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Rationale: Motivation and inhibitory control are dominantly regulated by the dopaminergic (DA) and noradrenergic (NA) systems, respectively. Hypothalamic hypocretin (orexin) neurons provide afferent inputs to DA and NA nuclei and hypocretin-1 receptors (HcrtR1) are implicated in reward and addiction. However, the role of the HcrtR1 in inhibitory control is not well understood., Objectives: To determine the effects of HcrtR1 antagonism and motivational state in inhibitory control using the go/no-go task in mice., Methods: n = 23 male C57Bl/6JArc mice were trained in a go/no-go task. Decision tree dendrogram analysis of training data identified more and less impulsive clusters of animals. A HcrtR1 antagonist (BI001, 12.5 mg/kg, per os) or vehicle were then administered 30 min before go/no-go testing, once daily for 5 days, under high (food-restricted) and low (free-feeding) motivational states in a latin-square crossover design. Compound exposure levels were assessed in a satellite group of animals., Results: HcrtR1 antagonism increased go accuracy and decreased no-go accuracy in free-feeding animals overall, whereas it decreased go accuracy and increased no-go accuracy only in more impulsive, food restricted mice. HcrtR1 antagonism also showed differential effects in premature responding, which was increased in response to the antagonist in free-feeding, less impulsive animals, and decreased in food restricted, more impulsive animals. HcrtR1 receptor occupancy by BI001 was estimated at ~ 66% during the task., Conclusions: These data indicate that hypocretin signalling plays roles in goal-directed behaviour and inhibitory control in a motivational state-dependant manner. While likely not useful in all settings, HcrtR1 antagonism may be beneficial in improving inhibitory control in impulsive subpopulations., (© 2024. The Author(s).)

Impulsive decision-making has been linked to impulse control disorders and substance use disorders. However, the neural mechanisms underlying impulsive choice are not fully understood. While previous PET imaging and autoradiography studies have shown involvement of dopamine and D2/3 receptors in impulsive behavior, the roles of distinct D1, D2, and D3 receptors in impulsive decision-making remain unclear. In this study, we used a food reward delay-discounting task (DDT) to identify low- and high-impulsive rats, in which low-impulsive rats exhibited preference for large delayed reward over small immediate rewards, while high-impulsive rats showed the opposite preference. We then examined D1, D2, and D3 receptor gene expression using RNAscope in situ hybridization assays. We found that high-impulsive male rats exhibited lower levels of D2 and D3, and particularly D3, receptor expression in the nucleus accumbens (NAc), with no significant changes in the insular, prelimbic, and infralimbic cortices. Based on these findings, we further explored the role of the D3 receptor in impulsive decision-making. Systemic administration of a selective D3 receptor agonist (FOB02-04) significantly reduced impulsive choices in high-impulsive rats but had no effects in low-impulsive rats. Conversely, a selective D3 receptor antagonist (VK4-116) produced increased both impulsive and omission choices in both groups of rats. These findings suggest that impulsive decision-making is associated with a reduction in D3 receptor expression in the NAc. Selective D3 receptor agonists, but not antagonists, may hold therapeutic potentials for mitigating impulsivity in high-impulsive subjects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: Whether selective serotonin reuptake inhibitors (SSRI) increase suicide risk, especially in young adults, is still a controversial issue. This study aimed to examine the change in impulsivity characteristics and to evaluate the relationship between impulsivity and suicidality in young adults with major depression who were started on SSRIs., Method: The study included 50 patients between the ages of 18-24 years with a diagnosis of major depression who were planned to start SSRIs. Participants were evaluated with the Beck Depression Scale, Beck Anxiety Scale, Young Mania Rating Scale, Columbia Suicide Severity Rating Scale, Barratt Impulsivity Scale, Daily Impulsivity Scale (DIS), and Go/ No-Go Task (GNG) before and at the end of the first week of treatment., Results: Seventy percent of the patients (n: 35) completed the assessments at baseline and at the end of the first week. At the end of one-week there was a statistically significant decrease in the DIS (t=2.283, p=0.029) and commission errors in GNG (t=3.19, p=0.003). In addition, 7 out of 11 patients who had suicidal ideation at the first evaluation did not continue to have suicidal ideation at the end of the first week and there was a significant decrease in the severity of suicidal ideation at the end of the follow-up (W:132.0, p<0.001)., Conclusion: One-week SSRI use in young adults resulted in a decrease in impulsivity in self-report scales assessing state impulsivity and in the GNG. It was observed that the severity of suicidal ideation decreased at the end of the one-week treatment period.

Impulsivity is a trait associated with several psychiatric conditions, not least addictive disorders. While the neural mechanisms behind certain aspects of impulsivity have been studied extensively, there are few imaging studies examining this neurocircuitry in populations with substance use disorders. Therefore, we aimed to examine the functional connectivity of relevant neural networks, and their possible association with trait impulsivity, in a sample with severe amphetamine use disorder and a control group of healthy subjects. We used data collected in a randomized clinical trial studying the acute effects of oral naltrexone in amphetamine use disorder. Our final sample included 32 amphetamine users and 27 healthy controls. Trait impulsivity was rated with the Barratt Impulsiveness Scale-11, and functional connectivity was measured during resting-state fMRI, looking specifically at networks involving prefrontal regions previously implicated in studies of impulsivity. Amphetamine users had higher subjective ratings of impulsivity as compared to healthy controls, and these scores correlated positively with a wide-spread prefrontal hyperconnectivity that was found among the amphetamine users. These findings highlight the importance of aberrant prefrontal function in severe addiction., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Clinical and preclinical evidence has demonstrated an increased risk for neuropsychiatric disorders following prenatal cannabinoid exposure. However, given the phytochemical complexity of cannabis, there is a need to understand how specific components of cannabis may contribute to these neurodevelopmental risks later in life. To investigate this, a rat model of prenatal cannabinoid exposure was utilized to examine the impacts of specific cannabis constituents (Δ9-tetrahydrocannabinol [THC]; cannabidiol [CBD]) alone and in combination on future neuropsychiatric liability in male and female offspring. Prenatal THC and CBD exposure were associated with low birth weight. At adolescence, offspring displayed sex-specific behavioural changes in anxiety, temporal order and social cognition, and sensorimotor gating. These phenotypes were associated with sex and treatment-specific neuronal and gene transcriptional alterations in the prefrontal cortex, and ventral hippocampus, regions where the endocannabinoid system is implicated in affective and cognitive development. Electrophysiology and RT-qPCR analysis in these regions implicated dysregulation of the endocannabinoid system and balance of excitatory and inhibitory signalling in the developmental consequences of prenatal cannabinoids. These findings reveal critical insights into how specific cannabinoids can differentially impact the developing fetal brains of males and females to enhance subsequent neuropsychiatric risk., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Prenatal alcohol exposure (PAE) can lead to a wide range of adverse effects in humans, including impaired self-control and increased impulsive behavior. Deficits in self-control can interfere with academic performance and have lasting impacts. In the present study, a rodent model of PAE was used to assess impulsivity through operant conditioning. Pregnant rats were assigned to one of three groups: ad-lib control (CON), pair-fed (PF), and alcohol-exposed (ALC). ALC rats were given a liquid diet containing 6% alcohol, PF rats were yoked to an ALC rat and given a CON liquid diet, and CON rats received ad libitum food. Operant conditioning was used to evaluate extinction in adolescents (Experiment 1) and differential reinforcement of low rates (DRL) in adolescents and adults (Experiment 2). PAE resulted in an increase in responses and resets during DRL testing, indicative of impaired self-control, an effect that was only observed in adolescent males. Females, regardless of age, did not show increased impulsivity following PAE. This indicates that children with PAE may exhibit attentional deficits similar to those with attention deficit hyperactivity disorder, with males at a higher risk., (© 2024 The Author(s). Developmental Psychobiology published by Wiley Periodicals LLC.)

Deficits in impulse control are observed in several neurocognitive disorders, including attention deficit hyperactivity (ADHD), substance use disorders (SUDs), and those following traumatic brain injury (TBI). Understanding brain circuits and mechanisms contributing to impulsive behavior may aid in identifying therapeutic interventions. We previously reported that intact lateral habenula (LHb) function is necessary to limit impulsivity defined by impaired response inhibition in rats. Here, we examine the involvement of a synaptic input to the LHb on response inhibition using cellular, circuit, and behavioral approaches. Retrograde fluorogold tracing identified basal forebrain (BF) inputs to LHb, primarily arising from ventral pallidum and nucleus accumbens shell (VP/NAcs). Glutamic acid decarboxylase and cannabinoid CB1 receptor (CB1R) mRNAs colocalized with fluorogold, suggesting a cannabinoid modulated GABAergic pathway. Optogenetic activation of these axons strongly inhibited LHb neuron action potentials and GABA release was tonically suppressed by an endogenous cannabinoid in vitro. Behavioral experiments showed that response inhibition during signaled reward omission was impaired when VP/NAcs inputs to LHb were optogenetically stimulated, whereas inhibition of this pathway did not alter LHb control of impulsivity. Systemic injection with the psychotropic phytocannabinoid, Δ 9 -tetrahydrocannabinol (Δ 9 -THC), also increased impulsivity in male, and not female rats, and this was blocked by LHb CB1R antagonism. However, as optogenetic VP/NAcs pathway inhibition did not alter impulse control, we conclude that the pro-impulsive effects of Δ 9 -THC likely do not occur via inhibition of this afferent. These results identify an inhibitory LHb afferent that is controlled by CB1Rs that can regulate impulsive behavior., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Temporal discounting, in which the recipient of a reward perceives the value of that reward to decrease with delay in its receipt, is associated with impulsivity and psychiatric disorders such as depression. Here, we investigate the role of the serotonin 5-HT 4 receptor (5-HT 4 R) in modulating temporal discounting in the macaque dorsal caudate nucleus (dCDh), the neurons of which have been shown to represent temporally discounted value. We first mapped the 5-HT 4 R distribution in macaque brains using positron emission tomography (PET) imaging and confirmed dense expression of 5-HT 4 R in the dCDh. We then examined the effects of a specific 5-HT 4 R antagonist infused into the dCDh. Blockade of 5-HT 4 R significantly increased error rates in a goal-directed delayed reward task, indicating an increase in the rate of temporal discounting. This increase was specific to the 5-HT 4 R blockade because saline controls showed no such effect. The results demonstrate that 5-HT 4 Rs in the dCDh are involved in reward-evaluation processes, particularly in the context of delay discounting, and suggest that serotonergic transmission via 5-HT 4 R may be a key component in the neural mechanisms underlying impulsive decisions, potentially contributing to depressive symptoms., (© 2024. The Author(s).)

The synthetic progestin, 17α-hydroxyprogesterone caproate (17-OHPC), is administered to pregnant individuals at risk for preterm birth and is likely transferred from mother to fetus. Yet, there is little information regarding the potential effects of 17-OHPC administration on behavioral and neural development in offspring. In rats, neonatal 17-OHPC exposure altered dopaminergic fiber distribution and density in the prelimbic medial prefrontal cortex (mPFC) in neonates and adolescents, respectively. Additionally, neonatal 17-OHPC exposure in male rats increased response omissions in a delay discounting task of impulsive decision-making. Because developmental 17-OHPC exposure has differential effects in males and females, investigating the effects of 17-OHPC on impulsive decision-making in female rats is necessary. The present study tested the effects of developmental 17-OHPC exposure (P1-P14) in a delay discounting task in which female rats chose between a small immediate reward and a larger delayed (0, 15 30, or 45 s) reward. 17-OHPC-exposed females made more omissions than controls. There was no effect of 17-OHPC on large reward preference nor on response time, and omissions were similar during both free- and forced-choice trials. The present study also aimed to investigate the neural mechanisms underlying omissions in 17-OHPC-exposed female rats. The dopamine transporter inhibitor, methylphenidate (MPH), was administered prior to delay discounting testing. MPH treatment did not reduce omissions in 17-OHPC-exposed females. If anything, MPH increased omissions in control females nearly fourfold during the longest delays. These results suggest that developmental 17-OHPC exposure increased omissions without affecting impulsivity or slowing decision-making. Furthermore, omissions may be regulated, at least in part, by dopaminergic mechanisms., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The relation between impulsivity and sleep indices is not well determined in patients receiving methadone maintenance treatment (MMT)., Aims: to evaluate high impulsivity prevalence, its risk factors and relation with sleep indices., Methods: a random MMT sample (n = 61) plus MMT current cocaine users (n = 20) were assessed for impulsivity (Barratt impulsivity scale [BIS-11] and Balloon Analogue Risk task [BART]), sleep quality (Pittsburg Sleep Quality Index [PSQI]), sleepiness (The Epworth sleepiness scale [ESS]), and substance in urine., Results: 81 patients, aged 56.6 ± 10, 54.3% tested positive to any substance, 53.1% with poor sleep (PSQI>5) and 43.2% with daytime sleepiness (ESS >7) were studied. Impulsivity (BIS-11 ≥ 72) prevalence was 27.9% (of the representative sample), and 30.9% of all participants. These patients characterized with any substance and shorter duration in MMT with no sleep indices or other differences including BART balloon task performance (that was higher only in any substance than non-substance user group). However, impulsive score linearly correlated with daytime sleepiness (R = 0.2, p = 0.05). Impulsivity proportion was lowest among those with no cocaine followed by cocaine use and the highest in those who used cocaine and opiates (20.8%, 33.3% and 60% respectively, p = 0.02), as daily sleep (38.3%, 42.1% and 60%, p = 0.3) although not statistically significant., Conclusion: Daytime sleepiness correlated with impulsivity, but cocaine usage is the robust factor. Further follow-up is warranted to determine whether substance discontinuing will lead to a reduction in impulsivity, and improved vigilance. Sleep quality did not relate to daytime sleepiness and impulsivity and need further research., Competing Interests: Declaration of competing interest The authors have no disclosures to report., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

We examined associations between prenatal tobacco exposure (with and without cannabis exposure) and children's performance on laboratory measures of sustained attention, attentional set shifting, and working memory in middle childhood (9-12 years of child age). Participants were recruited in the first trimester of pregnancy and oversampled for prenatal tobacco exposure; with a smaller sample (n = 133; n = 34 non-substance exposed, n = 37 exposed to tobacco only, n = 62 co-exposed) invited (oversampled for co-exposure) to participate in the middle-childhood assessment (M age = 10.6, SD = 0.77; 68% Black, 20% Hispanic). Results for sustained attention indicated lower attention (percent hits) at the first epoch for tobacco only exposed compared to non-exposed and co-exposed; a trend (p = .07) towards increases in impulsive responding across time (a total of 8 epochs) for tobacco exposed (with and without cannabis) compared to non-exposed children; and a significant association between higher number of cigarettes in the first trimester and greater increases in impulsive responding across epochs. However, children prenatally exposed to tobacco (with and without cannabis) demonstrated greater short-term memory compared to children not prenatally exposed, and this difference was driven by higher scores for children prenatally co-exposed to tobacco and cannabis compared to those who were non-exposed. Overall, results suggest that prenatal tobacco exposure, especially in the first trimester, may increase risk for impulsive responding on tasks requiring sustained attention, and that co-use of cannabis did not exacerbate these associations. The higher short-term memory scores among children who were co-exposed compared to non-exposed are perplexing and need replication, particularly in studies with larger sample sizes and samples exposed only to cannabis to examine this more closely., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: The Default Mode Network (DMN) is a central neural network, with recent evidence indicating that it is composed of functionally distinct sub-networks. Methylphenidate (MPH) administration has been shown before to modulate impulsive behavior, though it is not yet clear whether these effects relate to MPH-induced changes in DMN connectivity. To address this gap, we assessed the impact of MPH administration on functional connectivity patterns within and between distinct DMN sub-networks and tested putative relations to variability in sub-scales of impulsivity., Methods: Fifty-five right-handed healthy adults underwent two resting-state functional MRI (rs-fMRI) scans, following acute administration of either MPH (20 mg) or placebo, via a randomized double-blind placebo-controlled design. Graph modularity analysis was implemented to fractionate the DMN into distinct sub-networks based on the impact of MPH (vs. placebo) on DMN connectivity patterns with other neural networks., Results: MPH administration led to an overall decreased DMN connectivity, particularly with the auditory, cinguloopercular, and somatomotor networks, and increased connectivity with the parietomedial network. Graph analysis revealed that the DMN could be fractionated into two distinct sub-networks, with one exhibiting MPH-induced increased connectivity and the other decreased connectivity. Decreased connectivity of the DMN sub-network with the cinguloopercular network following MPH administration was associated with elevated impulsivity and non-planning impulsiveness., Conclusion: Current findings highlight the intricate effects of MPH administration on DMN rs-fMRI connectivity, uncovering its opposing impact on distinct DMN sub-divisions. MPH-induced dynamics in DMN connectivity patterns with other neural networks may account for some of the effects of MPH administration on impulsive behavior., (© 2024. The Author(s).)

Aims: Abuse of methamphetamine has aroused concern worldwide. Stimulant use and sexual behaviours have been linked in behavioural and epidemiological studies. Although methamphetamine-related neurofunctional differences are reported in previous studies, only few studies have examined neurofunctional changes related to methamphetamine and sexual cues in methamphetamine dependence from short- to long-term abstinence., Methods: Neurofunctional changes were measured using a cue-reactivity task involving methamphetamine, sexual, and neutral cues in 20 methamphetamine abusers who were evaluated after a short- (1 week to 3 months) and long-term (10-15 months) abstinence., Results: Five brain regions mainly involved in the occipital lobe and the parietal lobe were found with the group-by-condition interaction. Region-of-interest analyses found higher sexual-cue-related activation than other two activations in all five brain regions in the long-term methamphetamine abstinence group while no group differences were found. Negative relationships between motor impulsivity and methamphetamine- or sexual-cue-related activations in the left middle occipital gyrus, the superior parietal gyrus and the right angular gyrus were found., Conclusions: The findings suggested that methamphetamine abstinence may change the neural response of methamphetamine abusers to methamphetamine and sexual cues, and the neurofunction of the five brain regions reported in this study may partly recover with long-term methamphetamine abstinence. Given the use and relapse of methamphetamine for sexual purposes, the findings of this study may have particular clinical relevance., (© 2024 The Author(s). Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Background: A better understanding of the neural mechanisms regulating impaired satiety to palatable foods is essential to treat hyperphagia linked with obesity. The satiation hormone amylin signals centrally at multiple nuclei including the ventral tegmental area (VTA). VTA-to-medial prefrontal cortex (mPFC) projections encode food reward information to influence behaviors including impulsivity. We hypothesized that modulation of VTA-to-mPFC neurons underlies amylin-mediated decreases in palatable food-motivated behaviors., Methods: We used a variety of pharmacological, behavioral, genetic, and viral approaches (n = 4-16/experiment) to investigate the anatomical and functional circuitry of amylin-controlled VTA-to-mPFC signaling in rats., Results: To first establish that VTA amylin receptor (calcitonin receptor) activation can modulate mPFC activity, we showed that intra-VTA amylin decreased food-evoked mPFC cFos. VTA amylin delivery also attenuated food-directed impulsive behavior, implicating VTA amylin signaling as a regulator of mPFC functions. Palatable food activates VTA dopamine and mPFC neurons. Accordingly, dopamine receptor agonism in the mPFC blocked the hypophagic effect of intra-VTA amylin, and VTA amylin injection reduced food-evoked phasic dopamine levels in the mPFC, supporting the idea that VTA calcitonin receptor activation decreases dopamine release in the mPFC. Surprisingly, calcitonin receptor expression was not found on VTA-to-mPFC projecting neurons but was instead found on GABAergic (gamma-aminobutyric acidergic) interneurons in the VTA that provide monosynaptic inputs to this pathway. Blocking intra-VTA GABA signaling, through GABA receptor antagonists and DREADD (designer receptor exclusively activated by designer drugs)-mediated GABAergic neuronal silencing, attenuated intra-VTA amylin-induced hypophagia., Conclusions: These results indicate that VTA amylin signaling stimulates GABA-mediated inhibition of dopaminergic projections to the mPFC to mitigate impulsive consumption of palatable foods., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Pramipexole is a potent agonist of D 3 and D 2 dopamine receptors, currently approved for clinical use in Parkinson's disease (PD) and restless leg syndrome. Several studies have shown that pramipexole significantly increases the risk of pathological gambling and impulse-control disorders. While these iatrogenic complications can impose a severe social and financial burden, their treatment poses serious clinical challenges. Our group previously reported that the steroidogenic inhibitor finasteride reduced pathological gambling severity in PD patients who developed this complication following pramipexole treatment. To study the mechanisms underlying these effects, here we tested the impact of finasteride in a rat model of pramipexole-induced alterations of probability discounting. We previously showed that, in rats exposed to low doses of the monoamine-depleting agent reserpine (1 mg/kg/day, SC), pramipexole (0.3 mg/kg/day, SC) increased the propensity to engage in disadvantageous choices. This effect was paralleled by a marked D 3 receptor upregulation in the nucleus accumbens. First, we tested how finasteride (25-50 mg/kg, IP) intrinsically affects probability discounting. While the highest dose of finasteride produced a marked lack of interest in lever pressing (manifested as a significant increase in omissions), the 25 mg/kg (IP) dose did not intrinsically modify probability discounting. However, this finasteride regimen significantly reduced the adverse effects of reserpine and pramipexole in probability discounting by diminishing rats' propensity to engage in highly disadvantageous probabilistic choices. The same regimen also reversed the upregulation of D 3 receptors in the nucleus accumbens induced by reserpine and pramipexole. These findings confirm that finasteride opposes the impulsivity caused by pramipexole and suggest that this effect may be underpinned by a normalizing effect on D 3 receptor expression in the nucleus accumbens., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Traumatic brain injury (TBI) impacts millions worldwide and can cause lasting psychiatric symptoms. Chronic neuroinflammation is a characteristic of post-injury pathology and is also associated with psychiatric conditions such as ADHD and bipolar disorder. Therefore, the current study sought to determine whether TBI-induced impulsivity and inattention could be treated using minocycline, an antibiotic with anti-inflammatory properties. Rats were trained on the five-choice serial reaction time task (5CSRT), a measure of motor impulsivity and attention. After behavior was stable on the 5CSRT, rats received either a bilateral frontal TBI or sham procedure. Minocycline was given at either an early (1 h post-injury) or chronic (9 weeks post-injury) timepoint. Minocycline was delivered every 12 h for 5 days (45 mg/kg, i.p.). Behavioral testing on the 5CSRT began again after one week of recovery and continued for 12 more weeks, then rats were transcardially perfused. Impulsivity and inattention were both substantially increased following TBI. Minocycline had no therapeutic effects at either the early or late time points. TBI rats had increased lesion volume, but minocycline did not attenuate lesion size. Additionally, microglia count measured by IBA-1 + cells was only increased acutely after TBI, and minocycline did not differentially change the number of microglia in TBI rats. Despite this, minocycline had clear effects on the gut microbiome. Based on the results of this study, minocycline may have limited efficacy for post-injury psychiatric-like symptoms., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: It is known that increased impulsivity in schizophrenia patients causes poor treatment outcomes by increasing cost, stigma, hospitalization, treatment challenge, and physical harm. Dysfunction in the prefrontal cortex appears to be involved in the impulsivity associated with schizophrenia; nonetheless, there is a dearth of research on specific white matter alterations in the prefrontal cortex related to impulsivity., Methods: We enrolled in the present study 119 first-episode schizophrenia patients. We measured their symptom severity at baseline and after eight weeks of treatment, using the positive and negative syndrome scale. We performed neuroimaging analysis using the Tract-Based Spatial Statistics program and by specifying the prefrontal white matter as a region of interest., Results: In voxel-wise correlational analysis, we observed white matter regions showing significant positive correlations with poor impulse control scores, in both the right dorsolateral prefrontal cortex and the right frontal pole region. The fractional anisotropy values of these areas correlated positively with symptom severity at baseline. Moreover, after eight weeks, treatment non responders showed significantly higher fractional anisotropy values in the same areas., Conclusions: The results of the present study suggest that white matter tracts in the right dorsolateral prefrontal cortex and the right frontal pole may underlie dysfunctional impulse control and could be potential predictive markers for short-term treatment in patients with first-episode schizophrenia., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Stimulant drug-paired cues can acquire the ability to activate mesocorticolimbic pathways and lead to new bouts of drug use. Studies in laboratory animals suggest that these effects are augmented by progressively greater drug use histories, impulsive personality traits, and acute drug ingestion. As a preliminary test of these hypotheses in humans, we exposed cocaine users (n = 14) and healthy volunteers (n = 10) to cocaine-related videos during two functional magnetic resonance imaging (fMRI) sessions, once following acute administration of placebo and once following d-amphetamine (0.3 mg/kg, p.o.). Across sessions, cocaine users showed larger cocaine cue-induced responses than healthy controls in the associative striatum and midbrain. Among the cocaine users, larger drug cue-induced responses during the placebo session were correlated with higher Barratt Impulsiveness Scale (BIS-11) nonplanning scores (associative striatum) and greater lifetime use of stimulant drugs (limbic, associative, and sensorimotor striatum). The administration of d-amphetamine did not augment the cue-induced activations, but, in cocaine users, drug cue-induced striatal activations were more widespread following prolonged cocaine cue exposure. Together, these effects of past and present drug use might aggravate the risk for stimulant drug use problems., (© 2021 Society for the Study of Addiction.)

Long-term opioid abuse causes a variety of long-lasting cognitive impairments such as attention, impulsivity and working memory. These cognitive impairments undermine behavioural treatment for drug abuse and lead to poor treatment retention and outcomes. Modafinil is a wake-promoting drug that shows potential in improving attention and memory in humans and animals. However, modafinil's effect on opioid-induced cognitive impairments remains unclear, and the underlying mechanism is poorly understood. This study showed that repeated morphine administration significantly impairs attention, increases impulsivity and reduces motivation to natural rewards in mice. Systemic modafinil treatment at low dose efficiently ameliorates morphine-induced attention dysfunction and improves motivation and working memory in mice. High dose of modafinil has adverse effects on impulsive action and attention. Local infusion of D1R antagonist SCH-23390 reverses the morphine-induced synaptic abnormalities and activation of the D1R-ERK-CREB pathway in medial prefrontal cortex (mPFC). This study demonstrated a protective effect of modafinil in mPFC neurons and offered a therapeutic potential for cognitive deficits in opioid abuse., (© 2021 Society for the Study of Addiction.)

Impulsive action can be defined as the inability to withhold a response and represents one of the dimensions of the broad construct impulsivity. Here, we characterized a modified differential reinforcement of low rates of responding (DRL) task developed in our laboratory, in which impulsive action is measured in ad libitum fed/watered subjects. Specifically, we first determined the effects of both sex and estrous cycle on impulsive action by systematically comparing male and estrous-synchronized female subjects. In addition, we evaluated the convergent validity of this modified DRL task by testing the effects of the D 2 R/5HT 2A R antagonist, aripiprazole, and the noncompetitive NMDAR antagonist, MK-801. Finally, we tested the effects of the selective antagonist BD-1063 and agonist PRE-084 of Sigma-1 receptor (Sig-1R) on impulsive action using this modified DRL task. We found that female rats showed and increased inability to withhold a response when compared to males, and this effect was driven by the metestrus/diestrus phase of the estrous cycle. In addition, aripiprazole and MK-801 fully retained their capability to reduce and increase impulsive action, respectively. Finally, the selective Sig-1R antagonist, BD-1063 dose-dependently reduced the inability to withhold a response in both sexes, though more potently in female rats. In summary, we show that impulsive action, as measured in a modified DRL task which minimizes energy-homeostatic influences, is a function of both sex and estrous cycle. Furthermore, we validate the convergent validity of the task and provide evidence that Sig-1R antagonism may represent a novel pharmacological strategy to reduce impulsive action., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Cannabis exposure during adolescence is associated with emotional and motivational alterations that may entail an enhanced risk of developing psychiatric disorders. In rodent models, exposure to cannabinoids during adolescence leads to increased self-administration of opiates and cocaine, however, the psychological and neural mechanisms and the sex-specificity of this phenomenon are largely unknown., Methods: We exposed male and female adolescent rats to Δ9-tetrahydrocannabinol (THC) and studied at adulthood the effects of such treatment on psychological processes related to reward, such as Pavlovian conditioned approach, Pavlovian to instrumental transfer, habit formation and waiting impulsivity. In the light of these data and given the involvement of the nucleus accumbens in the processes examined, we performed an RNASeq transcriptomic study and assessed cocaine addiction-like behavior., Results: THC exposure increased goal-tracking (in males and females) and enhanced Pavlovian to instrumental transfer (especially in males) but did not affect habit formation. THC-exposed rats exhibited subtle, state-dependent changes in premature responding in the 2-CSRTT task. RNASeq data showed gene expression alterations in a marked sex-specific manner. While no effects were found on the acquisition of cocaine self-administration or punished drug-seeking, rats exposed to THC self-administered more cocaine under a progressive ratio schedule (males), had a higher rebound upon returning to continuous access to the drug (females) and showed reduced drug-seeking after 30 days of withdrawal (females)., Conclusions: Adolescent THC affects specific aspects of reward- (and cocaine-) guided behavior and the function of a key brain region mediating these effects, in a remarkable sex-specific manner., (© The Author(s) 2021. Published by Oxford University Press on behalf of CINP.)

Gambling and substance use disorders are highly comorbid. Both clinical populations are impulsive and exhibit risky decision-making. Drug-associated cues have long been known to facilitate habitual drug-seeking, and the salient audiovisual cues embedded within modern gambling products may likewise encourage problem gambling. The dopamine neurons of the ventral tegmental area (VTA) are exquisitely sensitive to drugs of abuse, uncertain rewards, and reward-paired cues and may therefore be the common neural substrate mediating synergistic features of both disorders. To test this hypothesis, we first gained specific inhibitory control over VTA dopamine neurons by transducing a floxed inhibitory DREADD (AAV5-hSyn-DIO-hM4D(Gi)-mCherry) in rats expressing Cre recombinase in tyrosine hydroxylase neurons. We then trained rats in our cued rat gambling task (crGT), inhibiting dopamine neurons throughout task acquisition and performance, before allowing them to self-administer cocaine in the same diurnal period as crGT sessions. The trajectories of addiction differ in women and men, and the dopamine system may differ functionally across the sexes; therefore, we used male and female rats here. We found that inhibition of VTA dopamine neurons decreased cue-induced risky choice and reduced motor impulsivity in males, but surprisingly, enhanced risky decision making in females. Inhibiting VTA dopamine neurons also prevented cocaine-induced changes in decision making in both sexes, but nevertheless drove all animals to consume more cocaine. These findings show that chronic dampening of dopamine signalling can have both protective and deleterious effects on addiction-relevant behaviours, depending on biological sex and dependent variable of interest., (© 2021 Society for the Study of Addiction.)

Purpose/background: The link between substances of abuse, impulsivity, and violence in psychotic patients remains unclear. This study aims at unraveling whether cannabis use disorder is associated with violent and/or psychotic behavior in patients who are hospitalized in a high-security hospital., Methods/procedures: We conducted a cross-sectional retrospective study in 124 patients with schizophrenia spectrum disorders admitted to a high-security hospital. Lifetime violent behavior was assessed using the History of Aggressive Behavior Form-Subject of the MacArthur Violence Risk Assessment Study and impulsivity using the Psychopathy Checklist-Revised (considering items: "proneness to boredom," "lack of self-control," and "impulsive thoughtless gestures"). Substance use disorder was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. Positive and Negative Syndrome Scale was also administered., Findings/results: Violent and nonviolent psychotic patients showed similar prevalence of cannabis use disorder. Alcohol and cocaine use disorders were more prevalent among violent psychotic patients. Cannabis use disorder was not associated with any dimension of impulsivity, whereas alcohol use disorder was positively correlated to impulsive thoughtless gestures (standardized β = 0.213, P = 0.027) and cocaine use disorder with proneness to boredom (standardized β = 0.290, P = 0.002). Finally, logistic regression analysis revealed that, unlike cannabis and cocaine use disorders, alcohol use disorder (odds ratio, 3.964; 95% confidence interval, 1.729-9.087; P = 0.001) was a factor associated with violence., Implications/conclusions: These findings show that cannabis and alcohol are largely abused and coabused by psychotic patients with a propsensity for violence, but only alcohol is associated with impulsive and violent behavior. Therefore, especially alcohol abuse should be seriously considered by practitioners when evaluating the dangerousness of patients with schizophrenia spectrum disorders., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

In humans, adverse childhood experiences are associated with an increased risk of developing a neuropsychiatric disorder. Changes in social behavior and cognitive function are hallmarks of numerous neuropsychiatric disorders. Here we examined the effects of exposure to variable stress during the juvenile period on social behavior, reward, and cognitive function (as measured in the 5-choice serial reaction time task (5CSRTT)) in rats. From postnatal days (PND) 25-29 male and female rats were exposed to a variable stress protocol. In adulthood, social interactions and sucrose preference were assessed prior to training on the 5CSRTT. Once successfully trained, rats were challenged with different task versions, and then the effects of cocaine (0, 10, or 20 mg/kg, IP) on performance were assessed. A follow-up experiment examined the ability of the D2 receptor antagonist eticlopride (0.0, 0.025, 0.05 mg/kg, IP) to block the effects of cocaine on 5CSRTT performance in female rats. Male rats exposed to juvenile stress tended to engage in less social behavior and had an increased correct response latency in the 5CSRTT following cocaine administration. Female rats exposed to juvenile stress exhibited a trend towards increased social behavior and demonstrated increased cocaine-induced impulsivity. The increase in impulsivity was not blocked by co-administration of eticlopride. Juvenile stress had minimal effects on adult behavior in male rats, but increased cocaine-induced impulsivity in female rats. Such an effect could contribute to the enhanced escalation of drug-use observed in females that experience juvenile stress. This possibility awaits further testing., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Considerable evidence supports an association between poor impulse control (impulsivity) and violent crime. Furthermore, impulsivity and aggression has been associated with reduced levels of serotonergic activity in the brain. Selective serotonin reuptake inhibitors (SSRIs) are a class of anti-depressants that aim to regulate brain serotonin concentrations. Several small studies in psychiatric populations have administered SSRIs to impulsive--aggressive individuals, resulting in reduced impulsivity, anger, aggression and depression. However, no clinical trial has been undertaken in a criminal justice population. This protocol describes the design and implementation of the first systematic study of the potential benefits of SSRIs in impulsive---violent offenders who are at high risk of reoffending., Methods and Analysis: A randomised, double-blinded, multicentre trial to test the clinical efficacy of an SSRI, sertraline hydrochloride, compared with placebo on recidivism and behavioural measures (including impulsivity, anger, aggression, depression and self-reported offending) over 12 months. 460 participants with histories of violence and screening positive for impulsivity are recruited at several local courts and correctional service offices in New South Wales, Australia., Ethics and Dissemination: Results will be submitted for publication in a peer-reviewed journal. Possible implications of the effectiveness of this pharmacological intervention include economic benefits of reducing prison costs and societal benefits of improving safety. This study has received ethical approval from the University of New South Wales, Aboriginal Health & Medical Research Council, Corrective Services NSW and the NSW Justice Health and Forensic Mental Health Network., Trial Registration Number: ACTRN12613000442707., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: "Impulse Control Disorders" are behavioral conditions (e.g., gambling, hypersexuality), which are increasingly reported as reactions to dopamine agonists in Parkinson's disease. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease focuses only on 6 behaviors. Nonetheless, impulsivity could affect the entire range of human practices. Because of their heterogeneity and undefined boundaries, it is not clear what conditions should be considered as Impulse Control Disorders. This results in poorly standardized scientific literature and underdiagnosis., Objective: We aimed to create a comprehensive list of possible manifestations of drug-induced Impulse Control Disorders in Parkinson's disease and test it on pharmacosurveillance data., Methods: PubMed was used to identify reviews in English about Impulse Control Disorders in Parkinson's disease. Mentioned conditions were charted and translated to the lexicon of MedDRA, ICD-11, and DSM-5. The relevant MedDRA terms were used to test potential association with dopamine agonists on the FDA Adverse Event Reporting System., Results: 50 reviews published between 2001 and 2020 were identified. 66 conditions were collected as possible Impulse Control Disorders. Pathological gambling, shopping, eating and sexuality, dopamine dysregulation syndrome, hobbyism and punding were the most frequently mentioned, together with leisure activities, body-focused compulsivity, disruptive, impulse control and conduct disorders, and substance abuse. All these conditions were disproportionately reported with dopamine agonists, except for substance abuse., Conclusions: We defined a potential extended list of ICDs, which, along with its conversion to international taxonomies, can support the identification of drug-induced conditions in pharmacovigilance archives, as well as monitoring processes in clinical practice., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Standard treatment of Parkinson's disease involves the dopaminergic medications. Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an important neurosurgical intervention often used as alternative treatment to drug therapy; however, it can be associated with increase of impulsive behaviors. This descriptive review focused on studies investigating the correlation between Deep brain stimulation of the subthalamic nucleus and impulsivity in Parkinson's disease patients, arguing, the action's mechanism and the specific role of the subthalamic nucleus. We searched on PubMed and Web of Science databases and screening references of included studies and review articles for additional citations. From initial 106 studies, only 15 met the search criteria. Parkinson's Disease patients with and without Deep Brain Stimulation were compared with healthy controls, through 16 different tasks that assessed some aspects of impulsivity. Both Deep brain stimulation of the subthalamic nucleus and medication were associated with impulsive behavior and influenced decision-making processes. Moreover, findings demonstrated that: Impulse Control Disorders (ICDs) occurred soon after surgery, while, in pharmacological treatment, they appeared mainly after the initiation of treatment or the increase in dosage, especially with dopamine agonists. The subthalamic nucleus plays a part in the fronto-striato-thalamic-cortical loops mediating motor, cognitive, and emotional functions: this could explain the role of the Deep Brain Stimulation in behavior modulation in Parkinson's Disease patients. Indeed, increase impulsivity has been reported also after deep brain stimulation of the subthalamic nucleus independently by dopaminergic medication status., (© 2021. The Author(s).)

Amphetamine (AMP) and atomoxetine (ATX) represent two of the most widely studied drug treatments used in the investigation of impulsive behaviour. While both drugs have relatively well defined effects in tests designed to investigate impulsive action (e.g. 5-choice task; 5-CSRTT), the effects of both drugs in tests of impulsive choice (e.g. delay discounting) are less consistent. In the present study both AMP and ATX were tested in a rodent gambling task (rGT) and delay discounting in rats separately trained to either an ascending or descending delay schedule. Effects of both drugs were compared to measures of impulsive action (premature (PREM) responses) and perseverative (PSV) responses measured in the 5-choice and rGT tasks. Consistent with previous studies, AMP (0.1-1 mg/kg) increased both PREM and PSV responses, and ATX (0.5-2 mg/kg) reduced both measures in the 5-choice and rGT tasks. At equivalent doses ATX had no reliable effect on choice behaviour in either the rGT or delay discounting suggesting a null effect of this drug on impulsive choice and risky decision making. The effects of AMP were more complex, with a subtle shift in preference to a low risk (P1) choice in the rGT, and an effect on discounting that was unrelated to reinforcer value, but instead dependent on delay sequence and baseline choice preference. One aspect to these outcomes is to highlight the importance of multiple methodological factors when assessing drug effects on complex behaviours such as impulsive choice, and question what are the most appropriate test conditions under which to examine these drugs on discounting., (Copyright © 2021. Published by Elsevier Inc.)

Rationale: Noradrenaline (NE) is closely related to attentive performance and impulsive control. However, the potential sex differences regarding attention and impulsivity under the noradrenergic modulation have been largely neglected. Therefore, our study aimed to investigate whether male and female rats exhibit differential responses to NE-related drugs during the five-choice serial reaction time task (5CSRT)., Methods: Male and female rats were trained in 5CSRT and administered with different NE drugs after obtaining stable baseline performance: atipamezole, a highly selective α2 receptor antagonist; prazosin, an α1 receptor antagonist; and atomoxetine, a selective NE reuptake inhibitor. Later, prazosin was selected to co-administration with atomoxetine., Results: Male and female rats exhibited equal learning speed, and no significant baseline differences were found as measured by the 5CSRT. Atomoxetine decreased premature responses in both sexes, but the extent of this reduction was different, with the reduction greater in males. Besides, atomoxetine (1.8 mg/kg) increased the error of omissions in females. The high dose of prazosin (0.5 mg/kg) decreased the accuracy only in male rats, but this was ameliorated by the co-administration with atomoxetine., Conclusions: Atomoxetine showed significant improvement in impulsivity, but atomoxetine had less beneficial effects on impulsive control in females than in males, and it even impaired attentional performance in female rats. The α1 receptors were mainly responsible for NE drug-related sex differences in attention rather than impulsivity. The results obtained in this study indicate that the sex differences exist in both attention and impulsivity by the modulation of noradrenaline and raise the concern to improve sex-specific treatments., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Altered interactions between endocannabinoid and glutamate signaling may be involved in the pathophysiology of schizophrenia and acute psychosis. As cognitive disturbances are involved in schizophrenia, increased understanding of the roles of these neurotransmitter systems in cognition may lead to the development of novel therapeutics for disorder. In the present study, we examined the effects of a recently synthesized cannabinoid receptor 1 (CB1R) positive allosteric modulator GAT211 in a rodent model of acute psychosis induced by systemic treatment with MK-801. To assess cognitive function, we used the Five-Choice Serial Reaction Time (5CSRT) task, conducted in touchscreen-equipped operant conditioning chambers. Our measures of primary interest were accuracy - indicative of visual attentional capacity - and the number of premature responses - indicative of impulsivity. We also measured latencies, omissions, and perseverative responding during all test sessions. Thirteen adult male Long Evans rats were trained on the 5CSRT and were then tested using a repeated measures design with acute MK-801 (0 or 0.15 mg/kg, i.p.) and GAT211 (0, 3, or 10 mg/kg, i.p.) administration. Acute MK-801 severely impaired accuracy, increased omissions, and increased the number of premature responses. MK-801 also significantly increased correct response latencies, without significant effects on incorrect or reward correction latencies. GAT211 had no significant effects when administered alone, or in combination with acute MK-801. These data confirm the dramatic effects of acute MK-801 treatment on behavioral measures of attention and impulsivity. Continued investigation of CB1R positive allosteric modulators as potential treatments for the cognitive symptoms of schizophrenia and related disorders should be pursued in other rodent models., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Rationale: There is increasing interest in and evidence for the negative impacts of cannabis use in cognitive performance and symptoms of attention-deficit/hyperactivity disorder (ADHD), with age of first cannabis use as a potential amplifier of these associations. However, the existing literature is inconsistent, which may be due to methodological limitations, including small sample sizes., Objective: To examine current cannabis use and age of first cannabis use in relation to neurocognitive task performance and ADHD symptoms in a large sample of binge-drinking young adults., Methods: Participants were young adults (N=730, M age=21.44, 52.6% female) assessed for current cannabis use, neurocognitive task performance, and ADHD symptoms. Three-group ANCOVAs compared individuals reporting frequent (daily/multiple times daily), occasional (weekly/monthly), or no cannabis use., Results: Covarying alcohol use, tobacco use, age, sex, income, and education, daily cannabis users exhibited significantly more impulsive delay discounting and hyperactive-impulsive ADHD symptoms compared to both other groups. However, cannabis use was not associated with inattentive ADHD symptoms, verbal intelligence, working memory, probability discounting, short-term verbal memory, or behavioral inhibition. Age of initiation of cannabis use exhibited neither main effects nor interactions in relation to any domains of cognitive performance or ADHD symptomatology., Conclusions: The current findings provide support for a link between cannabis use in relation to immediate reward preference and symptoms of hyperactive-impulsive ADHD in young adults, but only among frequent users. No other neurocognitive domains exhibited associations with cannabis and age of first use was neither independently nor interactively associated with cognitive outcomes.

Animal and human studies show that cannabis or its derivatives can increase relapse to cocaine seeking following withdrawal. Moreover, cannabis use in humans is associated with impulse control deficits and animal studies implicate endogenous cannabinoids (eCB) in several impulsivity constructs. However, the brain areas where cannabinoids might control impulsivity or cocaine seeking are largely unknown. Here, we assess Lateral Habenula (LHb) involvement on performance in the 5-choice serial reaction time task (5CSRTT) in rats and investigate whether LHb cannabinoid CB1 receptors (CB1R) are involved in these effects. Systemic cocaine increased premature responding, a measure of impulsivity, at a dose (5 mg/kg) that did not alter other measures of task performance. Intra-LHb infusion of the CB1R antagonist AM251 blocked this effect. Systemic injection of the psychoactive constituent of cannabis, Δ 9 -tetrahydrocannabinol (Δ 9 -THC, 1 mg/kg), also increased 5CSRTT premature responding at a dose that did not otherwise disrupt task performance. This was blocked by intra-LHb infusion of AM251 in a subgroup of rats showing the largest increases in Δ 9 -THC-evoked premature responses. Systemic Δ 9 -THC also prompted impulsive cocaine seeking in a Go/NoGo cocaine self-administration task and this was blocked by intra-LHb AM251. These data show that LHb CB1Rs are involved in deficits in impulse control initiated by cocaine and Δ 9 -THC, as assessed by the 5CSRTT, and play a role in impulsive cocaine seeking during cocaine self-administration. This suggests that the LHb eCB system contributes to the control of impulsive behavior, and thus represents a potential target for therapeutic treatment of substance use disorders (SUDs) in humans., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Rationale: The flashing lights and sounds of modern casinos are alluring and may contribute to the addictive nature of gambling. Such cues can have a profound impact on the noradrenaline (NA) system, which could therefore be a viable therapeutic target for gambling disorder (GD). While there is substantial evidence to support the involvement of NA in the impulsive symptoms of GD, its function in mediating the "pro-addictive" impact of cues is less understood., Objective: We wished to investigate the role of NA in our rodent assay of decision making and impulsivity, the cued rat gambling task (crGT). Given that sex differences are prominent in addiction disorders, and increasingly reported in the monoaminergic regulation of behaviour, we also prioritised evaluating noradrenergic drugs in both sexes., Methods: Female and male rats were trained to stability on the crGT and then given intraperitoneal injections of the noradrenaline reuptake inhibitor atomoxetine, the α 2A receptor agonist guanfacine, the beta receptor antagonist propranolol, and the α 2 receptor antagonist yohimbine., Results: Atomoxetine dose-dependently improved decision-making score. Guanfacine selectively enhanced decision making in risk-preferring males and optimal performing females. Propranolol and yohimbine did not influence decision making. Atomoxetine and guanfacine reduced premature responses, while yohimbine bi-phasically affected this index of motor impulsivity., Conclusions: These results support the hypothesis that NA is an important neuromodulator of the cue-induced deficits in decision making observed in laboratory-based gambling paradigms, and suggest that NAergic drugs like atomoxetine and guanfacine may be useful in treating GD.

Pathological impulsivity is a debilitating symptom of multiple psychiatric diseases with few effective treatment options. To identify druggable receptors with anti-impulsive action we developed a systematic target discovery approach combining behavioural chemogenetics and gene expression analysis. Spatially restricted inhibition of three subdivisions of the prefrontal cortex of mice revealed that the anterior cingulate cortex (ACC) regulates premature responding, a form of motor impulsivity. Probing three G-protein cascades with designer receptors, we found that the activation of G i -signalling in layer-5 pyramidal cells (L5-PCs) of the ACC strongly, reproducibly, and selectively decreased challenge-induced impulsivity. Differential gene expression analysis across murine ACC cell-types and 402 GPCRs revealed that - among G i -coupled receptor-encoding genes - Grm2 is the most selectively expressed in L5-PCs while alternative targets were scarce. Validating our approach, we confirmed that mGluR2 activation reduced premature responding. These results suggest G i -coupled receptors in ACC L5-PCs as therapeutic targets for impulse control disorders.

The concept of 'impulse control' has its roots in early psychiatry and today has progressed into a well-described, although poorly understood, multidimensional endophenotype underlying many neuropsychiatric disorders (e.g., attention deficit hyperactivity disorder, schizophrenia, substance use disorders). There is mounting evidence suggesting that the cognitive and/or behavioral dimensions underlying impulsivity are driven by dysfunctional glutamate (Glu) neurotransmission via targeted ionotropic Glu receptor (GluR) [e.g., N-methyl-D-aspartate receptor (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)] mechanisms and associated synaptic alterations within key brain nodes. Ketamine, a noncompetitive NMDAR antagonist and FDA-approved for treatment-resistant depression, induces a 'glutamate burst' that drives resculpting of the synaptic milieu, which lasts for several days to a week. Thus, we hypothesized that single and repeated treatment with a subanesthetic ketamine dose would normalize motor impulsivity. Next, we hypothesized that AMPAR positive allosteric modulation, alone or in combination with ketamine, would attenuate impulsivity and provide insight into the mechanisms underlying GluR dysfunction relevant to motor impulsivity. To measure motor impulsivity, outbred male Sprague-Dawley rats were trained on the one-choice serial reaction time task. Rats pretreated with single or repeated (3 days) administration of ketamine (10 mg/kg; i.p.; 24-h pretreatment) or with the AMPAkine HJC0122 (1 or 10 mg/kg; i.p.; 30-min pretreatment) exhibited lower levels of motor impulsivity vs. control. Combination of single or repeated ketamine plus HJC0122 also attenuated motor impulsivity vs. control. We conclude that ligands designed to promote GluR signaling represent an effective pharmacological approach to normalize impulsivity and subsequently, neuropsychiatric disorders marked by aberrant impulse control., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Alterations of monoamine transmission in mesocorticolimbic regions have been suggested in the pathophysiology of attention deficit/hyperactivity disorder (ADHD). The habenula is an important brain area in regulation of monoamine transmission. In this study, we investigated behavioral and electrophysiological alterations induced by neonatal habenula lesion (NHL) in rats. In NHL rats, age-dependent behavioral alterations relevant to the ADHD symptoms, such as hyperlocomotion, impulsivity, and attention deficit, were observed. Local field potentials (LFPs) in mesocorticolimbic regions of anesthetized rats were examined with in vivo electrophysiological recordings. Abnormally enhanced synchronization of slow (delta) and fast (gamma) LFP oscillations between the amygdala (AMY) and prefrontal cortex (PFC) was found in juvenile, but not in adult, NHL rats. We further examined the effects of an extract and the active compound from the perennial large brown algae Ecklonia stolonifera (ES), which have previously been demonstrated to modulate monoamine transmission, on these NHL-induced alterations. One week of ES extract treatments normalized the NHL-induced behavioral alterations, whereas the active compound fucosterol improved attention deficit and impulsivity, but not hyperlocomotion, in NHL rats. Consistent with the behavioral effects, ES extract treatments also normalized augmented AMY-PFC coupling. These results suggest that altered limbic-cortical information processing may be involved in ADHD-like behavioral alterations induced by NHL, which could be ameliorated by the natural substance, such as ES that affects monoamine transmission., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The purpose of this study was to investigate the complementary effects of polyphenolic compounds from pine bark extract (PE) as a strong antioxidative substrate on the symptoms of inattention and impulsivity in children with attention-deficit hyperactivity disorder (ADHD). This was a randomized, double-blind, crossover, placebo-controlled study that included two experimental units (4 weeks with PE supplementation and 4 weeks with placebo supplementation) separated by a 2-week washout period. ADHD participants were supplemented with 25 mg or 50 mg PE. We recruited 20 participants (17 boys and 3 girls) with a mean age of 10.0 ± 2.1 years. PE supplementation caused a significant reduction in the inattention and hyperactivity-impulsivity items of SNAP-IV. During the period of PE supplementation, the item of commissions in the Continuous Performance Test III (CPT III) significantly decreased, which was used to evaluate the symptoms of inattention and impulsivity. In addition, the erythrocytic reduced glutathione/oxidized glutathione ratio significantly increased, and the plasma TBARs level significantly decreased after 4 weeks of PE supplementation. However, there was no significant correlation between CPT III (commission) and antioxidative status indictors. PE supplementation may have potential effects of ameliorating inattention and impulsivity, and elevating the antioxidative status in children with ADHD., (© 2021 John Wiley & Sons, Ltd.)

Background: Gathering and evaluating information leads to better decisions, but often at cost. The balance between information seeking and exploitation features in neurodevelopmental, mood, psychotic and substance-related disorders. Serotonin's role has been highlighted by experimental reduction of its precursor, tryptophan., Aims: We tested the boundaries and applicability of this role by asking whether changes to information sampling would be observed following acute doses of serotonergic and catecholaminergic clinical treatments. We used a variant of the Information Sampling Task (IST) to measure how much information a person requires before they make a decision. This task allows participants to sample information until satisfied to make a choice., Methods: In separate double-blind placebo-controlled experiments, we tested 27 healthy participants on/off 20 mg of the serotonin reuptake inhibitor (SRI) citalopram, and 22 participants on/off 40 mg of the noradrenergic reuptake inhibitor atomoxetine. The IST variant minimised effects of temporal impulsivity and loss aversion. Analyses used a variety of participant prior expectations of sampling spaces in the IST, including a new prior that accounts for learning of likely states across trials. We analysed behaviour by a new method that also accounts for baseline individual differences of risk preference., Results: Baseline preferences demonstrated risk aversion. Citalopram decreased the expected utility of choices and probability of being correct based on informational content of samples collected, suggesting participants collected less useful information before making a choice. Atomoxetine did not influence information seeking., Conclusion: Acute changes of serotonin activity by way of a single SRI dose alter information-seeking behaviour.

Background: Pairing rewards with sensory stimulation, in the form of auditory and visual cues, increases risky decision-making in both rats and humans. Understanding the neurobiological basis of this effect could help explain why electronic gambling machines are so addictive, and inform treatment development for compulsive gambling and gaming. Numerous studies implicate the dopamine system in mediating the motivational influence of reward-paired cues; recent data suggest the cholinergic system also plays a critical role. Previous work also indicates that cholinergic drugs alter decision-making under uncertainty., Aims: We investigated whether the addition of reward-concurrent cues to the rat gambling task (crGT) altered the effects of peripherally administered cholinergic compounds., Methods: Muscarinic and nicotinic agonists and antagonists were administered to 16 male, Long-Evans rats trained on the crGT. Measures of optimal/risky decision-making and motor impulsivity were the main dependent variables of interest., Results: The muscarinic receptor antagonist scopolamine improved decision-making overall, decreasing selection of one of the risky options while increasing choice of the more advantageous options. The muscarinic agonist oxotremorine increased choice latency but did not significantly affect option preference. Neither the nicotinic antagonist mecamylamine nor the agonist nicotine affected choice patterns, but mecamylamine decreased premature responding, an index of motor impulsivity., Conclusions: These results contrast sharply from those obtained previously using the uncued rGT, and suggest that the deleterious effects of win-paired cues on decision-making and impulse control may result from elevated cholinergic tone.

Background : Methamphetamine use disorder (MUD) associates with cognitive impulsivity deficits. However, few studies have examined longitudinal changes in cognition, and it remains unclear if deficits resolve during early recovery. Objectives : To compare: (1) cognitive function of individuals with MUD at treatment onset and six-weeks later with controls tested over the same period; (2) cognitive changes in MUD-individuals who remained abstinent versus relapsed. Method : We recruited 108 participants meeting DSM-IV-TR criteria for methamphetamine dependence (81 males) and 50 demographically matched controls (38 males); 77 methamphetamine- dependent participants (59 males) and 48 controls (36 males) were retained at follow-up. We administered response inhibition, delay discounting and uncertainty-based decision-making tests at both endpoints. Relapse was defined as methamphetamine concentrations >0.4 ng/mg at follow-up in hair toxicology. Results : We found a significant time-by-group interaction on uncertainty-based decision-making (effect size: η 2  =  .05), although post-hoc tests to disentangle this interaction yielded inconclusive results ( p -range = .14-.40; BF 10 -range = 0.43-1.67). There were no significant time-by-group interactions on response inhibition or delay discounting, with the former likely a null effect ( η 2 -interaction = .003 and .02; BF incl   = 0.23 and 0.71). There were no significant differences in cognitive recovery between individuals who maintained abstinence (n = 12) versus relapsed (n = 65) ( η 2 -range = .003-.04), although evidence was inconclusive toward whether findings reflected true null effects ( BF incl -range = 0.33-0.75). Conclusion : We did not find evidence that MUD-related cognitive impulsivity deficits improve beyond practice effects over 6 weeks. Findings do not support previous, albeit conflicting, evidence of early recovery of cognitive deficits in MUD.

Background: Impulsivity and novelty preference are both associated with an increased propensity to develop addiction-like behaviors, but their relationship and respective underlying dopamine (DA) underpinnings are not fully elucidated., Methods: We evaluated a large cohort (n = 49) of Roman high- and low-avoidance rats using single photon emission computed tomography to concurrently measure in vivo striatal D2/3 receptor (D2/3R) availability and amphetamine (AMPH)-induced DA release in relation to impulsivity and novelty preference using a within-subject design. To further examine the DA-dependent processes related to these traits, midbrain D2/3-autoreceptor levels were measured using ex vivo autoradiography in the same animals., Results: We replicated a robust inverse relationship between impulsivity, as measured with the 5-choice serial reaction time task, and D2/3R availability in ventral striatum and extended this relationship to D2/3R levels measured in dorsal striatum. Novelty preference was positively related to impulsivity and showed inverse associations with D2/3R availability in dorsal striatum and ventral striatum. A high magnitude of AMPH-induced DA release in striatum predicted both impulsivity and novelty preference, perhaps owing to the diminished midbrain D2/3-autoreceptor availability measured in high-impulsive/novelty-preferring Roman high-avoidance animals that may amplify AMPH effect on DA transmission. Mediation analyses revealed that while D2/3R availability and AMPH-induced DA release in striatum are both significant predictors of impulsivity, the effect of striatal D2/3R availability on novelty preference is fully mediated by evoked striatal DA release., Conclusions: Impulsivity and novelty preference are related but mediated by overlapping, yet dissociable, DA-dependent mechanisms in striatum that may interact to promote the emergence of an addiction-prone phenotype., (© The Author(s) 2020. Published by Oxford University Press on behalf of CINP.)

Impulse control deficits are often found to co-occur with substance use disorders (SUDs). On the one hand, it is well known that chronic intake of drugs of abuse remodels the brain with significant consequences for a range of cognitive behaviors. On the other hand, individual variation in impulse control may contribute to differences in susceptibility to SUDs. Both of these relationships have been described, thus leading to a "chicken or the egg" debate which remains to be fully resolved. Does impulsivity precede drug use or does it manifest as a function of problematic drug usage? The link between impulsivity and SUDs has been most strongly established for cocaine and alcohol use disorders using both preclinical models and clinical data. Much less is known about the potential link between impulsivity and cannabis use disorder (CUD) or the directionality of this relationship. The initiation of cannabis use occurs most often during adolescence prior to the brain's maturation, which is recognized as a critical period of development. The long-term effects of chronic cannabis use on the brain and behavior have started to be explored. In this review we will summarize these observations, especially as they pertain to the relationship between impulsivity and CUD, from both a psychological and biological perspective. We will discuss impulsivity as a multi-dimensional construct and attempt to reconcile the results obtained across modalities. Finally, we will discuss possible avenues for future research with emerging longitudinal data., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Exogenous causes, such as alcohol use, and endogenous factors, such as temperament and sex, can modulate developmental trajectories of adolescent neurofunctional maturation. We examined how these factors affect sexual dimorphism in brain functional networks in youth drinking below diagnostic threshold for alcohol use disorder (AUD). Based on the 3-year, annually acquired, longitudinal resting-state functional magnetic resonance imaging (MRI) data of 526 adolescents (12-21 years at baseline) from the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) cohort, developmental trajectories of 23 intrinsic functional networks (IFNs) were analyzed for (1) sexual dimorphism in 259 participants who were no-to-low drinkers throughout this period; (2) sex-alcohol interactions in two age- and sex-matched NCANDA subgroups (N = 76 each), half no-to-low, and half moderate-to-heavy drinkers; and (3) moderating effects of gender-specific alcohol dose effects and a multifactorial impulsivity measure on IFN connectivity in all NCANDA participants. Results showed that sex differences in no-to-low drinkers diminished with age in the inferior-occipital network, yet girls had weaker within-network connectivity than boys in six other networks. Effects of adolescent alcohol use were more pronounced in girls than boys in three IFNs. In particular, girls showed greater within-network connectivity in two motor networks with more alcohol consumption, and these effects were mediated by sensation-seeking only in girls. Our results implied that drinking might attenuate the naturally diminishing sexual differences by disrupting the maturation of network efficiency more severely in girls. The sex-alcohol-dose effect might explain why women are at higher risk of alcohol-related health and psychosocial consequences than men., (© 2020 Society for the Study of Addiction.)

The deficit in "interference control" found in children with Attention Deficit Hyperactivity Disorder (ADHD) could be due to two distinct processes, which are not disentangled in most studies: a larger susceptibility to activating prepotent response impulses and a deficit in suppressing them. Here, we investigated the effect of 1/ADHD and 2/ methylphenidate (MPH), on these two components of interference control. We compared interference control between untreated children with ADHD, children with ADHD under MPH, and typically developing children performing a Simon task. The main findings were that 1/ children with ADHD were more susceptible to reacting impulsively and less efficient at suppressing impulsive actions, and 2/ MPH improved the selective inhibition of impulsive actions but did not modify the strength of response impulse. This work provides an example of how pharmacological interventions and selective responses to them can be used to investigate and further our understanding of cognitive processing.

Background: Methadone maintenance treatment (MMT) is effective in decreasing opioid use or facilitating abstinence. Previous studies using small opioid use disorder samples suggest that cognitive impairments including impulsivity and executive functions may partially improve on MMT, but a range of deficits may persist. However, systematic assessments with larger samples are needed to confirm the profile of cognitive functions on MMT., Methods: We assessed four types of impulsivity (delay discounting, reflection impulsivity, risk taking and motoric impulsivity), executive functioning (spatial working memory, paired associative learning and strategic planning) and drug cue-induced craving in a relatively large population (115 MMT patients, 115 healthy controls). The relationships between impulsivity, drug cue-induced craving and addiction-related variables were also assessed., Results: Delay discounting, as well as drug cue-induced craving was increased in patients, while motoric impulsivity was lower than in controls. Paired associative learning was additionally impaired, which was explained by increased depression and anxiety levels in patients. Within the MMT group, the delay discounting and drug-cue induced craving scores were positively correlated with self-reported urgency, but unrelated to methadone dosage, duration on methadone, withdrawal symptoms, or presence of nicotine dependence., Conclusions: Our findings highlight increased delay discounting and cue-induced craving in MMT patients suggesting a potential role for trait effects in delay discounting. Although previous smaller studies have shown impaired executive function, in our large sample size on chronic MMT we only observed impaired associative learning related to depressive and anxiety symptoms highlighting a role for managing comorbid symptoms to further optimize cognitive function., (Copyright © 2020 Elsevier B.V. All rights reserved.)

It is the focus of increasing interest to investigate the effects of long-chain n-3 and long-chain n-6 polyunsaturated fatty acids (LC n-3 PUFAs; LC n-6 PUFAs) on psychiatric symptoms in a transdiagnostic perspective. There is some evidence that low levels of LC n-3 PUFAs and a higher ratio of LC n-6 to LC n-3 PUFAs in plasma and blood cells are associated with aggressive and impulsive behaviours. Therefore, implementation of LC n-3 PUFAs may produce positive effects on hostility, aggression, and impulsivity in both psychiatric and non-psychiatric samples across different stages of life. A possible mechanism of action of LC n-3 PUFAs in conditions characterized by a high level of impulsivity and aggression is due to the effect of these compounds on the serotonin system and membrane stability. Studies that evaluated the effects of LC n-3 PUFAs on impulsivity and aggressiveness indicated that addition of rather low doses of these agents to antipsychotic treatment might reduce agitation and violent behaviours in psychosis, attention deficit hyperactivity disorder, personality disorders, and impulsive control and conduct disorders. The present review is aimed at examining and discussing available data from recent trials on this topic.

Objective: Ethanol and zopiclone are both sedating drugs that impair traffic relevant skills, but that show vast differences in epidemiological traffic risk. One explanation for this could be that they impair various kinds of skills differently, but this is less previously studied. The aim of this study was to compare effects of zopiclone and ethanol on a large battery of computerized psychomotor and cognitive tests according to different test classifications. Methods: Ethanol (50 grams), zopiclone 5 mg, zopiclone 10 mg or placebo was administered in a randomized trial with a cross-over design. Blood was sampled nine times after administration and analyzed for zopiclone and ethanol using fully validated methods. The computerized tests Connors Continuous Performance Test (CPT), Stockings of Cambridge (SOC) and choice reaction time (CRT) was performed at baseline and after administration. The three tests yielded fifteen different test components, which were categorized according to the three well-known behavior levels (automative behavior, control behavior and executive planning). Secondly, they were categorized into tests measuring "reaction time", "impulsivity" and "attention/cognition". Results: On all tests belonging to behavior level 1 and on all tests measuring "reaction time", more subjects were impaired by zopiclone than ethanol. On all tests measuring "impulsivity", more subjects were impaired by ethanol than zopiclone. Conclusion: Zopiclone and ethanol both lead to impairment, but have a different profile on what kind of tests and neurocognitive functions they mostly impair. This could be important in the understanding of the differences in traffic risk connected to these two drugs.

Background: Thalamic subregions mediate various cognitive functions, including attention, inhibitory response control and decision making. Such neuronal activity is modulated by cholinergic thalamic afferents and deterioration of such modulatory signaling has been theorised to contribute to cognitive decline in neurodegenerative disorders. However, the thalamic subnuclei and cholinergic receptors involved in cognitive functioning remain largely unknown., Aims: We investigated whether muscarinic or nicotinic receptors in the mediodorsal thalamus and anterior thalamus contribute to rats' performance in the five-choice serial reaction time task, which measures sustained visual attention and impulsive action., Methods: Male Long-Evans rats were trained in the five-choice serial reaction time task then surgically implanted with guide cannulae targeting either the mediodorsal thalamus or anterior thalamus. Reversible inactivation of either the mediodorsal thalamus or anterior thalamus were achieved with infusions of the γ-aminobutyric acid-ergic agonists muscimol and baclofen prior to behavioural assessment. To investigate cholinergic mechanisms, we also assessed the behavioural effects of locally administered nicotinic (mecamylamine) and muscarinic (scopolamine) receptor antagonists., Results: Reversible inactivation of the mediodorsal thalamus severely impaired discriminative accuracy and response speed and increased omissions. Inactivation of the anterior thalamus produced less profound effects, with impaired accuracy at the highest dose. In contrast, blocking cholinergic transmission in these regions did not significantly affect five-choice serial reaction time task performance., Conclusions/interpretations: These findings show the mediodorsal thalamus plays a key role in visuospatial attentional performance that is independent of local cholinergic neurotransmission.

Background: Enhancement in cognitive impulsivity and the resulting alterations in decision making serve as a contributing factor for the development and maintenance of substance-use disorders. Nicotine-induced increases in impulsivity has been previously reported in male humans and rodents. Although the potential for sex differences in nicotine-induced impulsivity has not been examined., Aims and Methods: In the present study, male and female Sprague Dawley rats were submitted to a delay discounting task, in which several consecutive measures of self-control were taken. Firstly, rats were tested with vehicle, and next with nicotine doses of 0.4 and 0.8 mg/kg. Thereafter, chronic treatment with bupropion started, and the animals were tested again. Half the animals continued to receive 0.8 mg/kg of nicotine, while the rest received nicotine and also a daily dose of 30 mg/kg of bupropion., Results: When the animals were first tested with nicotine, female rats showed a significant nicotine dose dependent increase of impulsive behaviour, whereas male rats only showed a decrease on their elections of the larger but delayed reward under the highest dose of 0.8 mg/kg of nicotine. Treatment with bupropion blocked the effect of nicotine on decision making in female rats, as they showed results close to their baseline levels. On the other hand, bupropion did not affect the nicotine-induced delay discounting in male rats., Conclusion: These findings demonstrate sexually dimorphic effects of nicotine on cognitive impulsivity which may help to shed light on nicotine use vulnerabilities observed in women.

Rationale: Methylphenidate and d-amphetamine, medications used for treatment of attention deficit hyperactivity disorder (ADHD), are used recreationally and self-administered by laboratory animals. Benztropine (BZT) analogs, like those medications, increase synaptic dopamine levels but are less effective in maintaining self-administration, suggesting clinical utility with less abuse liability., Objectives: The current study was designed to evaluate potential therapeutic effects of BZT analogs related to ADHD., Methods: Rats responded under a delay-discounting procedure in which responses on one lever produced immediate delivery of a single food pellet and alternative responses produced four food pellets either immediately or with various temporal delays, with those delays arranged in ascending or random orders in different groups of rats. Selection of the smaller more immediate reinforcer has been suggested as an aspect of "impulsivity," a trait with suggested involvement in ADHD. Other rats were studied under fixed-interval (FI) 300-s schedules to assess drug effects on behavior under temporal control., Results: d-Amphetamine, methylphenidate, and the BZT analog AHN 1-055, but not AHN 2-005 or JHW 007, increased selection of the large, delayed reinforcer with either arrangement of delays. All drugs changed the temporal distribution of responses within the FI from one with responses concentrated at the end to a more uniform distribution. Changes in the temporal distribution of FI responding occurred with drugs that did not affect discounting suggesting that discounting does not arise directly from the same temporal control processes controlling FI responding., Conclusions: AHN 1-055 may be of clinical utility in the treatment of ADHD.