Evaluation of common variants in 16 genes involved in the regulation of neurotransmitter release in ADHD

Attention-deficit hyperactivity disorder (ADHD) is a neurobehavioral disorder characterized by inappropriate difficulties to sustain attention, control impulses and modulate activity level. Although ADHD is one of the most prevalent childhood psychiatric disorders, it also persists into adulthood in around 30–50% of the cases. Based on the effect of psychostimulants used in the pharmacological treatment of ADHD, dysfunctions in neuroplasticity mechanisms and synapses have been postulated to be involved in the pathophysiology of ADHD. With this background, we evaluated, both in childhood and adulthood ADHD, the role of several genes involved in the control of neurotransmitter release through synaptic vesicle docking, fusion and recycling processes by means of a population-based association study. We analyzed single nucleotide polymorphisms across 16 genes in a clinical sample of 950 ADHD patients (506 adults and 444 children) and 905 controls. Single and multiple-marker analyses identified several significant associations after correcting for multiple testing with a false discovery rate (FDR) of 15%: (i) the SYT2 gene was strongly associated with both adulthood and childhood ADHD (p=0.001, OR=1.49 (1.18–1.89) and p=0.007, OR=1.37 (1.09–1.72), respectively) and (ii) STX1A was found associated with ADHD only in adults (p=0.0041; OR=1.28 (1.08–1.51)). These data provide preliminary evidence for the involvement of genes that participate in the control of neurotransmitter release in the genetic predisposition to ADHD through a gene-system association study. Further follow-up studies in larger cohorts and deep-sequencing of the associated genomic regions are required to identify sequence variants directly involved in ADHD.     

Aberrant glutamate signaling in the prefrontal cortex and striatum of the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder

Rationale

Attention-deficit/hyperactivity disorder (ADHD) is thought to involve hypofunctional catecholamine systems in the striatum, nucleus accumbens, and prefrontal cortex (PFC); however, recent clinical evidence has implicated glutamate dysfunction in the pathophysiology of ADHD. Recent studies show that increased stimulation of dopamine D2 and D4 receptors causes inhibition of N-methyl-d-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, respectively. The spontaneously hypertensive rat (SHR) model of ADHD combined type (C) has been found to have a hypofunctional dopamine system in the ventral striatum, nucleus accumbens, and PFC compared to the control Wistar Kyoto (WKY) strain.

Objectives

Based on the current understanding of typical dopamine–glutamate interactions, we hypothesized that the SHR model of ADHD would have a hyperfunctional glutamate system terminating in the striatum, nucleus accumbens, and PFC.

Results

High-speed amperometric recordings combined with four-channel microelectrode arrays to directly measure glutamate dynamics showed increased evoked glutamate release in the PFC (cingulate and infralimbic cortices, p?<?0.05) and also in the striatum (p?<?0.05) of the SHR (ADHD-C) as compared to the WKY. Finally, glutamate uptake was discovered to be aberrant in the PFC, but not the striatum, of the SHR when compared to the control WKY strain.

Conclusions

These results suggest that the glutamatergic system in the PFC of the SHR model of ADHD is hyperfunctional and that targeting glutamate in the PFC could lead to the development of novel therapeutics for the treatment of ADHD.     

Multicenter Analysis of the SLC6A3/DAT1 VNTR Haplotype in Persistent ADHD Suggests Differential Involvement of the Gene in Childhood and Persistent ADHD

Attention deficit/hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders with a worldwide prevalence around 4–5% in children and 1–4% in adults. Although ADHD is highly heritable and familial risk may contribute most strongly to the persistent form of the disorder, there are few studies on the genetics of ADHD in adults. In this paper, we present the first results of the International Multicentre Persistent ADHD Genetics CollaboraTion (IMpACT) that has been set up with the goal of performing research into the genetics of persistent ADHD. In this study, we carried out a combined analysis as well as a meta-analysis of the association of the SLC6A3/DAT1 gene with persistent ADHD in 1440 patients and 1769 controls from IMpACT and an earlier report. DAT1, encoding the dopamine transporter, is one of the most frequently studied genes in ADHD, though results have been inconsistent. A variable number tandem repeat polymorphism (VNTR) in the 3′-untranslated region (UTR) of the gene and, more recently, a haplotype of this VNTR with another VNTR in intron 8 have been the target of most studies. Although the 10/10 genotype of the 3′-UTR VNTR and the 10-6 haplotype of the two VNTRs are thought to be risk factors for ADHD in children, we found the 9/9 genotype and the 9-6 haplotype associated with persistent ADHD. In conclusion, a differential association of DAT1 with ADHD in children and in adults might help explain the inconsistencies observed in earlier association studies. However, the data might also imply that DAT1 has a modulatory rather than causative role in ADHD.     

The dopamine transporter haplotype and reward-related striatal responses in adult ADHD

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable disorder and several genes increasing disease risk have been identified. The dopamine transporter gene, SLC6A3/DAT1, has been studied most extensively in ADHD research. Interestingly, a different haplotype of this gene (formed by genetic variants in the 3′ untranslated region and intron 8) is associated with childhood ADHD (haplotype 10-6) and adult ADHD (haplotype 9-6). The expression of DAT1 is highest in striatal regions in the brain. This part of the brain is of interest to ADHD because of its role in reward processing is altered in ADHD patients; ADHD patients display decreased striatal activation during reward processing. To better understand how the DAT1 gene exerts effects on ADHD, we studied the effect of this gene on reward-related brain functioning in the area of its highest expression in the brain, the striatum, using functional magnetic resonance imaging. In doing so, we tried to resolve inconsistencies observed in previous studies of healthy individuals and ADHD-affected children. In a sample of 87 adult ADHD patients and 77 healthy comparison subjects, we confirmed the association of the 9-6 haplotype with adult ADHD. Striatal hypoactivation during the reward anticipation phase of a monetary incentive delay task in ADHD patients was again shown, but no significant effects of DAT1 on striatal activity were found.Although the importance of the DAT1 haplotype as a risk factor for adult ADHD was again demonstrated in this study, the mechanism by which this gene increases disease risk remains largely unknown.     

Shared and unique genetic contributions to attention deficit/hyperactivity disorder and substance use disorders: A pilot study of six candidate genes

The shared genetic basis of attention deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs) was explored by investigating the association of candidate risk factors in neurotransmitter genes with both disorders. One hundred seven methadone maintenance treatment patients, 36 having an ADHD diagnosis, 176 adult patients with ADHD without SUDs, and 500 healthy controls were genotyped for variants in the DRD4 (exon 3 VNTR), DRD5 (upstream VNTR), HTR1B (rs6296), DBH (rs2519152), COMT (rs4680; Val158Met), and OPRM1 (rs1799971; 118A>G) genes. Association with disease was tested using logistic regression models. This pilot study was adequately powered to detect larger genetic effects (OR≥2) of risk alleles with a low frequency. Compared to controls, ADHD patients (with and without SUDs) showed significantly increased frequency of the DBH (rs2519152: OR 1.73; CI 1.15–2.59; P=0.008) and the OPRM1 risk genotypes (rs1799971: OR 1.71; CI 1.17–2.50; P=0.006). The DBH risk genotype was associated with ADHD diagnosis, with the association strongest in the pure ADHD group. The OPRM1 risk genotype increased the risk for the combined ADHD and SUD phenotype. The present study strengthens the evidence for a shared genetic basis for ADHD and addiction. The association of OPRM1 with the ADHD and SUD combination could help to explain the contradictory results of previous studies. The power limitations of the study restrict the significance of these findings: replication in larger samples is warranted.     

Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations

Background and purpose:

There is increasing evidence that not only the monoaminergic but also the glutamatergic system is involved in the pathophysiology of attention-deficit hyperactivity disorder (ADHD). Hyperactivity of glutamate metabolism might be causally related to a hypoactive state in the dopaminergic system. Atomoxetine, a selective noradrenaline reuptake inhibitor, is the first non-stimulant approved for the treatment of this disorder. Here we have evaluated the effects of atomoxetine on glutamate receptors in vitro.

Experimental approach:

The whole-cell configuration of the patch-clamp technique was used to analyse the effect of atomoxetine on N-methyl-d-aspartate (NMDA) receptors in cultured rodent cortical and hippocampal neurons as well as on NMDA receptors heterologously expressed in human TsA cells.

Key results:

Atomoxetine blocked NMDA-induced membrane currents. Half-maximal inhibition emerged at about 3 µM which is in the range of clinically relevant concentrations found in plasma of patients treated with this drug. The inhibition was voltage-dependent, indicating an open-channel blocking mechanism. Furthermore, the inhibitory potency of atomoxetine did not vary when measured on NMDA receptors from different brain regions or with different subunit compositions.

Conclusions and implications:

The effective NMDA receptor antagonism by atomoxetine at low micromolar concentrations may be relevant to its clinical effects in the treatment of ADHD. Our data provide further evidence that altered glutamatergic transmission might play a role in ADHD pathophysiology.     

Case–Control Genome-Wide Association Study of Persistent Attention-Deficit Hyperactivity Disorder Identifies FBXO33 as a Novel Susceptibility Gene for the Disorder

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high heritability. At least 30% of patients diagnosed in childhood continue to suffer from ADHD during adulthood and genetic risk factors may play an essential role in the persistence of the disorder throughout lifespan. To date, genome-wide association studies (GWAS) of ADHD have been completed in seven independent datasets, six of which were pediatric samples and one on persistent ADHD using a DNA-pooling strategy, but none of them reported genome-wide significant associations. In an attempt to unravel novel genes for the persistence of ADHD into adulthood, we conducted the first two-stage GWAS in adults with ADHD. The discovery sample included 607 ADHD cases and 584 controls. Top signals were subsequently tested for replication in three independent follow-up samples of 2104 ADHD patients and 1901 controls. None of the findings exceeded the genome-wide threshold for significance (P_GC<5e−08), but we found evidence for the involvement of the FBXO33 (F-box only protein 33) gene in combined ADHD in the discovery sample (P=9.02e−07) and in the joint analysis of both stages (P=9.7e−03). Additional evidence for a FBXO33 role in ADHD was found through gene-wise and pathway enrichment analyses in our genomic study. Risk alleles were associated with lower FBXO33 expression in lymphoblastoid cell lines and with reduced frontal gray matter volume in a sample of 1300 adult subjects. Our findings point for the first time at the ubiquitination machinery as a new disease mechanism for adult ADHD and establish a rationale for searching for additional risk variants in ubiquitination-related genes.     

Anterior cingulate cortex glutamate and its association with striatal functioning during cognitive control

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by structural, functional and neurochemical alterations of the fronto-striatal circuits and by deficits in cognitive control. In particular, ADHD has been associated with impairments in top-down fronto-striatal glutamate-signalling. However, it is unknown whether fronto-striatal glutamate is related to cognitive control dysfunction. Here we explored whether and how anterior cingulate cortex (ACC) glutamate relates to striatal BOLD-responses during cognitive control. We used proton magnetic resonance spectroscopy to evaluate glutamate-to-creatine ratios in 62 participants (probands with ADHD n=19, unaffected siblings n=24 and typical controls n=19, mean age=20.4). Spectra were collected from the ACC and the dorsal striatum and glutamate-to-creatine ratios were extracted. Thirty-two participants additionally took part in a functional magnetic resonance imaging (fMRI) Stroop task to investigate neural responses during cognitive control. Given small sample sizes we report all effects with p<0.10 along with effect sizes. ADHD subjects showed decreased glutamate-to-creatine ratios in the ACC (F=3.81, p=0.059, η_p²=0.104; medium to large effect-size) compared with controls. Importantly, decreased ACC glutamate-to-creatine ratios were associated with increased striatal BOLD-responses during cognitive control (rho=?0.41, p=0.019; medium effect-size), independent of diagnosis. Increased striatal responses tended to be associated with more errors during the task and more hyperactivity/impulsivity symptoms (rho=0.34, p=0.058 and rho=0.33, p=0.068, respectively); the latter two being correlated too (rho=0.37, p=0.037), all with medium effect sizes. Our results suggest that ACC glutamate in ADHD might be associated with striatal (dys)functioning during the Stroop task, supporting the role of fronto-striatal glutamate in cognitive control.     

Gβ5-RGS complexes are gatekeepers of hyperactivity involved in control of multiple neurotransmitter systems

Rationale and objectives  

Our knowledge about genes involved in the control of basal motor activity that may contribute to the pathology of the hyperactivity disorders, e.g., attention deficit hyperactivity disorder (ADHD), is limited. Disruption of monoamine neurotransmitter signaling through G protein-coupled receptors (GPCR) is considered to be a major contributing factor to the etiology of the ADHD. Genetic association evidence and functional data suggest that regulators of G protein signaling proteins of the R7 family (R7 RGS) that form obligatory complexes with type 5 G protein beta subunit (Gβ5) and negatively regulate signaling downstream from monoamine GPCRs may play a role in controlling hyperactivity.     

A high density linkage disequilibrium mapping in 14 noradrenergic genes: evidence of association between SLC6A2, ADRA1B and ADHD

Pharmacological evidence suggests the importance of noradrenergic and other monoaminergic neurotransmitters in the aetiology and treatment of attention deficit hyperactivity disorder (ADHD). Until recently, the genes of the noradrenergic pathway were not intensively investigated in ADHD compared to dopaminergic and serotonergic candidates. In this study, 91 SNP markers of 14 noradrenergic genes (an average density of one SNP per 4.5 kbp) were examined in ADHD samples from Ireland and Australia. Although suggestive evidence of association (nominal p?≤?0.05) with the genes SLC6A2, ADRA1A, ADRA1B and ADRA2B was observed, none remained significant after permutation adjustments. In contrast, haplotype analyses demonstrated a significant association between ADHD and a SLC6A2 haplotype comprising the markers rs36009, rs1800887, rs8049681, rs2242447 and rs9930182 (χ²?=?9.39, p-corrected?=?0.019, OR?=?1.51). A rare ADRA1B haplotype made of six SNPs (rs2030373, rs6884105, rs756275, rs6892282, rs6888306 and rs13162302) was also associated (χ²?=?7.79, p-corrected?=?0.042 OR?=?2.74) with the disorder. These findings provide evidence of a contribution of the noradrenaline system to the genetic aetiology of ADHD. The observed haplotype association signals may be driven by as yet unidentified functional risk variants in or around the associated regions. Functional genomic analysis is warranted to determine the biological mechanism of the observed association.     

Brain serotonin receptors and transporters: initiation vs. termination of escalated aggression

Rationale

Recent findings have shown a complexly regulated 5-HT system as it is linked to different kinds of aggression.

Objective

We focus on (1) phasic and tonic changes of 5-HT and (2) state and trait of aggression, and emphasize the different receptor subtypes, their role in specific brain regions, feed-back regulation and modulation by other amines, acids and peptides.

Results

New pharmacological tools differentiate the first three 5-HT receptor families and their modulation by GABA, glutamate and CRF. Activation of 5-HT_1A, 5-HT_1B and 5-HT_2A/2C receptors in mesocorticolimbic areas, reduce species-typical and other aggressive behaviors. In contrast, agonists at 5-HT_1A and 5-HT_1B receptors in the medial prefrontal cortex or septal area can increase aggressive behavior under specific conditions. Activation of serotonin transporters reduce mainly pathological aggression. Genetic analyses of aggressive individuals have identified several molecules that affect the 5-HT system directly (e.g., Tph2, 5-HT_1B, 5-HT transporter, Pet1, MAOA) or indirectly (e.g., Neuropeptide Y, ??CaMKII, NOS, BDNF). Dysfunction in genes for MAOA escalates pathological aggression in rodents and humans, particularly in interaction with specific experiences.

Conclusions

Feedback to autoreceptors of the 5-HT₁ family and modulation via heteroreceptors are important in the expression of aggressive behavior. Tonic increase of the 5-HT₂ family expression may cause escalated aggression, whereas the phasic increase of 5-HT₂ receptors inhibits aggressive behaviors. Polymorphisms in the genes of 5-HT transporters or rate-limiting synthetic and metabolic enzymes of 5-HT modulate aggression, often requiring interaction with the rearing environment.     

Methylation in Syn and Psd95 genes underlie the inhibitory effect of oxytocin on oxycodone-induced conditioned place preference

Oxycodone (Oxy) is one of the most effective analgesics in medicine, but is associated with the development of dependence. Recent studies demonstrating epigenetic changes in the brain after exposure to opiates have provided an insight into possible mechanisms underlying addiction. Oxytocin (OT), an endogenous neuropeptide well known for preventing drug abuse, is a promising pharmacotherapy to counteract addiction. Therefore, we explored the mechanism of Oxy addiction and the role of OT in Oxy-induced epigenetic alterations. In this study, drug-induced changes in conditioned place preference (CPP), i.e. the expression of synaptic proteins and synaptic density in the ventral tegmental area (VTA) were measured. We also sought to identify DNA methyltransferases (DNMTs), ten-eleven translocations (TETs), global 5-methylcytosine (5-mC), and DNA methylation of two genes implicated in plasticity (Synaptophysin, Syn; Post-synaptic density protein 95, Psd95). Oxy (3.0 mg/kg, i.p.) induced CPP acquisition in Sprague-Dawley rats. Oxy down-regulated DNMT1 and up-regulated TET1-3, leading to a decrease in global 5-mC levels and differential demethylation at exon 1 of Syn and exon 2 of Psd95. These changes in DNA methylation of Syn and Psd95 elevated the expression of synaptic proteins (SYN, PSD95) and synaptic density in the VTA. Pretreatment with OT (2.5 µg, i.c.v.) via its receptor specifically blocked Oxy CPP, normalized synaptic density, and regulated DNMT1 and TET2-3 causing reverse of DNA demethylation of Syn and Psd95. DNA methylation is an important gene regulation mechanism underlying Oxy CPP, and OT – via its receptor – could specifically inhibit Oxy addiction.     

Evaluation of single nucleotide polymorphisms in the miR-183–96–182 cluster in adulthood attention-deficit and hyperactivity disorder (ADHD) and substance use disorders (SUDs)

Attention deficit-hyperactivity disorder (ADHD) is a neuropsychiatric disorder characterized by inappropriate and impaired levels of hyperactivity, impulsivity and inattention. Around 75% of adults with ADHD show comorbidity with other psychiatric disorders such as disruptive behavior disorders or substance use disorders (SUDs). Recently, there has been growing interest in studying the role of microRNAs (miRNAs) in the susceptibility to complex disorders. Interestingly, converging evidence suggests that single nucleotide polymorphisms (SNPs) within miRNAs or miRNA target sites may modulate the miRNA-mediated regulation of gene expression through the alteration of the miRNA maturation, structure or expression pattern as well as the silencing mechanisms of target genes. Genetic studies and animal models support the involvement of the serotonin receptor (HTR1B) in ADHD. We evaluated the contribution of one SNP in the miR-96 target site at HTR1B and eight tagSNPs within the genomic region containing this miRNA in 695 adults with ADHD (266 and 396 subjects with and without comorbid SUD, respectively), 403 subjects with SUD without life-time diagnosis of ADHD and 485 sex-matched controls from Spain. Single and multiple marker analyses revealed association between two SNPs located at the 3′ region of miR-96 (rs2402959 and rs6965643) and ADHD without SUD. Our results provide preliminary evidence for the contribution of two sequence variants at the miR-183–96–182 cluster to ADHD without comorbid SUD, and emphasize the need to take comorbidities into account in genetic studies to minimize the effect of heterogeneity and to clarify these complex phenotypes.     

Childhood serotonergic function and early adult outcomes in youth with ADHD: A 15-year follow-up study

Longitudinal studies have shown that clinical precursors of antisocial personality disorder (ASPD) include attention-deficit/hyperactivity disorder (ADHD) and more notably comorbid ADHD and conduct disorder (CD). Despite existing evidence for the purported role of abnormal serotonergic function in aggressive youth and adults, little evidence exists on the role of serotonin in the progression from childhood disruptive behavior disorders to adult psychopathology, including ASPD. This study examined the relation between serotonergic function in children diagnosed with ADHD and the development of ASPD in early adulthood. We hypothesized that low serotonin response to a pharmacological probe in childhood would predict the development of adult ASPD. Towards this goal we divided 40 adults (M?=?37, F?=?3), ages 23–26 (m-24.57, sd-2.33) diagnosed with childhood ADHD into 2 groups: participants with (n?=?21) and without (n?=?19) ASPD. We used logistic regression to assess whether serotonergic measures in childhood assessed via prolactin and cortisol responses to a fenfluramine challenge, would selectively predict the development of ASPD in early adulthood. Logistic regression models showed that low central serotonergic response in childhood indexed by cortisol response significantly predicted adult ASPD (Wald?=?4.427, p?=?.035) but not ADHD diagnosis in adulthood. Adults without ASPD had the highest serotonergic response whereas adults with adolescent ASPD (i.e. early onset ASPD) had the lowest response. Thus we provide new evidence of the link between low serotonergic function in childhood and the development of ASPD in adulthood, particularly for boys with adolescent onset of ASPD. These findings are relevant for understanding the contribution of childhood neurobiology to risk for later ASPD.     

Carboxylesterase 1 gene polymorphism and methylphenidate response in ADHD

Methylphenidate (MPH) is the most frequently prescribed drug in the treatment of attention deficit hyperactivity disorder (ADHD). Several pharmacogenetic studies suggested that catecholamine candidate genes influence individual MPH-responses, but these results are mostly contradictory. Genetic analyses of MPH metabolizing carboxylesterase 1 enzyme (CES1) have not been carried out, whereas, meta-analysis of CYP2D6 genetic variants has been already indicated significant pharmacogenetic differences in atomoxetine treatment. Here we present an association analysis of the CES1 Gly143Glu functional polymorphism in a Hungarian ADHD group (n = 173). The genotype frequencies were similar to that of the general population (5.8% vs 4.1% of Gly/Glu heterozygote). Pharmacogenetic analysis was conducted among 122 ADHD children treated with MPH. Neither the categorical analysis comparing 90 responders vs 32 non-responders, nor the dimensional analysis of Inattention and Hyperactivity–Impulsivity score reduction showed a significant main genotype effect. However, analyzing the daily dose, we observed an association with the rare 143Glu-variant: 5 patients in the responder group carrying the Glu-allele required lower doses of MPH for symptom reduction (0.410 ± 0.127 vs 0.572 ± 0.153 mg/kg, t(1,88) = 2.33, p = 0.022). This result warrants for further investigations of the CES1 gene in larger ADHD samples.     

Abuse and dependence liability analysis of methylphenidate in the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder (ADHD): what have we learned?

Methylphenidate is the most prescribed stimulant medication for attention-deficit/hyperactivity disorder (ADHD). Despite the well documented clinical benefits of the drug, several questions remain unanswered concerning the effects of extended methylphenidate use (e.g. can methylphenidate be abused by ADHD patients? does repeated methylphenidate treatment produce addiction?). Preclinical studies can help address the long-term safety of clinical treatments, moreover animal studies provide valuable information on the details of drug actions. The spontaneously hypertensive rat (SHR), bred from normotensive Wistar Kyoto rat strain, is considered as the best validated and the most widely used animal model of ADHD. We reviewed the findings of research reports that investigated the abuse and dependence liability of methylphenidate in SHR. In particular, we surveyed the studies which investigated the effects of methylphenidate pretreatment on subsequent methylphenidate-induced conditioned place preference or self-administration for they may give insights into the abuse or dependence liability of long-term methylphenidate treatment in ADHD.     

Altered Serotonergic Function may Partially Account for Behavioral Endophenotypes in Steroid Sulfatase-deficient Mice

The X-linked gene STS encodes the steroid hormone-modulating enzyme steroid sulfatase. Loss-of-function of STS, and variation within the gene, have been associated with vulnerability to developing attention deficit hyperactivity disorder (ADHD), a neurodevelopmental condition characterized by inattention, severe impulsivity, hyperactivity, and motivational deficits. ADHD is commonly comorbid with a variety of disorders, including obsessive–compulsive disorder. The neurobiological role of steroid sulfatase, and therefore its potential role in ADHD and associated comorbidities, is currently poorly understood. The 39,X^Y*O mouse, which lacks the Sts gene, exhibits several behavioral abnormalities relevant to ADHD including inattention and hyperactivity. Here, we show that, unexpectedly, 39,X^Y*O mice achieve higher ratios than wild-type mice on a progressive ratio (PR) task thought to index motivation, but that there is no difference between the two groups on a behavioral task thought to index compulsivity (marble burying). High performance liquid chromatography analysis of monoamine levels in wild type and 39,X^Y*O brain tissue regions (the frontal cortex, striatum, thalamus, hippocampus, and cerebellum) revealed significantly higher levels of 5-hydroxytryptamine (5-HT) in the striatum and hippocampus of 39,X^Y*O mice. Significant correlations between hippocampal 5-HT levels and PR performance, and between striatal 5-HT levels and locomotor activity strongly implicate regionally-specific perturbations of the 5-HT system as a neurobiological candidate for behavioral differences between 40,XY and 39,X^Y*O mice. These data suggest that inactivating mutations and functional variants within STS might exert their influence on ADHD vulnerability, and disorder endophenotypes through modulation of the serotonergic system.     

Effects of smoking abstinence on impulsive behavior among smokers high and low in ADHD-like symptoms

Rationale  

Impulsivity, a multifaceted construct that includes inhibitory control and heightened preference for immediate reward, is central to models of drug use and abuse. Within a self-medication framework, abstinence from smoking may lead to an increase in impulsive behavior and the likelihood of relapse, particularly among persons with disorders (e.g., attention-deficit/hyperactivity disorder, ADHD) and personality traits (e.g., impulsivity) linked to impulsive behavior.