Methylmercury, attention, and memory: baseline-dependent effects of adult d-amphetamine and marginal effects of adolescent methylmercury.

Methylmercury (MeHg) is an environmental neurotoxicant known to disrupt behavior related to dopamine neurotransmission in experimental models. Such disruptions are sensitive to dopamine agonists when administered acutely after exposure to MeHg has ended or when administered concurrently with MeHg exposure. Sustained attention and short-term remembering, components of attention-deficit/hyperactivity disorder (ADHD), are partially mediated by dopamine neurotransmission. In order to observe MeHg-related alterations in sustained attention and short-term memory, as well as determine sensitivity of MeHg exposed animals to dopamine agonists commonly used in the treatment of ADHD symptoms, rats were exposed to 0, 0.5, or 5 ppm MeHg throughout adolescence and trained in a hybrid sustained attention/short term memory visual signal detection task in adulthood. Behavior was then probed with acute i.p. injections of the dopamine agonist, d-amphetamine, which improves impaired attention and inhibits short-term memory in clinical syndromes like ADHD. Acute d-amphetamine dose-dependently decreased short-term memory as well as sustained attention. While MeHg alone did not impair accuracy or memory, it did interact with d-amphetamine to produce baseline-dependent inhibition of behavior. These findings further show that changes in behavior following low-level exposure to MeHg during adolescence are augmented by dopamine agonists. Observed impairments in memory following acute d-amphetamine are consistent with previous findings.

The PTN-PTPRZ signal activates the AFAP1L2-dependent PI3K-AKT pathway for oligodendrocyte differentiation: Targeted inactivation of PTPRZ activity in mice.

Protein tyrosine phosphatase receptor type Z (PTPRZ) maintains oligodendrocyte precursor cells (OPCs) in an undifferentiated state. The inhibition of PTPase by its ligand pleiotrophin (PTN) promotes OPC differentiation; however, the substrate molecules of PTPRZ involved in the differentiation have not yet been elucidated in detail. We herein demonstrated that the tyrosine phosphorylation of AFAP1L2, paxillin, ERBB4, GIT1, p190RhoGAP, and NYAP2 was enhanced in OPC-like OL1 cells by a treatment with PTN. AFAP1L2, an adaptor protein involved in the PI3K-AKT pathway, exhibited the strongest response to PTN. PTPRZ dephosphorylated AFAP1L2 at tyrosine residues in vitro and in HEK293T cells. In OL1 cells, the knockdown of AFAP1L2 or application of a PI3K inhibitor suppressed cell differentiation as well as the PTN-induced phosphorylation of AKT and mTOR. We generated a knock-in mouse harboring a catalytically inactive Cys to Ser (CS) mutation in the PTPase domain. The phosphorylation levels of AFAP1L2, AKT, and mTOR were higher, and the expression of oligodendrocyte markers, including myelin basic protein (MBP) and myelin regulatory factor (MYRF), was stronger in CS knock-in brains than in wild-type brains on postnatal day 10; however, these differences mostly disappeared in the adult stage. Adult CS knock-in mice exhibited earlier remyelination after cuprizone-induced demyelination through the accelerated differentiation of OPCs. These phenotypes in CS knock-in mice were similar to those in Ptprz-deficient mice. Therefore, we conclude that the PTN-PTPRZ signal stimulates OPC differentiation partly by enhancing the tyrosine phosphorylation of AFAP1L2 in order to activate the PI3K-AKT pathway.

Primate Nigrostriatal Dopamine System Regulates Saccadic Response Inhibition.

Animals need to inhibit inappropriate actions that would lead to unwanted outcomes. Although this ability, called response inhibition, is impaired in neurological/psychiatric disorders with dopaminergic dysfunctions, how dopamine regulates response inhibition remains unclear. Here we investigated neuronal signals of the nigrostriatal dopamine system in monkeys performing a saccadic countermanding task. Subsets of dopamine neurons in the substantia nigra and striatal neurons receiving the dopaminergic input were activated when the monkey was required to cancel a planned saccadic eye movement. These activations were stronger when canceling the eye movements was successful compared with failed and were enhanced in demanding trials. The activated dopamine neurons were distributed mainly in the dorsolateral, but not in the ventromedial, part of the nigra. Furthermore, pharmacological blockade of dopaminergic neurotransmission in the striatum dampened the performance of canceling saccadic eye movements. The present findings indicate that disruption of nigrostriatal dopamine signaling causes impairments in response inhibition.

Inhibition of Lats1/p-YAP1 pathway mitigates neuronal apoptosis and neurological deficits in a rat model of traumatic brain injury.

AIMS: To investigate the roles of Lats1/p-YAP1 pathway in TBI-induced neuronal apoptosis and neurological deficits in rats. RESULTS: We found that Lats1 and YAP1 were expressed in cerebral cortex neurons of Sprague-Dawley rats, and the phosphorylation levels of Lats1 and YAP1 in injured regions were significantly increased after TBI. Furthermore, inhibition of Lats1 not only decreased the level of p-YAP1, but also attenuated neuronal apoptosis and neurological impairment. CONCLUSIONS: Our work demonstrates that inhibition of Lats1/p-YAP1 pathway mitigates neuronal apoptosis and neurological deficits in a rat model of TBI.

Effects of daily morphine treatment on impulsivity in rats responding under an adjusting stop-signal reaction time task.

Opioids can enhance delay discounting and premature responding under attentional tasks that might reflect increased impulsivity; although it is not clear whether repeated opioid administration alters behavioral inhibition. Effects of morphine and amphetamine were determined before, during, and after daily morphine administration in rats responding under a stop-signal reaction time task, measuring behavioral inhibition and motor impulsivity. Rats (n=5) completed a two-response sequence to earn food. Occasionally, a tone (stop signal) was presented signifying that food would only be presented if the second response was withheld. Responding after the stop signal measured inhibition, and responding before the start of the trial (premature) measured motor impulsivity. Before daily treatment, morphine (0.32-17.8 mg/kg, intraperitoneally) decreased premature responding but did not increase responding on stop trials, whereas amphetamine (0.1-3.2 mg/kg, intraperitoneally) increased premature responding. Daily morphine administration (3.2 mg/kg/day) enhanced its effects on premature responding but did not impact other effects. Daily morphine treatment diminished the effects of amphetamine on premature and timeout responding. Repeated morphine treatment increased motor impulsivity but did not enhance behavioral inhibition. These data add to studies elucidating the relationship between impulsivity and opioid treatment and suggest that opioids differentially impact impulsive behaviors.

Mechanism of noradrenaline-induced α1-adrenoceptor mediated regulation of Na-K ATPase subunit expression in Neuro-2a cells.

Rapid eye movement sleep (REMS) plays an important role in maintaining brain excitability by regulating noradrenaline (NA) level and Na-K ATPase activity. We showed earlier that REMS deprivation (REMSD) associated elevated NA increased neuronal, while decreased glial Na-K ATPase activity. However, our knowledge was insufficient on how the REMSD-associated effect is sustained particularly under chronic condition. Using Neuro-2a cells as a model, we investigated the molecular mechanism of NA-induced increase in mRNA expression of Na-K ATPase subunit and the enzyme activity. The cells were treated with NA in the presence or absence of either α1- or ß-adrenoceptor (AR) antagonists, Ca++-channel blocker or SERCA-inhibitor, and PKA or PKC inhibitor. We observed that NA acting on α1-AR increased Na-K ATPase activity and mRNA expression of the catalytic α1- and α3-Na-K ATPase subunits in the Neuro-2a cells. Further, PLC and PKC mediated modulation of intracellular Ca++ played a critical role in inducing the mRNA expression. On the other hand NA, acting on ß-AR up-regulated expression of the regulatory ß1-subunit of Na-K ATPase. The involvement of SP1 as well as phospho-CREB transcription factors in the NA-mediated increased expression of various subunit isoforms was established. The results of this study along with that of earlier reports support our proposed working model of NA-induced increase in mRNA expression of specific Na-K ATPase subunit leading to increased Na-K ATPase activity. The findings help us understand the molecular mechanism of NA-induced increased brain excitability, for example, upon REMSD including under chronic condition.

Methylphenidate Enhances Early-Stage Sensory Processing and Rodent Performance of a Visual Signal Detection Task.

Methylphenidate (MPH) is used clinically to treat attention-deficit/hyperactivity disorder (ADHD) and off-label as a performance-enhancing agent in healthy individuals. MPH enhances catecholamine transmission via blockade of norepinephrine (NE) and dopamine (DA) reuptake transporters. However, it is not clear how this action affects neural circuits performing cognitive and sensorimotor functions driving performance enhancement. The dorsal lateral geniculate nucleus (dLGN) is the primary thalamic relay for visual information from the retina to the cortex and is densely innervated by NE-containing fibers from the locus coeruleus (LC), a pathway known to modulate state-dependent sensory processing. Here, MPH was evaluated for its potential to alter stimulus-driven sensory responses and behavioral outcomes during performance of a visual signal detection task. MPH enhanced activity within individual neurons, ensembles of neurons, and visually-evoked potentials (VEPs) in response to task light cues, while increasing coherence within theta and beta oscillatory frequency bands. MPH also improved reaction times to make correct responses, indicating more efficient behavioral performance. Improvements in reaction speed were highly correlated with faster VEP latencies. Finally, immunostaining revealed that catecholamine innervation of the dLGN is solely noradrenergic. This work suggests that MPH, acting via noradrenergic mechanisms, can substantially affect early-stage sensory signal processing and subsequent behavioral outcomes.

Intranasal Insulin Boosts Gustatory Sensitivity.

Intranasal insulin has been the subject of attention not only with respect to enhancing memory processes, but also for its anorexic effects, as well as its effects on olfactory sensitivity. In the present study, the influence of intranasal insulin on gustatory sensitivity was investigated using intranasal applications of insulin or placebo in a double-blind manner alongside a control condition without any application. We hypothesised that, because it mediates satiety, intranasal insulin alters gustatory sensitivity, whereas placebo application and the control should not alter gustatory sensitivity. We did not expect the sensitivity to the different taste solutions to differ. Sweet, salty, bitter and sour liquids in four concentrations each were sprayed onto the tongue of healthy male subjects. Additionally, water with no taste was applied to enable calculation of taste sensitivity in terms of parameter d' of signal detection theory. The task of the subject was to identify the quality of the respective tastant. Gustatory sensitivity and blood parameters were evaluated using repeated-measures ANOVAs. Gustatory sensitivity (implying all tastants) improved significantly after intranasal insulin application compared to the application of placebo, although it did not reach significance compared to the control condition. Subjects performed best when detecting the sweet taste and worst when detecting the bitter taste. The blood parameters glucose, insulin, homeostatic model assessment and leptin did not differ with respect to insulin or placebo condition, nor did they differ regarding measurements preceding or following intranasal application, in confirmation of preserved peripheral euglycaemia during the experiment. Thus, it can be concluded that the application of intranasal insulin led to an improved gustatory sensitivity compared to placebo.

Interaction between hippocampal serotonin and cannabinoid systems in reactivity to spatial and object novelty detection.

Functional interaction between cannabinoid and serotonin neuronal systems have been reported in different tasks related to memory assessment. The present study investigated the effect of serotonin 5-HT4 agents into the dorsal hippocampus (the CA1 region) on spatial and object novelty detection deficits induced by activation of cannabinoid CB1 receptors (CB1Rs) using arachidonylcyclopropylamide (ACPA) in a non-associative behavioral task designed to forecast the ability of rodents to encode spatial and non-spatial relationships between distinct stimuli. Post-training, intra-CA1 microinjection of 5-HT4 receptor agonist RS67333 or 5-HT4 receptor antagonist RS23597 both at the dose of 0.016µg/mouse impaired spatial memory, while cannabinoid CB1R antagonist AM251 (0.1µg/mouse) facilitated object novelty memory. Also, post-training, intraperitoneal administration of CB1R agonist ACPA (0.005-0.05mg/kg) impaired both memories. However, a subthreshold dose of RS67333 restored ACPA response on both memories. Moreover, a subthreshold dose of RS23597 potentiated ACPA (0.01mg/kg) and reversed ACPA (0.05mg/kg) responses on spatial memory, while it potentiated ACPA response at the dose of 0.005 or 0.05mg/kg on object novelty memory. Furthermore, effective dose of AM251 restored ACPA response at the higher dose. AM251 blocked response induced by combination of RS67333 or RS23597 and the higher dose of ACPA on both memories. Our results highlight that hippocampal 5-HT4 receptors differently affect cannabinoid signaling in spatial and object novelty memories. The inactivation of CB1 receptors blocks the effect of 5-HT4 agents into the CA1 region on memory deficits induced by activation of CB1Rs via ACPA.

The modulatory effect of CA1 GABAb receptors on ketamine-induced spatial and non-spatial novelty detection deficits with respect to Ca(2+).

Glutamate and γ-aminobutyric acid (GABA) are among the most abundant neurotransmitters in the central nervous system. Ketamine and other noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists are known to induce deficits in learning and the performance of cognitive tasks. The present study was designed to assess the effects of dorsal hippocampal (CA1) GABAb receptors on ketamine-induced spatial and non-spatial memory deficits with regard to the role of Ca(2+) as a defining factor. Spatial and non-spatial novelty detection of male NMRI mice were investigated in a circular open-field apparatus. According to our results, the intraperitoneal injection of ketamine at its higher dose (0.1 mg/kg) impaired both spatial and non-spatial novelty detection. Moreover, the intra-CA1 injection of baclofen (a GABAb receptor agonist) at higher doses (0.02 and 0.2 µg/mouse) impaired the spatial but not non-spatial novelty detection. In addition, phaclofen (a GABAb receptor antagonist at 0.2 µg/mouse) impaired both spatial and non-spatial novelty detection. Baclofen restored and induced a modulatory effect on ketamine-induced responses in the spatial and non-spatial novelty detection task, respectively. On the contrary, phaclofen restored and induced a modulatory effect on ketamine-induced responses in the non-spatial and spatial novelty detection task, respectively. Finally, the subthreshold dose of SKF96365 (a Ca(2+) channel blocker) impaired only the spatial but not non-spatial restoration effects of baclofen or phaclofen following a higher dose of ketamine. Such findings suggest that the ketamine-induced impairment of memory consolidation may occur through GABAb receptors of the CA1 neurons. Moreover, baclofen and phaclofen were shown to possibly exert their effects on the ketamine-induced spatial novelty detection deficits through Ca(2+) channels.

Donepezil increases contrast sensitivity for the detection of objects in scenes.

We assessed the effects of donepezil, a drug that stimulates cholinergic transmission, and scopolamine, an antagonist of cholinergic transmission, on contrast sensitivity. 30 young male participants were tested under three treatment conditions: placebo, donepezil, and scopolamine in a random order. Pairs of photographs varying in contrast were displayed left and right of fixation for 50 ms. Participants were asked to locate the scene containing an animal. Accuracy was better under donepezil than under scopolamine, particularly for signals of high intensity (at higher levels of contrast). A control experiment showed that the lower performance under scopolamine did not result from the mydriasis induced by scopolamine. The results suggest that cholinergic stimulation, through donepezil, facilitates signal detection in agreement with studies on animals showing that the pharmacological activation of cholinergic receptors controls the gain in the relationship between the stimulus contrast (intensity of the visual input) and visual response. As Alzheimer disease is associated to depletion in acetylcholine, and there is evidence of deficits in contrast sensitivity in Alzheimer, it might be interesting to integrate such rapid and sensitive visual tasks in the biomarkers at early stage of drug development.

Effects of the noncompetitive N-methyl-D-aspartate receptor antagonist ketamine on visual signal detection performance in rats.

The noncompetitive N-methyl-D-aspartate receptor antagonist ketamine produces consistent, rapid, and sustained antidepressant effects in patients suffering from treatment-resistant depression. However, ketamine-induced cognitive impairments remain a major concern. The present study sought to extend the preclinical evaluation of ketamine-induced cognitive impairments by evaluating the dose (1.0-18.0 mg/kg) and time-course (10 min-24 h) of effects of ketamine on sustained attention using a visual signal detection procedure in rats. Overall, ketamine (10.0-18.0 mg/kg) dose-dependently decreased percent hit and correct rejection accuracy. Additionally, these same doses of ketamine increased response latency and trial omissions. In the time-course study, treatment with 18.0 mg/kg ketamine produced the greatest decrease in visual signal detection performance at 10 min, when ketamine decreased percent hit and correct rejection accuracy as well as increased response latency and trial omissions, but returned to saline baseline controls by 100 min. In conclusion, acute ketamine inhibited sustained attention in rats performing a visual signal detection task; however, these effects were short in duration, similar to the short duration (<2 h) of psychotomimetic effects reported in low-dose ketamine treatment in depressed patients.

In vivo coincidence detection in mammalian sound localization generates phase delays.

Sound localization critically depends on detection of differences in arrival time of sounds at the two ears (acoustic delay). The fundamental mechanisms are debated, but all proposals include a process of coincidence detection and a separate source of internal delay that offsets the acoustic delay and determines neural tuning. We used in vivo patch-clamp recordings of binaural neurons in the Mongolian gerbil and pharmacological manipulations to directly compare neuronal input to output and to separate excitation from inhibition. Our results cannot be accounted for by existing models and reveal that coincidence detection is not an instantaneous process, but is instead shaped by the interaction of intrinsic conductances with preceding synaptic activity. This interaction generates an internal delay as an intrinsic part of the process of coincidence detection. The multiplication and time-shifting stages thought to extract synchronous activity in many brain areas can therefore be combined in a single operation.

Oxytocin increases bias, but not accuracy, in face recognition line-ups.

Previous work indicates that intranasal inhalation of oxytocin improves face recognition skills, raising the possibility that it may be used in security settings. However, it is unclear whether oxytocin directly acts upon the core face-processing system itself or indirectly improves face recognition via affective or social salience mechanisms. In a double-blind procedure, 60 participants received either an oxytocin or placebo nasal spray before completing the One-in-Ten task-a standardized test of unfamiliar face recognition containing target-present and target-absent line-ups. Participants in the oxytocin condition outperformed those in the placebo condition on target-present trials, yet were more likely to make false-positive errors on target-absent trials. Signal detection analyses indicated that oxytocin induced a more liberal response bias, rather than increasing accuracy per se. These findings support a social salience account of the effects of oxytocin on face recognition and indicate that oxytocin may impede face recognition in certain scenarios.

Modulation of auditory deviance detection by acute nicotine is baseline and deviant dependent in healthy nonsmokers: a mismatch negativity study.

OBJECTIVE: Cognitive enhancement resulting from nicotinic acetylcholine receptor stimulation may be evidenced by increased efficiency of the auditory-frontal cortex network of auditory discrimination, which is impaired in schizophrenia, a cognitive disorder associated with excessive tobacco use. Investigating automatic (preattentive) detection of acoustic change with the mismatch negativity (MMN) brain event-related potential in response to nicotine in individuals with varying baseline levels of auditory discrimination may provide useful insight into the cholinergic regulation of this neural network and its potential amelioration with novel nicotinic agents. METHODS: Sixty healthy, non-smoking male volunteers were presented with an 'optimal' multi-feature MMN paradigm in a randomized, placebo controlled double-blind design with 6 mg of nicotine gum. RESULTS: Participants with low, medium, and high baseline amplitudes responded differently to nicotine (vs. placebo), and nicotine response was feature specific. Whereas MMN in individuals with high amplitudes was diminished by nicotine, MMN increased in those with low amplitudes. Nicotine effects were not shown in medium amplitude participants. CONCLUSIONS: These findings provide preliminary support for the role of nicotinic neurotransmission in sensory memory processing of auditory change and suggest that nicotinic receptor modulation can both enhance and diminish change detection, depending on baseline MMN and its eliciting stimulus feature.

Influence of kinin peptides on monocyte-endothelial cell adhesion.

Adhesion of leukocytes to vascular endothelium in response to proinflammatory mediators is an important component of the overall inflammatory reaction. In the current work, we used a retinoic acid-differentiated human promonocytic cell line, U937 and a human microvascular endothelial cell line, HMEC-1 to analyze the effect of the potent pro-inflammatory bradykinin-related peptides (kinins) on cell adhesion. Bradykinin (BK) and kinin metabolites without the C-terminal arginine residue enhanced adhesion of the monocyte-like cells to fibronectin and to the HMEC-1 cells. Expression of adhesion proteins on the surface of both cell types was altered by the kinin peptides. In the monocyte-like cells, expression of CD11b, a subunit of Mac-1 integrin, was significantly increased whilst in the endothelial cells, a strong increase in the production of intercellular adhesion molecule 1 (ICAM-1) was observed. The positive bradykinin-induced effect on the cell-cell interaction was reversed by a carboxypeptidase inhibitor (MGTA), hence we suspected a significant role of the des-Arg kinin metabolites, which acted through the kinin receptor type 1. Indeed, the expression of this receptor was up-regulated not only by agonists but also by interferon-γ and bradykinin. Kinin peptides also regulated signal transducer and activator of transcription proteins (STATs) activated by cytokines. Taken together, the above observations support our hypothesis that kinins stimulate monocyte adhesion to the vessel wall, especially during pathological states of the circulatory system accompanied by proinflammatory cytokine release.

The effects of clinically relevant doses of amphetamine and methylphenidate on signal detection and DRL in rats.

Low dose amphetamine (AMPH) and methylphenidate (MPH, Ritalin(®)) are the most widely prescribed and most effective pharmacotherapy for attention-deficit/hyperactivity disorder (ADHD). Certain low, clinically relevant doses of MPH improve sustained attention and working memory in normal rats, in contrast to higher doses that impair cognitive ability and induce locomotor activity. However, the effects of AMPH of MPH on sustained attention and behavioral inhibition remain poorly characterized. The present experiments examined the actions of AMPH (0.1 and 0.25 mg/kg) and MPH (0.5 and 1.0 mg/kg) in a rat model of 1) sustained attention, where signal and blank trials were interspersed randomly and occurred at unpredictable times, and 2) behavioral inhibition, using a differential reinforcement of low rate (DRL) schedule. In a signal detection paradigm, both 0.5 mg/kg and 1.0 mg/kg MPH and 0.25 mg/kg AMPH improve sustained attention, however neither AMPH nor MPH improve behavioral inhibition on DRL. Taken together with other recent studies, it appears that clinically-relevant doses of AMPH and MPH may preferentially improve attention-related behavior while having little effect on behavioral inhibition. These observations provide additional insight into the basic behavioral actions of low-dose psychostimulants and further suggest that the use of sustained attention tasks may be important in the development of novel pharmacological treatments for ADHD.

Membrane potential correlates of sensory perception in mouse barrel cortex.

Neocortical activity can evoke sensory percepts, but the cellular mechanisms remain poorly understood. We trained mice to detect single brief whisker stimuli and report perceived stimuli by licking to obtain a reward. Pharmacological inactivation and optogenetic stimulation demonstrated a causal role for the primary somatosensory barrel cortex. Whole-cell recordings from barrel cortex neurons revealed membrane potential correlates of sensory perception. Sensory responses depended strongly on prestimulus cortical state, but both slow-wave and desynchronized cortical states were compatible with task performance. Whisker deflection evoked an early (<50 ms) reliable sensory response that was encoded through cell-specific reversal potentials. A secondary late (50-400 ms) depolarization was enhanced on hit trials compared to misses. Optogenetic inactivation revealed a causal role for late excitation. Our data reveal dynamic processing in the sensory cortex during task performance, with an early sensory response reliably encoding the stimulus and later secondary activity contributing to driving the subjective percept.

Developmental hypothyroidism disrupts visual signal detection performance in rats.

Thyroid hormones (THs) are essential for proper brain development in mammals. TH insufficiency during early development causes structural and functional abnormalities in brain leading to cognitive dysfunction. The specific effects of developmental hypothyroidism on attention have not been well characterized in animal models. The present study was conducted to characterize the effects of developmental hypothyroidism on attention in rats, and tested the hypothesis that the hypothyroidism has adverse impacts on attention by means of a visual signal detection task. Pregnant rats were exposed to the anti-thyroid drug, methimazole (0.02% w/v) via drinking water from gestational day 15 through postnatal day (PND) 21 to induce maternal and neonatal hypothyroidism. Male offspring served as subjects for the task started on PND 90. A light stimulus (500 ms, 250 ms or 50 ms) was presented in signal trials and not in blank trials. The offspring were required to discriminate these signal events, and subsequently press the correct lever. The correct response for signal and non-signal events was considered as hit and correct rejection, respectively. The hypothyroid offspring exhibited a decreased hit response for short signals (250 ms and 50 ms) which requires the higher attentional demand. The total number of lever responses during inter-trial interval (ITI) was also increased in the hypothyroid group. The number of lever responses was negatively correlated with a hit response at 50 ms, not at 250 ms. These results suggest that developmental hypothyroidism disrupts signal detection performance via impairment of visual attention and the altered lever response behavior.

Dopamine D2 receptor modulation of human response inhibition and error awareness.

Response inhibition, comprising action cancellation and action restraint, and error awareness are executive functions of considerable clinical relevance to neuropsychiatric disorders. Nevertheless, our understanding of their underlying catecholamine mechanisms, particularly regarding dopamine, is limited. Here, we used the dopamine D2 agonist cabergoline to study its ability to improve inhibitory control and modulate awareness of performance errors. A randomized, double-blind, placebo-controlled, crossover design with a single dose of cabergoline (1.25 mg) and placebo (dextrose) was employed in 25 healthy participants. They each performed the stop-signal task, a well-validated measure of action cancellation, and the Error Awareness Task, a go/no-go measure of action restraint and error awareness, under each drug condition. Cabergoline was able to selectively reduce stop-signal RT, compared with placebo, indicative of enhanced action cancellation (p < .05). This enhancement occurred without concomitant changes in overall response speed or RT variability and was not seen for errors of commission on the Error Awareness Task. Awareness of performance errors on the go/no-go task was, however, significantly improved by cabergoline compared with placebo (p < .05). Our results contribute to growing evidence for the dopaminergic control of distinct aspects of human executive ability, namely, action cancellation and error awareness. The findings may aid the development of new, or the repurposing of existing, pharmacotherapy that targets the cognitive dysfunction of psychiatric and neurological disorders. They also provide further evidence that specific cognitive paradigms have correspondingly specific neurochemical bases.