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Predicting what will happen in the future in terms of potential reward is essential in daily life. The aim of the current study was to investigate the neurotransmitter systems involved in the anticipation of reward value and probability. We hypothesized that dopaminergic and noradrenergic antagonism would affect anticipation of reward value and probability, respectively. Twenty-three healthy participants were included in a haloperidol (2 mg) × clonidine (0.150 mg) × placebo cross-over design and subjected to a Go/NoGo experimental task during which cues signaled the probability of subsequent target appearance. Reward value (amount of money that could be won for correct and fast responding to the target) as well as probability of target appearance was orthogonally manipulated across four task blocks. Cue-elicited EEG event-related potentials were recorded to assess anticipation of value and probability, respectively. The processing of reward value was affected by dopaminergic antagonism (haloperidol), as evidenced by reduction of the reward-related positivity and P300 to reward cues. This reduction was specifically significant for subjects with high baseline dopamine levels for the P300 and most pronounced for these subjects for the reward-related positivity. In contrast, the processing of reward probability was affected by noradrenergic antagonism (clonidine). In addition, both drugs reduced overall performance (omission rate, response speed variability). We conclude that at least anticipation of reward value and probability, respectively, is specifically affected by dopaminergic versus noradrenergic antagonism.

Rationale: The dopaminergic system has been implicated in visuospatial attention and inhibition, but the exact role has yet to be elucidated. Scarce literature suggests that attenuation of dopaminergic neurotransmission negatively affects attentional focusing and inhibition. To the best of our knowledge, this is the first study that evaluated the effect of dopaminergic antagonism on stopping performance., Methods: Dopaminergic neurotransmission was attenuated in 28 healthy male participants by using 2 mg haloperidol. A repeated-measures placebo-controlled crossover design was implemented, and performance indices of attention and inhibition were assessed in the visual spatial cueing task (VSC) and stop signal task (SST). Additionally, the effect of haloperidol on motoric parameters was assessed. It was expected that haloperidol as contrasted to placebo would result in a reduction of the "validity effect," the benefit of valid cueing as opposed to invalid cueing of a target in terms of reaction time. Furthermore, an increase in stop signal reaction time (SSRT) in the SST was expected., Results and Conclusion: Results partially confirmed the hypothesis. Haloperidol negatively affected inhibitory motor control in the SST as indexed by SSRT, but there were no indications that haloperidol affected bias or disengagement in the VSC task as indicated by a lack of an effect on RTs. Pertaining to secondary parameters, motor activity increased significantly under haloperidol. Haloperidol negatively affected reaction time variability and errors in both tasks, as well as omissions in the SST, indicating a decreased sustained attention, an increase in premature responses, and an increase in lapses of attention, respectively.

Rationale: An increase in the potency of the cannabis cigarettes has been observed over the past three decades., Objectives: In this study, we aimed to establish the impact of Δ9-tetrahydrocannabinol (THC) on the rating of subjective effects (intensity and duration of the effects), up to 23 % THC potency (69 mg THC) among recreational users., Methods: Recreational users (N = 24) smoked cannabis cigarettes with four doses of THC (placebo 29, 49 and 69 mg of THC) on four separate test days in a randomized, double-blind, placebo-controlled, crossover study. The participants filled in three different questionnaires measuring subjective effects during the exposure up to 8 h post-smoking. The 'high' feeling, heart rate, blood pressure and THC serum concentrations were also regularly recorded during these 8 h., Results: THC significantly increased the high feeling, dizziness, dry-mouthed feeling, palpitations, impaired memory and concentration, and 'down', 'sedated' and 'anxious' feelings. In addition, THC significantly decreased alertness, contentment and calmness. A cubic relationship was observed between 'feeling the drug' and 'wanting more'. The THC-induced decrease in 'feeling stimulated' and increase in anxiety lasted up to 8 h post-smoking. Sedation at 8 h post-smoking was increased by a factor of 5.7 with the highest THC dose, compared to the placebo., Conclusions: This study shows a strong effect of cannabis containing high percentages of THC on the rating of subjective effects. Regular users and forensic toxicologists should be aware that the THC-induced increase in 'feeling sedated' continues longer with a 69 mg THC dose than with a 29 mg THC dose.

Background: Fear-potentiated startle has been suggested as a translational model for evaluating efficacy of anxiolytic compounds in humans. Several known anxiolytic compounds have been tested as well as several putative anxiolytics. Because results of these studies have been equivocal, the aim of the present study was to examine another pharmacological permutation of the human potentiated startle model by comparing two anxiolytic agents to a non-anxiolytic sedative and placebo., Methods: Twenty healthy volunteers participated in a double-blind, placebo-controlled, cross-over study with four sessions in which they received single doses of the anxiolytics alprazolam (1 mg) and pregabalin (200 mg), as well as diphenhydramine (50 mg) as a non-anxiolytic sedative control and placebo. The design included a cued shock condition that presumably evokes fear and an unpredictable shock context condition presumably evoking anxiety., Results: None of the treatments reliably reduced either fear- or anxiety-potentiated startle. Alprazolam and diphenhydramine reduced overall baseline startle. Alprazolam was found to only affect contextual anxiety in a statistical significant way after two subjects who failed to show a contextual anxiety effect in the placebo condition were excluded from the analysis. Pregabalin did not significantly affect any of the physiological measures., Discussion: The negative findings from this study are discussed in terms of methodological differences between designs and in variability of startle both between and within study participants., Conclusion: Even though fear-potentiated startle may be used to translate preclinical evidence to human populations, methodological issues still hamper the application of this model to early screening of putative anxiolytic drugs.

Both a reduced face expertise and a basic abnormality in visual information, e.g. spatial frequency, processing have been proposed as possible causes of the abnormal face processing in Pervasive Developmental Disorder (PDD). This study investigated both the roles of expertise and spatial frequency for face processing in PDD. Event-related potentials (ERPs) and dipole sources were measured in response to (upright/inverted) high- and low-pass filtered faces, houses, and stimuli for which children with PDD were experts. ERP analyses for specific posterior electrodes showed no differences between children with PDD and matched controls, but source analyses did. These showed that controls activated specialized brain sources for the processing of faces, which was dependent on low spatial frequency content. However, children with PDD did not. Importantly, present results argue against the idea that this is due to a reduced face expertise on the part of the children with PDD, but instead support an abnormality in spatial frequency processing.

Rationale: Little is known about the effects of low doses of amitriptyline, prescribed in the treatment of neuropathic pain, on attentional processing capacity., Objectives: Changes due to amitriptyline treatment on attentional processing capacity were investigated on behavioral measures and event-related brain potentials (ERPs) in six patients with neuropathic pain., Materials and Methods: Patients were treated for 15 consecutive days with 25 mg nocturnally administered amitriptyline or placebo in a double-blind crossover randomized design. Measurements were carried out on day 1 and day 15 of each treatment period. An attentional capacity probe task was used in which the difficulty level was manipulated, resulting in an easy and a hard condition, while task-irrelevant visual probes were presented. During task performance, ERPs were measured from the midline electrodes Fz, Cz, Pz, and Oz., Results: Amitriptyline increased reaction times (RTs) after acute but not after subchronic administration. ERP analyses showed that P3 amplitudes to the task stimuli were not affected by amitriptyline in either treatment phase. Moreover, P3 amplitudes to the probes were increased in the easy compared to the hard task condition after subchronic amitriptyline treatment, indicating beneficial effects of repeated amitriptyline administration. In contrast, acute amitriptyline administration did reduce an earlier visual evoked potential, N1, preceding the P3 component., Conclusions: The results suggest that amitriptyline, even at low dosages of 25 mg, affects performance after acute administration in chronic neuropathic pain patients. After 2 weeks of treatment, performance appears to be unaffected. No deficits in processing capacity due to amitriptyline treatment were found.

Rationale: Antidepressants may vary widely in their potential to impair cognitive and psychomotor functions. Little is known about their effects on event-related brain potentials (ERPs).OBJECTIVES. To compare the effects of three pharmacologically different antidepressants on performance and ERPs in tasks of selective attention and working memory., Methods: Subjects were treated for 8 days with amitriptyline (sedative/anticholinergic TCA), nefazodone (5-HT(2) receptor antagonist), paroxetine (SSRI) and placebo, in a double-blind, crossover design. Measurements were carried out on day 1 and 8 of each treatment period. A task was used in which memory load (two and four items) and attention (focused, divided) were orthogonally varied., Results: On day 1 amitriptyline increased reaction times (focused attention) and the percentage of misses (load 4>load 2) and false alarms. Sensitivity (A') was reduced as a function of memory load. Effects were greatly diminished on day 8. The ERP analysis yielded a reduced early frontal positive difference wave related to memory load (day 1). Attention-related search negativity was slightly prolonged. P3 latency (stimulus evaluation time) was prolonged. P3 amplitude was reduced (mainly on day 8) suggesting diminished attention capacity. Nefazodone increased reaction times and miss rates and reduced sensitivity (A') on day 8 only. Paroxetine speeded responses on day 1 and slightly increased miss rates on day 8. Performance effects of nefazodone and paroxetine did not interact with the task factors. Search negativity and P3 measures were not affected., Conclusions: The results suggest that the pharmacologically selective serotonergic antidepressants lack the specific memory and attention deficits seen with amitriptyline. Both performance and ERP data suggest that paroxetine and nefazodone may influence response-related processes, while for nefazodone an effect on other processes cannot be excluded.

Rationale: Pre-clinical and clinical investigations have provided a great deal of evidence that the fear-potentiated startle paradigm represents a valid model for the objective assessment of emotional states of anxiety and fear., Objective: The four studies presented in this report sought to further validate the "threat of shock" paradigm as a human analogue to fear-potentiated startle in rats, by examining the effect of benzodiazepine administration on both baseline and fear-potentiated startle., Methods: Three studies, conducted at Utrecht University, evaluated the effects of oxazepam and of diazepam on baseline and fear-potentiated startle, whereas a fourth study, conducted at Yale University, evaluated the effect of diazepam on baseline, contextual and cue-specific fear-potentiated startle. The threat of shock paradigm consisted of verbal instruction about two visual cues (the threat cue predicted the possible administration of electric shock, the other predicted a safe period), followed by a series of presentations of these cues. During these conditions, acoustic startle stimuli were presented in order to elicit startle responses. The magnitude of the startle response was used to index the degree of fear or alarm experienced during the periods of threat and safety. The fourth study examined the effect of IV administration of diazepam in a similar threat of shock paradigm except that there were two additional context manipulations: electrode placement and darkness., Results: None of the drug manipulations affected specific threat-cue potentiation of startle. However, reductions in baseline startle were observed. Further, startle potentiation by darkness was inhibited by diazepam., Conclusions: At least one type of fear-potentiated startle, i.e. potentiation by a cue-specific fear manipulation, is not susceptible to benzodiazepine treatment. In contrast, effects of manipulations more akin to anxiety (darkness, context) appear sensitive to benzodiazepines. Human experimental models differentiating between these cue specific and contextual responses are needed to shed more light on differences in the anatomy and pharmacology of anxiety disorders.

The effects of two doses of caffeine (1.5 and 3 mg/kg) on various aspects of visual selective attention were investigated in 24 healthy human subjects. Specific task conditions were compared to provide measures of selectivity for a location in the visual field, of distractibility, of selectivity among response alternatives, and of strategic influences. In two out of three tasks, caffeine speeded responses significantly. However, these effects did not differ across conditions within-task, so there was no indication that they were to due to (a) specific effect(s) on one or more of the attentional sub-functions. The results suggest that the beneficial effects of caffeine in low-load conditions cannot be attributed to reduced distractibility or increased suppression of task-irrelevant response tendencies.

Thirty females performed a visual vigilance task under the influence of bromazepam (6 and 12 mg) in a placebo-controlled, double blind, experiment. Measures employed were percentage of hits, percentage of false alarms, response latency (RT), A' (sensitivity), B" (cautiousness), and RI (responsivity), as well as signal- and non-signal event-related potentials (ERPs). Bromazepam did not aggravate the normally occurring decrement in performance in vigilance tasks, but had an effect on overall level of performance: accuracy was reduced under the influence of the drug, but speed improved. A Drug x Period interaction for cautiousness (B") indicated increasingly less cautiousness with bromazepam, which probably contributed to faster motor responses (and more errors) than in the placebo group. The ERP data suggest that the effects of bromazepam are already manifest in the early stages of information processing (attention-detection) as mirrored by a drug effect on N1 amplitude. Deterioration at this early stage may affect later processing stages (P2-N2 amplitudes). As a result, subjects under the influence of the drug probably accumulate less signal evidence for their final evaluation.