Relationship between impulsivity, prefrontal anticipatory activation, and striatal dopamine release during rewarded task performance.

Impulsivity, and in particular the negative urgency aspect of this trait, is associated with poor inhibitory control when experiencing negative emotion. Individual differences in aspects of impulsivity have been correlated with striatal dopamine D2/D3 receptor availability and function. This multi-modal pilot study used both positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to evaluate dopaminergic and neural activity, respectively, using modified versions of the monetary incentive delay task. Twelve healthy female subjects underwent both scans and completed the NEO Personality Inventory Revised to assess Impulsiveness (IMP). We examined the relationship between nucleus accumbens (NAcc) dopaminergic incentive/reward release, measured as a change in D2/D3 binding potential between neutral and incentive/reward conditions with [(11)C]raclopride PET, and blood oxygen level-dependent (BOLD) activation elicited during the anticipation of rewards, measured with fMRI. Left NAcc incentive/reward dopaminergic release correlated with anticipatory reward activation within the medial prefrontal cortex (mPFC), left angular gyrus, mammillary bodies, and left superior frontal cortex. Activation in the mPFC negatively correlated with IMP and mediated the relationship between IMP and incentive/reward dopaminergic release in left NAcc. The mPFC, with a regulatory role in learning and valuation, may influence dopamine incentive/reward release.

Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area.

Hypocretin (orexin) and dynorphin are neuropeptides with opposing actions on motivated behavior. Orexin is implicated in states of arousal and reward, whereas dynorphin is implicated in depressive-like states. We show that, despite their opposing actions, these peptides are packaged in the same synaptic vesicles within the hypothalamus. Disruption of orexin function blunts the rewarding effects of lateral hypothalamic (LH) stimulation, eliminates cocaine-induced impulsivity, and reduces cocaine self-administration. Concomitant disruption of dynorphin function reverses these behavioral changes. We also show that orexin and dynorphin have opposing actions on excitability of ventral tegmental area (VTA) dopamine neurons, a prominent target of orexin-containing neurons, and that intra-VTA orexin antagonism causes decreases in cocaine self-administration and LH self-stimulation that are reversed by dynorphin antagonism. Our findings identify a unique cellular process by which orexin can occlude the reward threshold-elevating effects of coreleased dynorphin and thereby act in a permissive fashion to facilitate reward.

Cortical dopamine release during a behavioral response inhibition task.

Dopamine (DA) dysregulation within fronto-striatal circuitry may underlie impulsivity in alcohol and other substance use disorders. To date, no one has directly demonstrated DA release during a task requiring the control of impulsive behavior. The current study was conducted to determine whether a response inhibition task (stop signal task; SST) would elicit detectable extrastriatal DA release in healthy controls. We hypothesized that DA release would be detected in regions previously implicated in different aspects of inhibitory control. [(18) F]Fallypride (FAL) PET imaging was performed in nine healthy males (24.6 ± 4.1 y.o.) to assess changes in cortical DA during a SST relative to a baseline "Go" task. On separate days, subjects received one FAL scan during the SST, and one FAL scan during a "Go" control; task-order was counter-balanced across subjects. Parametric BPND images were generated and analyzed with SPM8. Voxel-wise analysis indicated significant SST-induced DA release in several cortical regions involved in inhibitory control, including the insula, cingulate cortex, orbitofrontal cortex, precuneus, and supplementary motor area. There was a significant positive correlation between stop signal reaction time and DA release in the left orbitofrontal cortex, right middle frontal gyrus, and right precentral gyrus. These data support the feasibility of using FAL PET to study DA release during response inhibition, enabling investigation of relationships between DA function and impulsive behavior.

5-HT(2A) and mGlu2 receptor binding levels are related to differences in impulsive behavior in the Roman Low- (RLA) and High- (RHA) avoidance rat strains.

The Roman Low- and High-Avoidance rat strains (RLA-I vs RHA-I) have been bidirectionally selected and bred according to their performance in the two-way active avoidance response in the shuttle-box test. Numerous studies have reported a pronounced divergence in emotionality between the two rat strains including differences in novelty seeking, anxiety, stress coping, and susceptibility to addictive substances. However, the underlying molecular mechanisms behind these divergent phenotypes are not known. Here, we determined impulsivity using the 5-choice serial reaction time task and levels of serotonin transporter (SERT), 5-HT(2A) and 5-HT(1A) receptor binding using highly specific radioligands ((3)H-escitalopram, (3)H-MDL100907 and (3)H-WAY100635) and mGlu2/3 receptor binding ((3)H-LY341495) using receptor autoradiography in fronto-cortical sections from RLA-I (n=8) and RHA-I (n=8) male rats. In the more impulsive RHA-I rats, 5-HT(2A), 5-HT(1A) and SERT binding in the frontal cortex was significantly higher compared to RLA-I rats. In contrast, mGlu2/3 receptor binding was decreased by 40% in RHA-I rats compared to RLA-I rats. To differentiate between mGlu2 and mGlu3 receptor protein levels, these were further studied using western blotting, which showed non-detectable levels of mGlu2 receptor protein in RHA rats, while no differences were observed for mGlu3 receptor protein levels. Collectively, these data show general congenital differences in the serotonergic system and a pronounced difference in mGlu2 receptor protein levels. We suggest that the differences in the serotonergic system may mediate some of the phenotypic characteristics in this strain such as hyper-impulsivity and susceptibility to drug addiction.

The effect of acute tryptophan depletion on mood and impulsivity in polydrug ecstasy users.

RATIONALE: Several studies suggest users of 3,4-methylenedioxymethamphetamine (ecstasy) have low levels of serotonin. Low serotonin may make them susceptible to lowered mood. OBJECTIVE: This work aims to study the acute effects on mood and impulsivity of lowering serotonin levels with acute tryptophan depletion in polydrug ecstasy users and to determine whether effects were different in men and women. METHODS: In a double-blind cross-over study, participants who had used ecstasy at least 25 times (n = 13) and nonuser controls (n = 17) received a tryptophan-deficient amino acid mixture and a control amino acid mixture containing tryptophan, at least 1 week apart. Mood was measured using the profile of mood states, and impulsivity was measured with the Go/No-Go task. RESULTS: The main result shows that a lowering of mood after acute tryptophan depletion occurred only in female polydrug ecstasy users (n = 7), relative to controls (n = 9). Results from the Go/No-Go task suggested that impulsivity was not increased by acute tryptophan depletion in polydrug ecstasy users. LIMITATION: The group sizes were small, when males and females were considered separately. CONCLUSIONS: Women polydrug ecstasy users appear to be more susceptible than men to the effects of lowered serotonin levels. If use of ecstasy alone or in conjunction with other drugs causes progressive damage of serotonin neurons, women polydrug ecstasy users may become susceptible to clinical depression.

Gamma aminobutyric acidergic and neuronal structural markers in the nucleus accumbens core underlie trait-like impulsive behavior.

BACKGROUND: Pathological forms of impulsivity are manifest in a number of psychiatric disorders listed in DSM-5, including attention-deficit/hyperactivity disorder and substance use disorder. However, the molecular and cellular substrates of impulsivity are poorly understood. Here, we investigated a specific form of motor impulsivity in rats, namely premature responding, on a five-choice serial reaction time task. METHODS: We used in vivo voxel-based magnetic resonance imaging and ex vivo Western blot analyses to investigate putative structural, neuronal, and glial protein markers in low-impulsive (LI) and high-impulsive rats. We also investigated whether messenger RNA interference targeting glutamate decarboxylase 65/67 (GAD65/67) gene expression in the nucleus accumbens core (NAcbC) is sufficient to increase impulsivity in LI rats. RESULTS: We identified structural and molecular abnormalities in the NAcbC associated with motor impulsivity in rats. We report a reduction in gray matter density in the left NAcbC of high-impulsive rats, with corresponding reductions in this region of glutamate decarboxylase (GAD65/67) and markers of dendritic spines and microtubules. We further demonstrate that the experimental reduction of de novo of GAD65/67 expression bilaterally in the NAcbC is sufficient to increase impulsivity in LI rats. CONCLUSIONS: These results reveal a novel mechanism of impulsivity in rats involving gamma aminobutyric acidergic and structural abnormalities in the NAcbC with potential relevance to the etiology and treatment of attention-deficit/hyperactivity disorder and related disorders.

Delay discounting task in pigs reveals response strategies related to dopamine metabolite.

We developed a novel delay discounting task to investigate outcome impulsivity in pigs. As impulsivity can affect aggression, and might also relate to proactive and reactive coping styles, eight proactive (HR) and eight reactive (LR) pigs identified in a manual restraint test ("Backtest", after Bolhuis et al., 2003) were weaned and mixed in four pens of four unfamiliar pigs, so that each pen had two HR and two LR pigs, and aggression was scored in the 9h after mixing. In the delay discounting task, each pig chose between two levers, one always delivering a small immediate reward, the other a large delayed reward with daily increasing delays, impulsive individuals being the ones discounting the value of the large reward quicker. Two novel strategies emerged: some pigs gradually switched their preference towards the small reward ('Switchers') as predicted, but others persistently preferred the large reward until they stopped making choices ('Omitters'). Outcome impulsivity itself was unrelated to these strategies, to urinary serotonin metabolite (5-HIAA) or dopamine metabolite (HVA) levels, aggression at weaning, or coping style. However, HVA was relatively higher in Omitters than Switchers, and positively correlated with behavioural measures of indecisiveness and frustration during choosing. The delay discounting task thus revealed two response strategies that seemed to be related to the activity of the dopamine system and might indicate a difference in execution, rather than outcome, impulsivity.

[Neurochemistry of impulsiveness and aggression]. / Neurochemia impulsywnosci i agresji.

Aggression is the most frequent social reaction among animals and men, and plays an important role in survival of the fittest. The change of social conditions in the course of development of human civilisation rendered some forms of aggression counter-adaptive, but the neurobiological mechanism of expression of aggression have not fundamentally changed in the last stages of human evolution. The two different kinds of aggression: emotional, serving mainly as a threat, and rational, predatory, serving for the attainment of goal in the most effective way, have different anatomical and neurobiological background and reciprocally inhibit each other. Aggression is modulated by several neurotransmitter and hormonal systems, of which the key role is seemingly played by testosterone, a hormone involved in domination behaviour, and serotonin, whose deficit results in increased impulsiveness.

Cocaine modulation of frontostriatal expression of Zif268, D2, and 5-HT2c receptors in high and low impulsive rats.

Impulsivity shares high comorbidity with substance abuse in humans, and high impulsivity (HI) in rats has been identified as a predictive factor for cocaine addiction-like behavior. Despite the evidence that high impulsivity is associated with altered function of corticostriatal networks, the specific neural substrates underlying the increased vulnerability of impulsive individuals to develop cocaine addiction remain unknown. We therefore investigated specific neural correlates of HI within the corticostriatal circuitry and determined how they interact with a protracted history of cocaine self-administration. We used in situ hybridization to map brain expression of two major genes implicated in impulsivity, encoding the dopamine D2 receptor (DA D2R) and the 5-HT2c receptor (5-HT2cR), and an immediate early gene associated with neuronal plasticity, zif268, in groups of rats selected for HI and low impulsivity (LI) on a 5-choice serial reaction time task (5-CSRTT) immediately after 5-CSRTT training, and following 10 or 50 days of cocaine self-administration. HI rats exhibited decreased DA D2R mRNA in the mesolimbic pathway, and increased 5-HT2cR mRNA in the orbitofrontal cortex compared with LI rats. HI rats also showed decreased zif268 mRNA in the ventral and dorsomedial striatum. Cocaine exposure decreased striatal D2R mRNA in both HI and LI rats, decreased 5-HT2cR mRNA differentially in striatal and prefrontal areas between HI and LI rats, and selectively decreased zif268 mRNA in the orbitofrontal and infralimbic cortices of HI animals. These findings implicate novel markers underlying the vulnerability of impulsive rats to cocaine addiction that localize to the OFC, infralimbic cortex, and striatum.

The effects of brain serotonin deficiency on behavioural disinhibition and anxiety-like behaviour following mild early life stress.

Aberrant serotonin (5-HT) signalling and exposure to early life stress have both been suggested to play a role in anxiety- and impulsivity-related behaviours. However, whether congenital 5-HT deficiency × early life stress interactions influence the development of anxiety- or impulsivity-like behaviour has not been established. Here, we examined the effects of early life maternal separation (MS) stress on anxiety-like behaviour and behavioural disinhibition, a type of impulsivity-like behaviour, in wild-type (WT) and tryptophan hydroxylase 2 (Tph2) knock-in (Tph2KI) mice, which exhibit ~60-80% reductions in the levels of brain 5-HT due to a R439H mutation in Tph2. We also investigated the effects of 5-HT deficiency and early life stress on adult hippocampal neurogenesis, plasma corticosterone levels and several signal transduction pathways in the amygdala. We demonstrate that MS slightly increases anxiety-like behaviour in WT mice and induces behavioural disinhibition in Tph2KI animals. We also demonstrate that MS leads to a slight decrease in cell proliferation within the hippocampus and potentiates corticosterone responses to acute stress, but these effects are not affected by brain 5-HT deficiency. However, we show that 5-HT deficiency leads to significant alterations in SGK-1 and GSK3ß signalling and NMDA receptor expression in the amygdala in response to MS. Together, these findings support a potential role for 5-HT-dependent signalling in the amygdala in regulating the long-term effects of early life stress on anxiety-like behaviour and behavioural disinhibition.

Dietary and genetic manipulations of folate metabolism differentially affect neocortical functions in mice.

Converging evidence suggests that folate-mediated one-carbon metabolism may modulate cognitive functioning throughout the lifespan, but few studies have directly tested this hypothesis. This study examined the separate and combined effects of dietary and genetic manipulations of folate metabolism on neocortical functions in mice, modeling a common genetic variant in the MTHFD1 gene in humans. Mutant (Mthfd1(gt/+)) and wildtype (WT) male mice were assigned to a folate sufficient or deficient diet at weaning and continued on these diets throughout testing on a series of visual attention tasks adapted from the 5-choice serial reaction time task. WT mice on a deficient diet exhibited impulsive responding immediately following a change in task parameters that increased demands on attention and impulse control, and on trials following an error. This pattern of findings indicates a heightened affective response to stress and/or an inability to regulate negative emotions. In contrast, Mthfd1(gt/+) mice (regardless of diet) exhibited attentional dysfunction and a blunted affective response to committing an error. The Mthfd1(gt/+) mice also showed significantly decreased expression levels for genes encoding choline dehydrogenase and the alpha 7 nicotinic cholinergic receptor. The effects of the MTHFD1 mutation were less pronounced when combined with a deficient diet, suggesting a compensatory mechanism to the combined genetic and dietary perturbation of folate metabolism. These data demonstrate that common alterations in folate metabolism can produce functionally distinct cognitive and affective changes, and highlight the importance of considering genotype when making dietary folate recommendations.

Frontal lobe γ-aminobutyric acid levels during adolescence: associations with impulsivity and response inhibition.

BACKGROUND: The brain undergoes major remodeling during adolescence, resulting in improved cognitive control and decision-making and reduced impulsivity, components of behavior mediated in part by the maturing frontal lobe. γ-Aminobutyric acid (GABA), the main inhibitory neurotransmitter system, also matures during adolescence, with frontal lobe GABA receptors reaching adult levels late in adolescence. Thus, the objective of this study was to characterize in vivo developmental differences in brain GABA levels. METHODS: Proton magnetic resonance spectroscopy was used at 4 T to acquire metabolite data from the anterior cingulate cortex (ACC) and the parieto-occipital cortex (POC) in adolescents (n=30) and emerging adults (n = 20). RESULTS: ACC GABA/creatine (Cr) levels were significantly lower in adolescents relative to emerging adults, whereas no age differences were observed in the POC. Lower ACC GABA/Cr levels were significantly associated with greater impulsivity and worse response inhibition, with relationships being most pronounced for ACC GABA/Cr and No-Go response inhibition in adolescent males. CONCLUSIONS: These data provide the first human developmental in vivo evidence confirming frontal lobe GABA maturation, which was linked to impulsiveness and cognitive control. These findings suggest that reduced GABA may be an important neurobiological mechanism in the immature adolescent brain, contributing to the reduced yet rapidly developing ability to inhibit risky behaviors and to make suboptimal decisions, which could compromise adolescent health and safety.

Biochemical correlates of neuropsychiatric illness in maple syrup urine disease.

Maple syrup urine disease (MSUD) is an inherited disorder of branched chain amino acid metabolism presenting with neonatal encephalopathy, episodic metabolic decompensation, and chronic amino acid imbalances. Dietary management enables survival and reduces risk of acute crises. Liver transplantation has emerged as an effective way to eliminate acute decompensation risk. Psychiatric illness is a reported MSUD complication, but has not been well characterized and remains poorly understood. We report the prevalence and characteristics of neuropsychiatric problems among 37 classical MSUD patients (ages 5-35 years, 26 on dietary therapy, 11 after liver transplantation) and explore their underlying mechanisms. Compared with 26 age-matched controls, MSUD patients were at higher risk for disorders of cognition, attention, and mood. Using quantitative proton magnetic resonance spectroscopy, we found lower brain glutamate, N-acetylaspartate (NAA), and creatine concentrations in MSUD patients, which correlated with specific neuropsychiatric outcomes. Asymptomatic neonatal course and stringent longitudinal biochemical control proved fundamental to optimizing long-term mental health. Neuropsychiatric morbidity and neurochemistry were similar among transplanted and nontransplanted MSUD patients. In conclusion, amino acid dysregulation results in aberrant neural networks with neurochemical deficiencies that persist after transplant and correlate with neuropsychiatric morbidities. These findings may provide insight into general mechanisms of psychiatric illness.

Prefrontal cortical-striatal dopamine receptor mRNA expression predicts distinct forms of impulsivity.

Variation in dopamine receptor levels has been associated with different facets of impulsivity. To further delineate the neural substrates underlying impulsive action (inability to withhold a prepotent motor response) and impulsive choice (delay aversion), we characterised rats in the Differential Reinforcement of Low Rates of Responding task and a delay discounting task. We also measured performance on an effort-based discounting task. We then assessed D1 and D2 dopamine receptor mRNA expression in subregions of the prefrontal cortex and nucleus accumbens using in situ hybridisation, and compared these data with behavioral performance. Expression of D1 and D2 receptor mRNA in distinct brain regions was predictive of impulsive action. A dissociation within the nucleus accumbens was observed between subregions and receptor subtypes; higher D1 mRNA expression in the shell predicted greater impulsive action, whereas lower D2 mRNA expression in the core predicted greater impulsive action. We also observed a negative correlation between impulsive action and D2 mRNA expression in the prelimbic cortex. Interestingly, a similar relationship was present between impulsive choice and prelimbic cortex D2 mRNA, despite the fact that behavioral indices of impulsive action and impulsive choice were uncorrelated. Finally, we found that both high D1 mRNA expression in the insular cortex and low D2 mRNA expression in the infralimbic cortex were associated with willingness to exert effort for rewards. Notably, dopamine receptor mRNA in these regions was not associated with either facet of impulsivity. The data presented here provide novel molecular and neuroanatomical distinctions between different forms of impulsivity, as well as effort-based decision-making.

Baseline-dependent effects of cocaine pre-exposure on impulsivity and D2/3 receptor availability in the rat striatum: possible relevance to the attention-deficit hyperactivity syndrome.

We have previously shown that impulsivity in rats predicts the emergence of compulsive cocaine seeking and taking, and is coupled to decreased D2/3 receptor availability in the ventral striatum. As withdrawal from cocaine normalises high impulsivity in rats, we investigated, using positron emission tomography (PET), the effects of response-contingent cocaine administration on D2/3 receptor availability in the striatum. Rats were screened for impulsive behavior on the five-choice serial reaction time task. After a baseline PET scan with the D2/3 ligand [(18)F]fallypride, rats were trained to self-administer cocaine for 15 days under a long-access schedule. As a follow-up, rats were assessed for impulsivity and underwent a second [(18)F]fallypride PET scan. At baseline, we found that D2/3 receptor availability was significantly lower in the left, but not right, ventral striatum of high-impulsive rats compared with low-impulsive rats. While the number of self-administered cocaine infusions was not different between the two impulsivity groups, impulsivity selectively decreased in high-impulsive rats withdrawn from cocaine. This effect was accompanied by a significant increase in D2/3 receptor availability in the left, but not right, ventral striatum. We further report that D2/3 receptor availability was inversely related to baseline D2/3 receptor availability in the ventral striatum of high-impulsive rats, as well as to the left and right dorsal striatum of both low-impulsive and high-impulsive rats. These findings indicate that the reduction in impulsivity in high-impulsive rats by prior cocaine exposure may be mediated by a selective correction of deficient D2/3 receptor availability in the ventral striatum. A similar baseline-dependent mechanism may account for the therapeutic effects of stimulant drugs in clinical disorders such as ADHD.

Divergent effects of D2/3 receptor activation in the nucleus accumbens core and shell on impulsivity and locomotor activity in high and low impulsive rats.

RATIONALE: Previously we demonstrated reduced D2/3 receptor availability in the ventral striatum of hyper-impulsive rats on the five-choice serial reaction time task (5-CSRTT). However, the anatomical locus of D2/3 receptor dysfunction in high impulsive (HI) rats is unknown. OBJECTIVE: In the present study, we investigated whether D2/3 receptor dysfunction in HI rats is localised to the core or shell sub-regions of the nucleus accumbens (NAcb). METHODS: Rats were selected for low (low impulsive, LI) and high impulsivity on the 5-CSRTT and implanted with guide cannulae targeting the NAcb core and shell. The D2/3 receptor agonist quinpirole was locally injected in the NAcb (0.1, 0.3 and 1 µg per infusion) and its effects investigated on the performance of LI and HI rats on the 5-CSRTT as well as spontaneous locomotor activity in an open field. RESULTS: Intra-NAcb core quinpirole increased premature responding in HI rats but not in LI rats. In contrast, intra-NAcb shell quinpirole strongly increased locomotor activity in HI rats, unlike LI rats. This effect was blocked by intra-NAcb shell infusions of the D2/3 receptor antagonist nafadotride (0.03 µg). However, nafadotride was ineffective in blocking the effects of intra-NAcb core quinpirole on premature responding in HI rats. CONCLUSIONS: These findings indicate that impulsivity and hyperactivity are separately regulated by core and shell sub-regions of the NAcb and that HI rats show an enhanced response to D2/3 receptor activation in these regions. These results suggest that the symptom clusters of hyperactivity and impulsivity in attention-deficit hyperactivity disorder may be neurally dissociable at the level of the NAcb.

Dopaminergic and GABA-ergic markers of impulsivity in rats: evidence for anatomical localisation in ventral striatum and prefrontal cortex.

Accumulating evidence indicates that impulsivity, in its multiple forms, involves cortical and subcortical mechanisms and abnormal dopamine (DA) transmission. Although decreased DA D2/D3 receptor availability in the nucleus accumbens (NAcb) predicts trait-like impulsivity in rats it is unclear whether this neurochemical marker extends to both the NAcb core (NAcbC) and shell (NAcbS) and whether markers for other neurotransmitter systems implicated in impulsivity such as serotonin (5-HT), endogenous opioids and γ-amino-butyric acid (GABA) are likewise altered in impulsive rats. We therefore used autoradiography to investigate DA transporter (DAT), 5-HT transporter (5-HTT) and D1, D2/D3, µ-opioid and GABA(A) receptor binding in selected regions of the prefrontal cortex and striatum in rats expressing low and high impulsive behaviour on the five-choice serial reaction-time task. High-impulsive (HI) rats exhibited significantly lower binding for DAT and D2/D3 receptors in the NAcbS and for D1 receptors in the NAcbC compared with low-impulsive (LI) rats. HI rats also showed significantly lower GABA(A) receptor binding in the anterior cingulate cortex. For all regions where receptor binding was altered in HI rats, binding was inversely correlated with impulsive responding on task. There were no significant differences in binding for 5-HTT or µ-opioid receptors in any of the regions investigated. These results indicate that altered D2/D3 receptor binding is localised to the NAcbS of trait-like impulsive rats and is accompanied by reduced binding for DAT. Alterations in binding for D1 receptors in the NAcbC and GABA(A) receptors in the anterior cingulate cortex demonstrate additional markers and putative mechanisms underlying the expression of behavioural impulsivity.

Early social experience is critical for the development of cognitive control and dopamine modulation of prefrontal cortex function.

Social experiences during youth are thought to be critical for proper social and cognitive development. Conversely, social insults during development can cause long-lasting behavioral impairments and increase the vulnerability for psychopathology later in life. To investigate the importance of social experience during the juvenile and early adolescent stage for the development of cognitive control capacities, rats were socially isolated from postnatal day 21 to 42 followed by re-socialization until they reached adulthood. Subsequently, two behavioral dimensions of impulsivity (impulsive action in the five-choice serial reaction time task (5-CSRTT) and impulsive choice in the delayed reward task) and decision making (in the rat gambling task) were assessed. In a separate group of animals, long-lasting cellular and synaptic changes in adult medial prefrontal cortex (PFC) pyramidal neurons were determined following social isolation. Juvenile and early adolescent social isolation resulted in impairments in impulsive action and decision making under novel or challenging circumstances. Moreover, socially isolated rats had a reduced response to enhancement of dopaminergic neurotransmission (using amphetamine or GBR12909) in the 5-CSRTT under challenging conditions. Impulsive choice was not affected by social isolation. These behavioral deficits were accompanied by a loss of sensitivity to dopamine of pyramidal neurons in the medial PFC. Our data show long-lasting deleterious effects of early social isolation on cognitive control and its neural substrates. Alterations in prefrontal cognitive control mechanisms may contribute to the enhanced risk for psychiatric disorders induced by aberrations in the early social environment.

Biological mechanisms associated with increased perseveration and hyperactivity in a genetic mouse model of neurodevelopmental disorder.

Chromosomal deletions at Xp22.3 appear to influence vulnerability to the neurodevelopmental disorders attention deficit hyperactivity disorder (ADHD) and autism. 39,X(Y*)O mice, which lack the murine orthologue of the Xp22.3 ADHD candidate gene STS (encoding steroid sulfatase), exhibit behavioural phenotypes relevant to such disorders (e.g. hyperactivity), elevated hippocampal serotonin (5-HT) levels, and reduced serum levels of dehydroepiandrosterone (DHEA). Here we initially show that 39,X(Y*)O mice are also deficient for the recently-characterised murine orthologue of the Xp22.3 autism candidate gene ASMT (encoding acetylserotonin-O-methyltransferase). Subsequently, to specify potential behavioural correlates of elevated hippocampal 5-HT arising due to the genetic lesion, we compared 39,X(Y*)O MF1 mice to 40,XY MF1 mice on behavioural tasks taxing hippocampal and/or 5-HT function (a 'foraging' task, an object-location task, and the 1-choice serial reaction time task of impulsivity). Although Sts/Asmt deficiency did not influence foraging behaviour, reactivity to familiar objects in novel locations, or 'ability to wait', it did result in markedly increased response rates; these rates correlated with hippocampal 5-HT levels and are likely to index behavioural perseveration, a frequent feature of neurodevelopmental disorders. Additionally, we show that whilst there was no systematic relationship between serum DHEA levels and hippocampal 5-HT levels across 39,X(Y*)O and 40,XY mice, there was a significant inverse linear correlation between serum DHEA levels and activity. Our data suggest that deficiency for genes within Xp22.3 could influence core behavioural features of neurodevelopmental disorders via dissociable effects on hippocampal neurochemistry and steroid hormone levels, and that the mediating neurobiological mechanisms may be investigated in the 39,X(Y*)O model.

The effects of acute tryptophan depletion on impulsivity and mood in adolescents engaging in non-suicidal self-injury.

OBJECTIVE: Non-suicidal self-injury (NSSI) is associated with impaired emotion regulation and impulsivity. Low serotonin (5-hydroxytryptamine) function is associated with NSSI, impaired emotion regulation and impulsivity. We investigated the effects of experimentally lowered 5-hydroxytryptamine activity, via acute tryptophan depletion (ATD), on impulsive action, reflection impulsivity and mood in female adolescents engaging in NSSI. METHODS: Thirty-two female adolescents engaging in NSSI participated in a parallel group ATD study. Following ATD, impulsive action was assessed using the Continuous Performance Test, Identical Pairs Version. Reflection impulsivity was assessed using the Matching Familiar Figures Test. Mood-lowering was examined using the Profile of Mood States. RESULTS: Following ATD, the participants showed an impulsive response style (as reflected in their low ß) and increased attentional capacity (as reflected in their elevated d'). ATD did not affect reflection impulsivity or mood. CONCLUSIONS: Acute tryptophan depletion caused an impulsive response style and increased attentional capacity. Importantly, the findings suggest that low serotonin function is a vulnerability among female adolescents for engaging in NSSI when in emotional distress.