stability could be increased by dopamine-induced enhancements of the persistent Na(+) and N-methyl-D-aspartate (NMDA) conductances. Stability also was enhanced by a reduction in AMPA conductances. The increase in GABA(A) conductances that occurs after stimulation of dopaminergic D1 receptors was necessary in this context to prevent uncontrolled, spontaneous switches into high-activity states (i.e., spontaneous activation of task-irrelevant representations). In conclusion, the dopamine-induced changes in the biophysical properties of intrinsic ionic and synaptic conductances conjointly acted to highly increase stability of activated representations in PFC networks and at the same time retain control over network behavior and thus preserve its ability to adequately respond to task-related stimuli. Predictions of the model can be tested in vivo by locally applying specific D1 receptor, NMDA, or GABA(A) antagonists while recording from PFC neurons in delayed reaction-type tasks with interfering stimuli.     

Age-related spatial working memory impairment is caused by prefrontal cortical dopaminergic dysfunction in rats

There is evidence of prefrontal cortex (PFC)–dependent cognitive deficits, such as working memory impairment, during the normal aging process in humans and animals. Although working memory function and the PFC dopaminergic system are thought to be closely related, the relationship between them in aged subjects remains unclear. The present study was aimed to clarify the involvement of PFC dopaminergic activity in age-related working memory impairment. For this purpose, we examined working memory in young (3-month-old) and aged (24-month-old) rats, using the T-maze delayed alternation task. As a result, delayed alternation performance was impaired in aged rats compared to young rats, indicating age-related working memory impairment. In addition, aged rats showed reduced dopaminergic transmission in the prelimbic cortical region of the PFC, concomitant with attenuated tyrosine hydroxylase activity in the PFC, but not in the ventral tegmental area and substantia nigra, which was evaluated immunohistochemically and enzymatically. Moreover, age-related working memory impairment was improved by direct stimulation of the prelimbic cortical region of the PFC with 10 or 30 ng, but not 100 ng, of a D1 receptor agonist, SKF 81297, indicating that the SKF 81297 response was an inverted “U” pattern. The maximum SKF 81297 response (30 ng) was abolished by a D1 receptor antagonist, SCH 23390. Thus, age-related working memory impairment was through reduced PFC dopaminergic transmission caused by decreased dopamine synthesis in the prefrontal termination region, but not at the site where the projections originate. This finding provides direct evidence showing the involvement of dopaminergic dysfunction in the development of PFC cognitive deficits during the normal aging process and would help to understand the aging physiology and pathology of the brain.     

Age- and sex-related disturbance in a battery of sensorimotor and cognitive tasks in Kunming mice

A battery of tasks, i.e. beam walking, open field, tightrope, radial six-arm water maze (RAWM), novel-object recognition and olfactory discrimination, was used to determine whether there was age- and sex-related memory deterioration in Kunming (KM) mice, and whether these tasks are independent or correlated with each other. Two age groups of KM mice were used: a younger group (7-8 months old, 12 males and 11 females) and an older group (17-18 months old, 12 males and 12 females). The results showed that the spatial learning ability and memory in the RAWM were lower in older female KM mice relative to younger female mice and older male mice. Consistent with this, in the novel-object recognition task, a non-spatial cognitive task, older female mice but not older male mice had impairment of short-term memory. In olfactory discrimination, another non-spatial task, the older mice retained this ability. Interestingly, female mice performed better than males, especially in the younger group. The older females exhibited sensorimotor impairment in the tightrope task and low locomotor activity in the open-field task. Moreover, older mice spent a longer time in the peripheral squares of the open-field than younger ones. The non-spatial cognitive performance in the novel-object recognition and olfactory discrimination tasks was related to performance in the open-field, whereas the spatial cognitive performance in the RAWM was not related to performance in any of the three sensorimotor tasks. These results suggest that disturbance of spatial learning and memory, as well as selective impairment of non-spatial learning and memory, existed in older female KM mice.     

Transcranial direct current stimulation decreased cognition-related reaction time in older adults: A systematic review and meta-analysis

BackgroundThis systematic review and meta-analysis investigated the effects of transcranial direct current stimulation (tDCS) on the cognitive functions of healthy older adults by focusing on the changes in reaction time during cognitive tasks.MethodA total of 31 studies qualified for this meta-analysis, and we acquired 36 comparisons from the included studies for data synthesis. The individual effect sizes were calculated by comparing the altered reaction time during the performance of a specific cognitive task between the active tDCS and sham groups. In two moderator variable analyses, we examined the potentially different effects of the tDCS protocols on the cognition-related reaction time based on the tDCS protocol used (i.e., online vs. offline tDCS) and the five cognitive domains: (a) perceptual-motor function, (b) learning and memory, (c) executive function / complex attention, (d) language, and (e) social cognition. Meta-regression analyses were conducted to estimate the relationship between demographic and tDCS parameter characteristics and the changes in reaction time.ResultsThe random-effects model meta-analysis revealed significant small effects of tDCS on cognition-related reaction time. Specifically, providing online tDCS significantly reduced the reaction time, and these patterns were observed during learning and memory and executive function / complex attention tasks. However, applying offline tDCS failed to find any significant reduction of reaction time across various cognitive tasks. The meta-regression analysis revealed that the effects of tDCS on the reaction time during the performance of cognitive tasks increased for the older people.ConclusionsThese findings suggest that providing online tDCS may effectively improve the ageing-induced reaction time related to specific cognitive functions of elderly people.     

Altered frontal cortical dopaminergic transmission in monkeys after subchronic phencyclidine exposure: involvement in frontostriatal cognitive deficits

Long-term exposure to the psychotomimetic drug phencyclidine produces prefrontal cortical cognitive and dopaminergic dysfunction in rats and monkeys, effects possibly relevant to the frontal cortical impairments of schizophrenia. In the present study, the effects of subchronic phencyclidine administration (0.3 mg/kg twice-daily for 14 days) on monoamine systems in the monkey brain were examined and related to cognitive performance on an object retrieval/detour task, which has been linked with frontostriatal function. Long-term (14 days) administration of phencyclidine resulted in a marked and persistent reduction in dopamine utilization in the frontal cortex. Moreover, the degree of cognitive impairment in phencyclidine-treated monkeys correlated significantly with the magnitude of dopaminergic inhibition within the dorsolateral prefrontal cortex and prelimbic cortex. No specific correlation was measured for dopamine utilization in other cortical regions or for indices of serotonin transmission in any brain region. These data show that repeated exposure to phencyclidine reduces prefrontal cortical dopamine transmission, and this inhibition of dopaminergic function is associated with performance impairments on a task sensitive to frontostriatal cognitive dysfunction. Thus, the cognitive deficits of phencyclidine-treated monkeys, as in schizophrenia, appear to be mediated, in part, by reduced dopaminergic function in specific subregions of the frontal cortex.     

Essential hypotension is accompanied by deficits in attention and working memory

In the present study, the authors investigated the relationship between low blood pressure (BP) and attentional performance through the application of a multidimensional diagnostic approach. The authors compared 40 subjects with essential hypotension (mean systolic BP = 97.6 mmHg) with 40 normotensive controls (mean systolic BP = 124.1 mmHg) using 6 computer-based tasks measuring tonic and phasic alertness; selective, divided, and sustained attention; and working memory. To control for possible confounders, the authors used a test battery examining motor performance and a mood questionnaire. BP was monitored continuously during the entire experiment. Hypotensives showed prolonged execution times in each of the attentional tasks (p < .001). Moderately decreased accuracy was found in the tests assessing sustained attention (p = .059) and working memory (p = .012). Moreover hypotensives showed smaller elevations in BP during the execution of the cognitive tasks. This study is the first to demonstrate the relationship between BP and cognitive performance while controlling for motor function and mood.     

Qualitative similarities in cognitive impairment associated with 24 h of sustained wakefulness and a blood alcohol concentration of 0.05%

Previous studies that have quantified fatigue-related cognitive impairment as blood alcohol concentration (BAC) equivalents have been limited by two issues: the effect of practice on tests of cognition and, more importantly, the statistic used to quantify change in cognitive performance. The current study addressed these issues by adopting an ABACA design, which allowed for the adequate control of practice effects, and by using effect size metrics, which enabled direct comparisons to be made in performance impairments as a result of fatigue (i.e. sustained wakefulness of 24 h) and alcohol (i.e. BAC of 0.05%). Cognitive performance under the fatigue and alcohol conditions required the use of the CogState battery. It was demonstrated that fatigue caused greater impairment than alcohol on the speed of continuous attention and memory and learning, and on the accuracy of complex matching. Alcohol was more detrimental than fatigue only on the accuracy of memory and learning. Performances on the remaining tasks were the same for both the fatigue and alcohol conditions. These differences and similarities in performance impairment are discussed emphasizing the deleterious cognitive effects of relatively short periods of sustained wakefulness.     

Improvement of auditory discrimination learning by Ginkgo biloba extract EGb 761

The effect of oral application of Ginkgo biloba extract EGb 761^® on auditory discrimination learning in Mongolian gerbils was investigated using discrimination tasks with three different degrees of difficulty and two protocols for administration starting 2 weeks prior to or at the beginning of training. In comparison to placebo-treated controls we observed significant improvement of learning performance in EGb 761^® treated gerbils in discrimination tasks of all degrees of difficulty, from the easiest to the most demanding. EGb 761^® has been reported to increase the extracellular concentration of dopamine in prefrontal cortex of rats which plays a major role in the type of discrimination learning used in the present study. We, therefore, suppose that EGb 761^® improves discrimination learning through its effect on the dopaminergic system.