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Converging evidence from clinical, preclinical, neuroimaging, and genetic research implicates dopamine neurotransmission in the pathophysiology of attention deficit hyperactivity disorder (ADHD). The in vivo neuroreceptor imaging evidence also suggests alterations in the dopamine system in ADHD; however, the nature and behavioral significance of those have not yet been established. Here, we investigated striatal dopaminergic function in ADHD using [(11)C]raclopride PET with a d-amphetamine challenge. We also examined the relationship of striatal dopamine responses to ADHD symptoms and neurocognitive function. A total of 15 treatment-free, noncomorbid adult males with ADHD (age: 29.87 ± 8.65) and 18 healthy male controls (age: 25.44 ± 6.77) underwent two PET scans: one following a lactose placebo and the other following d-amphetamine (0.3 mg/kg, p.o.), administered double blind and in random order counterbalanced across groups. In a separate session without a drug, participants performed a battery of neurocognitive tests. Relative to the healthy controls, the ADHD patients, as a group, showed greater d-amphetamine-induced decreases in striatal [(11)C]raclopride binding and performed more poorly on measures of response inhibition. Across groups, a greater magnitude of d-amphetamine-induced change in [(11)C]raclopride binding potential was associated with poorer performance on measures of response inhibition and ADHD symptoms. Our findings suggest an augmented striatal dopaminergic response in treatment-naive ADHD. Though in contrast to results of a previous study, this finding appears consistent with a model proposing exaggerated phasic dopamine release in ADHD. A susceptibility to increased phasic dopamine responsivity may contribute to such characteristics of ADHD as poor inhibition and impulsivity.

Drugs that increase dopamine levels in the brain can cause psychotic symptoms in healthy individuals and worsen them in schizophrenic patients. Psychological stress also increases dopamine release and is thought to play a role in susceptibility to psychotic illness. We hypothesized that healthy individuals at elevated risk of developing psychosis would show greater striatal dopamine release than controls in response to stress. Using positron emission tomography and [(11)C]raclopride, we measured changes in synaptic dopamine concentrations in 10 controls and 16 psychometric schizotypes; 9 with perceptual aberrations (PerAb, ie positive schizotypy) and 7 with physical anhedonia (PhysAn, ie negative schizotypy). [(11)C]Raclopride binding potential was measured during a psychological stress task and a sensory-motor control. All three groups showed significant increases in self-reported stress and cortisol levels between the stress and control conditions. However, only the PhysAn group showed significant stress-induced dopamine release. Dopamine release in the entire sample was significantly negatively correlated with smooth pursuit gain, an endophenotype linked to frontal lobe function. Our findings suggest the presence of abnormalities in the dopamine response to stress in negative symptom schizotypy, and provide indirect evidence of a link to frontal function.

Previous research has suggested that there may be overlap between schizophrenia and attention-deficit hyperactivity disorder (ADHD). The relationship between schizotypal personality traits, ADHD features and polymorphisms was evaluated in dopamine-related genes. Thirty-one healthy, Caucasian men completed the Rust Inventory of Schizotypal Cognitions (RISC) and the ADHD Self-Report Scale (ASRS). Catechol-O-methyltransferase (COMT) Val158Met, dopamine receptors of the D3 type (DRD3) Ser9Gly, DRD4 variable number of tandem repeats (VNTR), and SLC6A3 VNTR polymorphisms were analyzed. RISC score was correlated with ASRS score (r = 0.54, P = 0.003). COMT Met homozygotes had higher ASRS scores than Val homozygotes (P = 0.005). These findings are consistent with evidence of overlap between schizophrenia and ADHD and support an involvement of COMT genotype in ADHD features.

Alterations in catecholamine signaling and cortical morphology have both been implicated in the pathophysiology of attention deficit/hyperactivity disorder (ADHD). However, possible links between the two remain unstudied. Here, we report exploratory analyses of cortical thickness and its relation to striatal dopamine transmission in treatment-naïve adults with ADHD and matched healthy controls. All participants had one magnetic resonance imaging (MRI) and two [11C]raclopride positron emission tomography scans. Associations between frontal cortical thickness and the magnitude of d-amphetamine-induced [11C]raclopride binding changes were observed that were divergent in the two groups. In the healthy controls, a thicker cortex was associated with less dopamine release; in the ADHD participants the converse was seen. The same divergence was seen for baseline D2/3 receptor availability. In healthy volunteers, lower D2/3 receptor availability was associated with a thicker cortex, while in the ADHD group lower baseline D2/3 receptor availability was associated with a thinner cortex. Individual differences in cortical thickness in these regions correlated with ADHD symptom severity. Together, these findings add to the evidence of associations between dopamine transmission and cortical morphology, and suggest that these relationships are altered in treatment-naïve adults with ADHD. [ABSTRACT FROM AUTHOR]

Eye movements are sensitive indicators of pharmacological effects on sensorimotor and cognitive processing. Methylphenidate (MPH) is one of the most prescribed medications in psychiatry. It is increasingly used as a cognitive enhancer by healthy individuals. However, little is known of its effect on healthy cognition. Here we used oculomotor tests to evaluate the effects of MPH on basic oculomotor and executive functions. Twenty-nine males were given 20mg of MPH orally in a double-blind placebo-controlled crossover design. Participants performed visually-guided saccades, sinusoidal smooth pursuit, predictive saccades and antisaccades one hour post-capsule administration. Heart rate and blood pressure were assessed prior to capsule administration, and again before and after task performance. Visually-guided saccade latency decreased with MPH (p<0.004). Smooth pursuit gain increased on MPH (p<0.001) and number of saccades during pursuit decreased (p<0.001). Proportion of predictive saccades increased on MPH (p<0.004), specifically in conditions with predictable timing. Peak velocity of predictive saccades increased with MPH (p<0.01). Antisaccade errors and latency were unaffected. Physiological variables were also unaffected. The effects on visually-guided saccade latency and peak velocity are consistent with MPH effects on dopamine in basal ganglia. The improvements in predictive saccade conditions and smooth pursuit suggest effects on timing functions. [ABSTRACT FROM AUTHOR]

Abstract: Psychological stress causes dopamine release in the striatum and is thought to play a role in susceptibility to psychotic illness. Previous work suggests that an elevated dopaminergic response to stress may index vulnerability to psychosis in certain individuals. With functional magnetic resonance imaging, we measured stress-induced changes in brain activity in healthy individuals at elevated risk of developing psychosis. Participants were 15 controls and 25 psychometric schizotypes: 12 with positive symptom schizotypy (perceptual aberrations) and 13 with negative symptom schizotypy (physical anhedonia), as determined by questionnaires (). In the scanner, participants performed the Montreal Imaging Stress Task and a matched sensory-motor control task. Measures of self-reported stress and salivary cortisol levels were taken throughout the experiment. All three groups showed significant increases in self-reported stress and significant fMRI signal change in the striatal, limbic and cortical regions. However, the Physical Anhedonia group showed greater stress-induced striatal and limbic deactivation than the other two groups. Deactivation in the striatum was significantly correlated with Physical Anhedonia score across all subjects. Our findings suggest the presence of abnormalities in striatal response to stress in negative symptom schizotypy. [Copyright &y& Elsevier]

Drugs that increase dopamine levels in the brain can cause psychotic symptoms in healthy individuals and worsen them in schizophrenic patients. Psychological stress also increases dopamine release and is thought to play a role in susceptibility to psychotic illness. We hypothesized that healthy individuals at elevated risk of developing psychosis would show greater striatal dopamine release than controls in response to stress. Using positron emission tomography and [11C]raclopride, we measured changes in synaptic dopamine concentrations in 10 controls and 16 psychometric schizotypes; 9 with perceptual aberrations (PerAb, ie positive schizotypy) and 7 with physical anhedonia (PhysAn, ie negative schizotypy). [11C]Raclopride binding potential was measured during a psychological stress task and a sensory-motor control. All three groups showed significant increases in self-reported stress and cortisol levels between the stress and control conditions. However, only the PhysAn group showed significant stress-induced dopamine release. Dopamine release in the entire sample was significantly negatively correlated with smooth pursuit gain, an endophenotype linked to frontal lobe function. Our findings suggest the presence of abnormalities in the dopamine response to stress in negative symptom schizotypy, and provide indirect evidence of a link to frontal function.Neuropsychopharmacology (2008) 33, 2033–2041; doi:10.1038/sj.npp.1301597; published online 24 October 2007 [ABSTRACT FROM AUTHOR]