Interactions of catecholamines and GABA+ in cognitive control: Insights from EEG and 1H-MRS.

Catecholamines and amino acid transmitter systems are known to interact, the exact links and their impact on cognitive control functions have however remained unclear. Using a multi-modal imaging approach combining EEG and proton-magnetic resonance spectroscopy (1H-MRS), we investigated the effect of different degrees of pharmacological catecholaminergic enhancement onto theta band activity (TBA) as a measure of interference control during response inhibition and execution. It was central to our study to evaluate the predictive impact of in-vivo baseline GABA+ concentrations in the striatum, the anterior cingulate cortex (ACC) and the supplemental motor area (SMA) of healthy adults under varying degrees of methylphenidate (MPH) stimulation. We provide evidence for a predictive interrelation of baseline GABA+ concentrations in cognitive control relevant brain areas onto task-induced TBA during response control stimulated with MPH. Baseline GABA+ concentrations in the ACC, the striatum, and the SMA had a differential impact on predicting interference control-related TBA in response execution trials. GABA+ concentrations in the ACC appeared to be specifically important for TBA modulations when the cognitive effort needed for interference control was high - that is when no prior task experience exists, or in the absence of catecholaminergic enhancement with MPH. The study highlights the predictive role of baseline GABA+ concentrations in key brain areas influencing cognitive control and responsiveness to catecholaminergic enhancement, particularly in high-effort scenarios.

The effect of methylphenidate on anaesthesia recovery: An experimental study in pigs.

INTRODUCTION: Due to the lack of specific antagonists for general anaesthetics, the pharmacological stimulation of the arousal pathways might contribute to reduce recovery time. We aimed at assessing the effect of methylphenidate on physiological parameters, nociceptive withdrawal reflex thresholds, electroencephalographic variables and time of reappearance of reflexes in pigs undergoing propofol anaesthesia. MATERIALS AND METHODS: Two experiments have been performed. Five (experiment 1) and sixteen (experiment 2) healthy juvenile pigs were anaesthetised with propofol. In experiment 1, saline, methylphenidate 10 mg/kg or methylphenidate 20 mg/kg was administered intravenously at the end of propofol administration, using a cross-over design. In experiment 2, saline (n = 8) or methylphenidate 20 mg/kg (n = 8) was administered immediately after extubation. In both experiments, physiological parameters, nociceptive withdrawal reflex thresholds, electroencephalographic variables and time of reappearance of reflexes were assessed. Comparison among groups was performed using either the two-way repeated measures ANOVA followed by Bonferroni-Test or the t-test in case of parametric data, and either the Kruskal-Wallis test or the Mann-Whitney Rank Sum test in case of non-parametric data. A p value < 0.05 was considered statistically significant. RESULTS: No clinically relevant changes were observed in both experiments for physiological parameters, nociceptive withdrawal reflex thresholds and electroencephalographic variables. CONCLUSIONS: Methylphenidate does not shorten or modify anaesthesia recovery in pigs, when the sole propofol is administered.

A Post-Hoc Analysis of Emotional Lability With Delayed-Release/Extended-Release Methylphenidate in Children Aged 6 to 12 Years of Age Participating in Two Phase 3 Clinical Trials.

OBJECTIVE: DR/ER-MPH (formerly HLD200) is an evening-dosed delayed-release and extended-release methylphenidate approved for the treatment of ADHD in patients ≥6 years. Post hoc analyses of two pivotal Phase 3 trials: HLD200-107 (NCT02493777) and HLD200-108 (NCT02520388) evaluated emotional lability (EL) with DR/ER-MPH treatment. METHODS: Differences in Conners Global Index-Parent (CGI-P) EL subscale scores and age- and gender-adjusted T-scores over an open-label titration phase (HLD200-107) and between treatment and placebo groups at endpoint (HLD200-108) were evaluated. RESULTS: In HLD200-107 (N = 117) mean CGI-P EL subscale scores improved from 5.3 to 1.3 (p < .0001) after 6 weeks; in HLD200-108 significant improvements were observed in the treatment group (n = 81) versus placebo (n = 80; 3.11 vs. 4.08; p = .0053). T-scores showed an improvement with DR/ER-MPH treatment in both trials. Few emotional adverse events (AEs) were reported. CONCLUSION: DR/ER-MPH treatment resulted in statistically significant improvements in EL to the level of non-ADHD peers as contextualized by T-scores.

Effects of acute and chronic methylphenidate on prepulse inhibition: A sex difference study in Wistar rats.

BACKGROUND: The utilization of methylphenidate (MPH) is experiencing a notable surge within the adult population. This growth can be attributed to two key factors: its recreational and cognitive enhancement purposes, as well as the rising prevalence of ADHD diagnoses within this population. This study examined acute and chronic oral MPH effects on attention in male and female Wistar rats. To this end, we used a prepulse inhibition (PPI) task, which is widely used to assess psychoactive drug effects in both humans and rodents. This task allowed us to evaluate changes in attention by analyzing sensorimotor gating associated with stimulus selection process. METHODS: Animals were administered a clinically relevant dose of MPH (5 mg/kg) daily for seven days. The estrous cycle phases of the female rats were measured during behavioral sessions. The PPI task was conducted 20 min after drug administration on day 1 (acute), day 7 (chronic), and 48 h post-treatment. RESULTS: Results indicated that both acute and chronic MPH treatment impaired PPI expression in male rats, but not in female rats, regardless of their estrous cycle phase. Furthermore, a differential effect of chronic MPH treatment on the PPI task was found in male rats. Specifically, on the seventh treatment day, the PPI effect was observed when animals undertook the PPI task for the first time but was impaired in those animals in which the initial PPI session occurred under the acute influence of the drug (day 1). CONCLUSIONS: These findings suggest that the impact of MPH on sensorimotor gating responses may vary based on sex and task experience, possibly leading to state-dependent effects in healthy individuals.

Brain connectivity changes to fast versus slow dopamine increases.

The rewarding effects of stimulant drugs such as methylphenidate (MP) depend crucially on how fast they raise dopamine in the brain. Yet how the rate of drug-induced dopamine increases impacts brain network communication remains unresolved. We manipulated route of MP administration to generate fast versus slow dopamine increases. We hypothesized that fast versus slow dopamine increases would result in a differential pattern of global brain connectivity (GBC) in association with regional levels of dopamine D1 receptors, which are critical for drug reward. Twenty healthy adults received MP intravenously (0.5 mg/kg; fast dopamine increases) and orally (60 mg; slow dopamine increases) during simultaneous [11C]raclopride PET-fMRI scans (double-blind, placebo-controlled). We tested how GBC was temporally associated with slow and fast dopamine increases on a minute-to-minute basis. Connectivity patterns were strikingly different for slow versus fast dopamine increases, and whole-brain spatial patterns were negatively correlated with one another (rho = -0.54, pspin < 0.001). GBC showed "fast>slow" associations in dorsal prefrontal cortex, insula, posterior thalamus and brainstem, caudate and precuneus; and "slow>fast" associations in ventral striatum, orbitofrontal cortex, and frontopolar cortex (pFDR < 0.05). "Fast>slow" GBC patterns showed significant spatial correspondence with D1 receptor availability (estimated via normative maps of [11C]SCH23390 binding; rho = 0.22, pspin < 0.05). Further, hippocampal GBC to fast dopamine increases was significantly negatively correlated with self-reported 'high' ratings to intravenous MP across individuals (r(19) = -0.68, pbonferroni = 0.015). Different routes of MP administration produce divergent patterns of brain connectivity. Fast dopamine increases are uniquely associated with connectivity patterns that have relevance for the subjective experience of drug reward.

Neural and Cognitive Predictors of Stimulant Treatment Efficacy in Medication-Naïve ADHD Adults: A Pilot Diffusion Tensor Imaging Study.

OBJECTIVE: Stimulant medications are the main treatment for Attention Deficit Hyperactivity Disorder (ADHD), but overall treatment efficacy in adults has less than a 60% response rate. This study aimed to identify neural and cognitive markers predictive of longitudinal improvement in response to stimulant treatment in drug-naïve adults with ADHD. METHOD: We used diffusion tensor imaging (DTI) and executive function measures with 36 drug-naïve adult ADHD patients in a prospective study design. RESULTS: Structural connectivity (measured by fractional anisotropy, FA) in striatal regions correlated with ADHD clinical symptom improvement following stimulant treatment (amphetamine or methylphenidate) in better medication responders. A significant positive correlation was also found between working memory performance and stimulant-related symptom improvement. Higher pre-treatment working memory scores correlated with greater response. CONCLUSION: These findings provide evidence of pre-treatment neural and behavioral markers predictive of longitudinal treatment response to stimulant medications in adults with ADHD.

Phasic dopamine signals are reduced in the spontaneously hypertensive rat and increased by methylphenidate.

The spontaneously hypertensive rat (SHR) is a selectively bred animal strain that is frequently used to model attention-deficit hyperactivity disorder (ADHD) because of certain genetically determined behavioural characteristics. To test the hypothesis that the characteristically altered response to positive reinforcement in SHRs may be due to altered phasic dopamine response to reward, we measured phasic dopamine signals in the SHRs and Sprague Dawley (SD) rats using in vivo fast-scan cyclic voltammetry. The effects of the dopamine reuptake inhibitor, methylphenidate, on these signals were also studied. Phasic dopamine signals during the pairing of a sensory cue with electrical stimulation of midbrain dopamine neurons were significantly smaller in the SHRs than in the SD rats. Over repeated pairings, the dopamine response to the sensory cue increased, whereas the response to the electrical stimulation of dopamine neurons decreased, similarly in both strains. However, the final amplitude of the response to the sensory cue after pairing was significantly smaller in SHRs than in the SD rats. Methylphenidate increased responses to sensory cues to a significantly greater extent in the SHRs than in the SD rats, due largely to differences in the low dose effect. At a higher dose, methylphenidate increased responses to sensory cues and electrical stimulation similarly in SHRs and SD rats. The smaller dopamine responses may explain the reduced salience of reward-predicting cues previously reported in the SHR, whereas the action of methylphenidate on the cue response suggests a potential mechanism for the therapeutic effects of low-dose methylphenidate in ADHD.

Sensorimotor dysfunction due to developmental manganese exposure is less severe in adult female than male rats and partially improved by acute methylphenidate treatment.

Epidemiological studies have reported associations between elevated manganese (Mn) exposure and poorer psychomotor performance in children. Our studies in adult male rats have established that this relationship is causal and that prolonged methylphenidate (MPH) treatment is efficacious in treating this area of dysfunction. However, it is unclear if sensitivity to these Mn deficits differs between females and males, and whether existing pharmacological therapies are efficacious in improving sensorimotor dysfunction in females. To address these questions, we used our rat model of childhood environmental Mn exposure and the Montoya staircase test to determine whether 1) there are sex differences in the lasting sensorimotor dysfunction caused by developmental Mn exposure, and 2) MPH treatment is efficacious in ameliorating the sensorimotor deficits in females. Female and male neonates were treated orally with Mn (50 mg Mn/kg/d) from postnatal day 1 to 21 and evaluated for skilled forelimb sensorimotor performance as adults. Subsequently, the efficacy of acute oral MPH treatment (doses of 0, 0.5, and 3.0 mg MPH/kg/d) was assessed in females using a within-subject MPH treatment design. Developmental postnatal Mn exposure produced lasting sensorimotor reaching and grasping deficits that were milder in females than in males. Acute MPH treatment of Mn-exposed females with the 0.5 mg/kg/d dose attenuated the reaching dysfunction without alleviating grasping dysfunction. These findings show sex-based variations in sensitivity to the sensorimotor impairment caused by developmental Mn exposure, and they are consistent with prior studies showing less vulnerability of females to Mn-induced dysfunction in other functional domains, possibly due to the protective effects of estrogen. Given our previous work showing the efficacy of MPH treatment to alleviate Mn-induced inattention, impulsiveness, and sensorimotor dysfunctions in adult male rats, they also highlight the need for further research into sex-based differences in cognitive and behavioral areas of brain function, and the efficacy of therapeutics in treating behavioral dysfunction in females. Supported by NIEHS R01ES028369.

Comparison of neuroprotective effects of a topiramate-loaded biocomposite based on mesoporous silica nanoparticles with pure topiramate against methylphenidate-induced neurodegeneration.

BACKGROUND: Methylphenidate (MPH) abuse has been criticized for its role in neurodegeneration. Also, a high risk of seizure was reported in the first month of MPH treatment. Topiramate, a broad-spectrum Antiepileptic Drug (AED), has been used as a neuroprotective agent in both aforementioned complications. Nanotechnology is introduced to increase desirable neurological treatment with minimum side effects. We aimed to investigate the potential neuroprotective activity of topiramate loaded on nanoparticles. METHODS AND RESULTS: MTT assay was performed to evaluate the cellular cytotoxicity of Mesoporous Silica Nanoparticles (MSN). Male rats were randomly divided into eight groups. Rats received an intraperitoneal (i.p) MPH (10 mg/kg) injection and a daily oral dose of topiramate (TPM, 30 mg/kg), MSN with Zn core (10 and 30 mg/kg), and MSN with Cu core (10 and 30 mg/kg) for three weeks. On day 21, a seizure was induced by a single injection of pentylenetetrazole (PTZ) to evaluate the protective effects of TPM-loaded nanoparticles on seizure latency and duration following MPH-induced neurotoxicity. Moreover, the hippocampal content of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), malondialdehyde (MDA), and the anti-oxidant enzymes (SOD, GPx, and GR) activities were assessed. Also, BAX and Bcl-2 as two main apoptotic markers were evaluated. RESULTS: MPH neurotoxicity was observed as a raised duration and reduced latency in PTZ-induced seizure. However, TPM-loaded MSN with Zn species (NE) treatment reduced the duration and improved the latency time. Also, NE and, somewhat, TPM-loaded MSN with Cu species (NM) administration reduced inflammatory cytokines, MDA, and Bax levels and increased activities in the rat hippocampus. CONCLUSION: TPM-loaded nanoparticles could be used as neuroprotective agents against MPH-induced neurodegeneration by improving seizure parameters and reducing inflammatory, oxidant, and apoptotic factors.

Impaired monoamine neural system in the mPFC of SHRSP/Ezo as an animal model of attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is the most common childhood-onset psychiatric disorder. We investigated the effects of systemic administration of monoamine reuptake inhibitors on long-term potentiation (LTP) formation and monoamine release in the medial prefrontal cortex (mPFC) of the stroke-prone spontaneously hypertensive rat (SHRSP)/Ezo, an animal model of ADHD, and its genetic control, Wistar Kyoto (WKY)/Ezo, to elucidate the functional changes in the mPFC monoamine neural system. Methylphenidate (dopamine (DA) and noradrenaline (NA) reuptake inhibitor) and desipramine (NA reuptake inhibitor) improved LTP formation defects in the mPFC of SHRSP/Ezo, suggesting that NA or both DA and NA are required for improvement of impaired LTP. Methylphenidate increased mPFC DA in both WKY/Ezo and SHRSP/Ezo, but the increase was greater in the former. GBR-12909 (DA reuptake inhibitor) increased mPFC DA in WKY/Ezo but had no effect in SHRSP/Ezo. This may be because DA transporter in SHRSP/Ezo is functionally impaired and contributes less to DA reuptake, so its inhibition did not increase DA level. Meanwhile, basal DA levels in the mPFC of SHRSP/Ezo were paradoxically decreased. These results suggest that functional changes in the DA and NA neural system in the frontal lobe are involved in the pathology of ADHD.

Methylphenidate alleviates cognitive dysfunction caused by early manganese exposure: Role of catecholaminergic receptors.

Environmental manganese (Mn) exposure is associated with impaired attention and psychomotor functioning, as well as impulsivity/hyperactivity in children and adolescents. We have shown previously that developmental Mn exposure can cause these same dysfunctions in a rat model. Methylphenidate (MPH) lessens impairments in attention, impulse control, and psychomotor function in children, but it is unknown whether MPH ameliorates these dysfunctions when induced by developmental Mn exposure. Here, we sought to (1) determine whether oral MPH treatment ameliorates the lasting attention and sensorimotor impairments caused by developmental Mn exposure, and (2) elucidate the mechanism(s) of Mn neurotoxicity and MPH effectiveness. Rats were given 50 mg Mn/kg/d orally over PND 1-21 and assessed as adults in a series of attention, impulse control and sensorimotor tasks during oral MPH treatment (0, 0.5, 1.5, or 3.0 mg/kg/d). Subsequently, selective catecholaminergic receptor antagonists were administered to gain insight into the mechanism(s) of action of Mn and MPH. Developmental Mn exposure caused persistent attention and sensorimotor impairments. MPH treatment at 0.5 mg/kg/d completely ameliorated the Mn attentional dysfunction, whereas the sensorimotor deficits were ameliorated by the 3.0 mg/kg/d MPH dose. Notably, the MPH benefit on attention was only apparent after prolonged treatment, while MPH efficacy for the sensorimotor deficits emerged early in treatment. Selectively antagonizing D1, D2, or α2A receptors had no effect on the Mn-induced attentional dysfunction or MPH efficacy in this domain. However, antagonism of D2R attenuated the Mn sensorimotor deficits, whereas the efficacy of MPH to ameliorate those deficits was diminished by D1R antagonism. These findings demonstrate that MPH is effective in alleviating the lasting attentional and sensorimotor dysfunction caused by developmental Mn exposure, and they clarify the mechanisms underlying developmental Mn neurotoxicity and MPH efficacy. Given that the cause of attention and psychomotor deficits in children is often unknown, these findings have implications for the treatment of environmentally induced attentional and psychomotor dysfunction in children more broadly.

Development of a novel rodent rapid serial visual presentation task reveals dissociable effects of stimulant versus nonstimulant treatments on attentional processes.

The rapid serial visual presentation (RSVP) task and continuous performance tasks (CPT) are used to assess attentional impairments in patients with psychiatric and neurological conditions. This study developed a novel touchscreen task for rats based on the structure of a human RSVP task and used pharmacological manipulations to investigate their effects on different performance measures. Normal animals were trained to respond to a target image and withhold responding to distractor images presented within a continuous sequence. In a second version of the task, a false-alarm image was included, so performance could be assessed relative to two types of nontarget distractors. The effects of acute administration of stimulant and nonstimulant treatments for ADHD (amphetamine and atomoxetine) were tested in both tasks. Methylphenidate, ketamine, and nicotine were tested in the first task only. Amphetamine made animals more impulsive and decreased overall accuracy but increased accuracy when the target was presented early in the image sequence. Atomoxetine improved accuracy overall with a specific reduction in false-alarm responses and a shift in the attentional curve reflecting improved accuracy for targets later in the image sequence. However, atomoxetine also slowed responding and increased omissions. Ketamine, nicotine, and methylphenidate had no specific effects at the doses tested. These results suggest that stimulant versus nonstimulant treatments have different effects on attention and impulsive behaviour in this rat version of an RSVP task. These results also suggest that RSVP-like tasks have the potential to be used to study attention in rodents.

Long-term medication for ADHD (LMA) trial: 2-year prospective observational study in children and adolescents. Core symptoms, daily functioning, and comorbidity outcomes.

More knowledge is needed about long-term ADHD medication and symptom, daily functioning, comorbidity, and tolerability outcomes. This "Long-term Medication for ADHD (LMA) trial" was a prospective observational 2-year trial in children and adolescents aged 6-18 years (extension of 1-year trial). Participants met criteria for DSM-5 ADHD (inattentive or combined), with complex comorbidities; autism spectrum disorder (31%), autistic traits (24%), oppositional symptoms (59%), anxiety (32%), dyslexia/language disorder (16%), borderline intellectual functioning (17%). Medication was individually tailored and followed-up at clinical visits (1, 2, 3, 6, 12, 18, 24 months). Primary outcome: Clinical Global Impression-Severity and Improvement scales (CGI-S, CGI-I). Secondary outcomes: Investigator-rated ADHD-Rating Scale, Weiss Functional Impairment Rating Scale-Parent report (WFIRS-P; Family, School Learning and Behavior, Life Skills, Self-Concept, Social Activities, and Risky Activities domains), comorbidity symptoms and adverse events (AEs). One hundred twenty-eight participants were enrolled (1-year trial only n = 27, LMA trial n = 101). Of these 29 (23%) discontinued, mainly due to AEs (n = 7), moving (n = 7), or no longer needing medication (n = 6). Main AEs were poor appetite, low mood, anxiety, irritability, fatigue. Improvements from baseline to 2 years were large in CGI-S (effect size (ES) 2.28), ADHD-RS (ES 2.06), and moderate to large in WFIRS-P (ES total 0.73, learning 0.4, family 0.67). Overall, the trial showed robust and sustained improvements in ADHD symptom severity and daily functioning over a period of 2 years of ADHD medication in children and adolescents with ADHD and complex comorbidities. Most AEs were mild. Comorbidity symptoms were improved after 1 year, particularly oppositional symptoms, depression, and anxiety.

The Ability to Voluntarily Regulate Theta Band Activity Affects How Pharmacological Manipulation of the Catecholaminergic System Impacts Cognitive Control.

BACKGROUND: The catecholaminergic system influences response inhibition, but the magnitude of the impact of catecholaminergic manipulation is heterogeneous. Theoretical considerations suggest that the voluntary modulability of theta band activity can explain this variance. The study aimed to investigate to what extent interindividual differences in catecholaminergic effects on response inhibition depend on voluntary theta band activity modulation. METHODS: A total of 67 healthy adults were tested in a randomized, double-blind, cross-over study design. At each appointment, they received a single dose of methylphenidate or placebo and performed a Go/Nogo task with stimuli of varying complexity. Before the first appointment, the individual's ability to modulate theta band activity was measured. Recorded EEG data were analyzed using temporal decomposition and multivariate pattern analysis. RESULTS: Methylphenidate effects and voluntary modulability of theta band activity showed an interactive effect on the false alarm rates of the different Nogo conditions. The multivariate pattern analysis revealed that methylphenidate effects interacted with voluntary modulability of theta band activity at a stimulus processing level, whereas during response selection methylphenidate effects interacted with the complexity of the Nogo condition. CONCLUSIONS: The findings reveal that the individual's theta band modulability affects the responsiveness of an individual's catecholaminergic system to pharmacological modulation. Thus, the impact of pharmacological manipulation of the catecholaminergic system on cognitive control most likely depends on the existing ability to self-modulate relevant brain oscillatory patterns underlying the cognitive processes being targeted by pharmacological modulations.

Overactivated contextual visual perception and response to a single dose of methylphenidate in children with ADHD.

The pathogenesis of overactivated visual perception in attention-deficit hyperactivity disorder (ADHD) remains unclear, which is interpreted as a cognitive compensation. The existing studies have proposed that perceptual abnormalities in neurodevelopmental disorders are associated with dysfunction of the contextual knowledge system, which influences the development and formation of perception. We hypothesized that alterations in contextual states may also be responsible for inducing perceptual abnormalities in ADHD. Therefore, the present study evaluated the characteristics of pre-stimulus alpha and its response to a single dose of methylphenidate (MPH). A total of 135 Chinese children participated in the first study, including 70 children with ADHD (age = 10.61 ± 1.93 years, female = 17) and 65 age- and sex-matched control children (age = 10.73 ± 1.93 years, female = 20). The second clinical trial included 19 Chinese children with ADHD (age = 11.85 ± 1.72 years, female = 4), with an identical visual spatial search task. Pre-stimulus alpha oscillations and P1 activity were significantly greater in children with ADHD than in the controls. Overactivated pre-stimulus alpha positively predicted P1. Both pre-stimulus alpha and P1 overactivation have beneficial effects on cognitive performance in children with ADHD. No intervening effect of a single dose of MPH on the compensatory activation of pre-stimulus alpha and P1 were observed. Our findings extended the perceptual activation to the contextual knowledge system, suggesting that compensatory perception in children with ADHD is more likely to be a top-down regulated cognitive operational process.

Preclinical Models of Attention Deficit Hyperactivity Disorder: Neurobiology, Drug Discovery, and Beyond.

OBJECTIVE: We offer an overview of ADHD research using mouse models of nicotine exposure. METHOD: Nicotine exposure of C57BL/6 or Swiss Webster mice occurred during prenatal period only or during the prenatal and the pre-weaning periods. Behavioral, neuroanatomical and neurotransmitter assays were used to investigate neurobiological mechanisms of ADHD and discover candidate ADHD medications. RESULTS: Our studies show that norbinaltorphimine, a selective kappa opioid receptor antagonist is a candidate novel non-stimulant ADHD treatment and that a combination of methylphenidate and naltrexone has abuse deterrent potential with therapeutic benefits for ADHD. Other studies showed transgenerational transmission of ADHD-associated behavioral traits and demonstrated that interactions between untreated ADHD and repeated mild traumatic brain injury produced behavioral traits not associated with either condition alone. CONCLUSION: Preclinical models contribute to novel insights into ADHD neurobiology and are valuable tools for drug discovery and translation to benefit humans with ADHD.

The effect of long-term use of methylphenidate on cardiac autonomic functions and ventricular arrhythmogenesis: a prospective case-control study.

OBJECTIVE: We aimed to assess cardiac autonomic balance with heart rate variability by using 24-hour Holter electrocardiography and also to assess susceptibility to ventricular arrhythmias by using microvolt T wave alternance in children with attention deficit hyperactivity disorder. METHOD: This study was conducted with age- and gender-matched groups of 40 patients taking long-acting methylphenidate for more than a year and 55 healthy controls. Heart rate variability analysis for cardiac autonomic functions and microvolt T wave alternance measurements for susceptibility to ventricular arrhythmias were evaluated by 24-hour Holter electrocardiography. RESULTS: The mean age 10.9 ± 2.7 years, mean duration of therapy 22.76 months, and mean methylphenidate doses were 37.64 mg/day. The study group had considerably higher rMSSD, higher HF, and a lower LF/HF ratio (respectively, p : 0.02, p : 0.001 and p : 0.01). While parasympathetic activity parameters were elevated, sympathetic activity parameters were low during the sleep period. Increase in the microvolt T wave alternance values of the study group was not found to be statistically significant (p > 0.05). CONCLUSION: In children taking long-acting methylphenidate, the autonomic balance was shown to be in favour of the parasympathetic system. Determination of the vulnerability to life-threatening ventricular arrhythmias has been evaluated for the first time in children with attention deficit hyperactivity disorder. Accordingly, microvolt T-wave alternance values give the notion that drug use is safe.

Cognition-enhancing and cognition-impairing doses of psychostimulants exert opposing actions on frontostriatal neural coding of delay in working memory.

The prefrontal cortex (PFC) and extended frontostriatal circuitry play a critical role in executive cognitive processes that guide goal-directed behavior. Dysregulation of frontostriatal-dependent cognition is implicated in a variety of cognitive/behavioral disorders, including addiction and attention deficit hyperactivity disorder (ADHD). Psychostimulants exert dose-dependent and opposing actions on frontostriatal cognitive function. Specifically, low and clinically-relevant doses improve, while higher doses associated with abuse and addiction impair, frontostriatal-dependent cognitive function. Frontostriatal cognition is supported by the coordinated activity of neurons across this circuit. To date, the neural coding mechanisms that support the diverse cognitive actions of psychostimulants are unclear. This represents a significant deficit in our understanding of the neurobiology of frontostriatal cognition and limits the development of novel treatments for frontostriatal cognitive impairment. The current studies examined the effects of cognition-enhancing and cognition-impairing doses of methylphenidate (MPH) on the spiking activity of dorsomedial PFC (dmPFC) and dorsomedial striatal (dmSTR) neurons in 17 male rats engaged in a working memory task. Across this frontostriatal circuit, we observed opposing actions of low- and high-dose MPH on the population-based representation of delay: low-dose strengthened, while high-dose weakened, representation of this event. MPH elicited a more complex pattern of actions on reward-related signaling, that were highly dose-, region- and neuron-dependent. These observations provide novel insight into the neurophysiological mechanisms that support the cognitive actions of psychostimulants.

Vilazodone, a Selective Serotonin Reuptake Inhibitor with Diminished Impact on Methylphenidate-Induced Gene Regulation in the Striatum: Role of 5-HT1A Receptor.

Selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, are frequently combined with medical psychostimulants such as methylphenidate (Ritalin), for example, in the treatment of attention-deficit hyperactivity disorder/depression comorbidity. Co-exposure to these medications also occurs with misuse of methylphenidate as a recreational drug by patients on SSRIs. Methylphenidate, a dopamine reuptake blocker, produces moderate addiction-related gene regulation. Findings show that SSRIs such as fluoxetine given in conjunction with methylphenidate potentiate methylphenidate-induced gene regulation in the striatum in rats, consistent with a facilitatory action of serotonin on addiction-related processes. These SSRIs may thus increase methylphenidate's addiction liability. Here, we investigated the effects of a novel SSRI, vilazodone, on methylphenidate-induced gene regulation. Vilazodone differs from prototypical SSRIs in that, in addition to blocking serotonin reuptake, it acts as a partial agonist at the 5-HT1A serotonin receptor subtype. Studies showed that stimulation of the 5-HT1A receptor tempers serotonin input to the striatum. We compared the effects of acute treatment with vilazodone (10-20 mg/kg) with those of fluoxetine (5 mg/kg) on striatal gene regulation (zif268, substance P, enkephalin) induced by methylphenidate (5 mg/kg), by in situ hybridization histochemistry combined with autoradiography. We also assessed the impact of blocking 5-HT1A receptors by the selective antagonist WAY-100635 (0.5 mg/kg) on these responses. Behavioral effects of these drug treatments were examined in parallel in an open-field test. Our results show that, in contrast to fluoxetine, vilazodone did not potentiate gene regulation induced by methylphenidate in the striatum, while vilazodone enhanced methylphenidate-induced locomotor activity. However, blocking 5-HT1A receptors by WAY-100635 unmasked a potentiating effect of vilazodone on methylphenidate-induced gene regulation, thus confirming an inhibitory role for 5-HT1A receptors. Our findings suggest that vilazodone may serve as an adjunct SSRI with diminished addiction facilitating properties and identify the 5-HT1A receptor as a potential therapeutic target to treat addiction.

Dopamine, Norepinephrine and Serotonin Participate Differently in Methylphenidate Action in Concomitant Behavioral and Ventral Tegmental Area, Locus Coeruleus and Dorsal Raphe Neuronal Study in Young Rats.

Methylphenidate (MPD), known as Ritalin, is a psychostimulant used to treat children, adults, and the elderly. MPD exerts its effects through increasing concentrations of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in the synaptic cleft. Concomitant behavioral and neuronal recording from the ventral tegmental area (VTA), locus coeruleus (LC), and from the dorsal raphe (DR) nucleus, which are the sources of DA, NE, and 5-HT to the mesocorticolimbic circuit, were investigated following acute and repetitive (chronic) saline, 0.6, 2.5, or 10.0 mg/kg MPD. Animals received daily saline or MPD administration on experimental days 1 to 6 (ED1-6), followed by a 3-day washout period and MPD rechallenge on ED10. Each chronic MPD dose elicits behavioral sensitization in some animals while inducing behavioral tolerance in others. The uniqueness of this study is in the evaluation of neuronal activity based on the behavioral response to chronic MPD. Neuronal excitation was observed mainly in brain areas of animals exhibiting behavioral sensitization, while neuronal attenuation following chronic MPD was observed in animals expressing behavioral tolerance. Different ratios of excitatory/inhibitory neuronal responses were obtained from the VTA, LC, or DR following chronic MPD. Thus, each brain area responds differently to each MPD dose used, suggesting that DA, NE, and 5-HT in the VTA, LC, and DR exert different effects.