2A Receptor Availability Research Articles

Effect of dopaminergic medication on adenosine 2A receptor availability in patients with Parkinson's disease

ObjectiveTo assess the necessity of withdrawing dopaminergic medication in Parkinson's disease (PD) patients for accurate estimation of adenosine 2A receptor (A2AR) availability using [11C]TMSX PET imaging. This was accomplished by studying the short-term effect of the cessation of dopaminergic medication on A2AR availability in non-dyskinetic patients with PD treated with dopaminergic medication. MethodsEight PD patients (age 67.9 ± 5.6 years; 6 men, 2 women) without dyskinesia were enrolled in this study. A2AR availability was measured using PET imaging with a [7-methyl-11C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine ([11C]TMSX) radioligand after a short term cessation of dopaminergic medication (12hrs for levodopa, 24hrs for dopamine agonists and MAO-B inhibitors). Repeated PET imaging was performed while the patients were back ‘on’ their regular dopaminergic medication (median 13 days after first imaging). Conventional MRI was acquired for anatomical reference. Specific binding of [11C]TMSX was quantified as distribution volume ratios (DVR) for caudate, pallidum and putamen using Logan graphical method with clustered gray matter reference region. ResultsNo significant differences were observed for the DVRs in all three striatal regions between ‘on’ and ‘off’ medication states. Strong correlations were also observed between the two states. Statistical equivalence was found in pallidum (TOST equivalence test, p = 0.045) and putamen (TOST equivalence test, p = 0.022), but not in caudate DVR (TOST equivalence test, p = 0.201) between the two medication states. ConclusionsOur results show that dopaminergic medication has no significant short-term effect on the availability of A2A receptors in putamen and pallidum of patients with PD. However, relatively poor repeatability was demonstrated in the caudate.

Effect of Dopaminergic Medication on Adenosine 2A Receptor Availability in Patients with Parkinson’s Disease (30)

Effect of Dopaminergic Medication on Adenosine 2A Receptor Availability in Patients with Parkinson’s Disease (30)

The Relationship Between Serotonin-2A Receptor and Cognitive Functions in Nondemented Parkinson's Disease Patients with Visual Hallucinations.

There is growing evidence that the serotonergic system, in particular serotonin 2A receptors, is involved in neuropsychiatric symptoms in Parkinson's disease (PD), including cognitive processing and visual hallucinations. However, the relationship between serotonin 2A receptor availability, visual hallucinations, and cognitive profile is unknown. The objective of this study was to investigate the level of serotonin 2A receptor availability in brain regions affected by visual hallucinations and to test the association with cognitive/behavioral changes in patients who have PD with visual hallucinations. Nondemented patients who had PD with (n = 11) and without (n = 8) visual hallucinations and age-matched controls (n = 10) were recruited. All participants completed neuropsychological testing, which consisted of visuoperceptual, executive, memory, language, and frontal-behavioral function. Positron emission tomography scans using [18F]setoperone, a serotonin 2A antagonist radioligand, were acquired in patients with PD, and a parametric binding potential map of [18F]setoperone was calculated with the simplified reference tissue model using the cerebellum as a reference. Patients who had PD with visual hallucinations exhibited significantly lower scores on measures of executive and visuoperceptual functions compared with age-matched controls. These changes were paralleled by decreased [18F]setoperone binding in the right insula, bilateral dorsolateral prefrontal cortex, right orbitofrontal cortex, right middle temporal gyrus, and right fusiform gyrus. The psychometric correlation analysis revealed significant relationships among tests associated with visuoperceptual function, memory and learning, and serotonin 2A binding in different prefrontal and ventral visual stream regions. There was also reduced serotonin 2A receptor binding in patients who had PD with depression. These findings support a complex interaction between serotonin 2A receptor function and cognitive processing in patients who have PD with visual hallucinations.

Increased Serotonin 2A Receptor Availability in the Orbitofrontal Cortex of Physically Aggressive Personality Disordered Patients

Impulsive physical aggression is a common and problematic feature of many personality disorders. The serotonergic system is known to be involved in the pathophysiology of aggression, and multiple lines of evidence have implicated the serotonin 2A receptor (5-HT(2A)R). We sought to examine the role of the 5-HT(2A)R in impulsive aggression specifically in the orbitofrontal cortex (OFC), given that our own studies and an extensive literature indicate that serotonergic disturbances in the OFC are linked to aggression. We have previously hypothesized that increased 5-HT(2A)R function in the OFC is a state phenomenon that promotes impulsive aggression. Serotonin 2A receptor availability was measured with positron emission tomography and the selective 5-HT(2A)R antagonist radioligand [(11)C]MDL100907 in two groups of impulsively aggressive personality disordered patients-14 with current physical aggression, and 15 without current physical aggression-and 25 healthy control subjects. Clinical ratings of various symptom dimensions were also obtained. Orbitofrontal 5-HT(2A)R availability was greater in patients with current physical aggression compared with patients without current physical aggression and healthy control subjects; no differences in OFC 5-HT(2A)R availability were observed between patients without current physical aggression and healthy control subjects. No significant differences in 5-HT(2A)R availability were observed in other brain regions examined. Among both groups of impulsively aggressive personality disordered patients combined, OFC 5-HT(2A)R availability was correlated, specifically, with a state measure of impulsive aggression. These findings are consistent with our previously described model in which impulsive aggression is related to dynamic changes in 5-HT(2A)R function in the OFC.

In vivo PET study of 5HT 2A serotonin and D 2 dopamine dysfunction in drug-naive obsessive-compulsive disorder

There are several lines of evidence, the majority indirect, suggesting that changes in serotonergic or dopaminergic neurotransmission may contribute to the pathogenesis of obsessive-compulsive disorder (OCD). We evaluated the co-occurrence of serotonergic and dopaminergic dysfunctions in OCD subjects, all drug-naive, with no co-morbidity and homogeneous for symptoms. Each subject underwent two positron emission tomography (PET) scans to measure in vivo both serotonin (5-HT 2A) and dopamine (D 2) receptor distribution. For this, we used [ 11C]MDL and [ 11C]Raclopride, highly selective antagonists of 5-HT 2A and D 2 receptors, respectively. The comparison with a control group was carried out using both voxel-wise (SPM2) and regions of interest (ROI) approaches. There was a significant reduction of 5-HT 2A receptor availability in frontal polar, dorsolateral, and medial frontal cortex, as well as in parietal and temporal associative cortex of OCD patients. We also found a significant correlation between 5-HT 2A receptor availability in orbitofrontal and dorsolateral frontal cortex and clinical severity, suggesting a specific role for serotonin in determining the OCD symptoms. There was also a significant reduction of [ 11C]Raclopride uptake in the whole striatum, particularly in the ventral portion, possibly reflecting endogenous dopaminergic hyperactivity. The co-existence of serotonergic and dopaminergic dysfunction in the same homogeneous group of drug-naive OCD patients provides in vivo evidence for the complex molecular mechanisms of OCD, and represents the basis for further studies on the effect of therapeutic agents with specific modulatory effects on these neurotransmission systems.

Long-term estrogen therapy and 5-HT 2A receptor binding in postmenopausal women; a single photon emission tomography (SPET) study

Variation in estrogen level is reported by some to affect brain maturation and memory. The neurobiological basis for this may include modulation of the serotonergic system. No neuroimaging studies have directly examined the effect of extended estrogen therapy (ET), on the 5-HT 2A receptor in human brain. We investigated the effect of long-term ET on cortical 5-HT 2A receptor availability in postmenopausal women. In a cross-sectional study, we compared cortical 5-HT 2A receptor availability in 17 postmenopausal ERT-naive women and 17 long-term oophorectomised estrogen-users, age- and IQ-matched using single photon emission tomography and the selective 5-HT 2A receptor ligand 123I-5-I-R91150. Also, we used the Revised Wechsler Memory Scale to relate memory function to 5-HT 2A receptor availability. Never-users had significantly higher 5-HT 2A receptor availability than estrogen-users in hippocampus (1.17 vs. 1.11, respectively, p = 0.02), although this did not remain significant after correction for multiple comparisons. Hippocampal 5-HT 2A receptor availability correlated negatively with verbal and general memory and delayed recall ( r = − 0.45, p = 0.01; r = − 0.40, p = 0.02; r = − 0.36, p = 0.04). Right superior temporal 5-HT 2A receptor availability correlated negatively with verbal memory ( r = − 0.36, p = 0.04). In estrogen-users, receptor availability correlated negatively with verbal and general memory ( r = − 0.70, p = 0.002; r = − 0.69, p = 0.002); and in never-users, receptor availability negatively correlated with attention and concentration ( r = − 0.54, p = 0.02). Long-term ET may be associated with lower 5-HT 2A receptor availability in hippocampus. This may reflect increased activity within the serotonergic pathway leading to down-regulation of post-synaptic receptor. Also, increased availability of the 5-HT 2A receptor in hippocampus is associated with poorer memory function.

Increased 5-HT<char aid="99820963" id="sub">2A</char> Receptor Binding in Euthymic, Medication-Free Patients Recovered From Depression: A Positron Emission Study With [<char aid="99820964" id="sup">11</char>C]MDL 100,907

Objective: A previous positron emission tomography (PET) study reported increased serotonin 5-HT 2A receptor binding in unmedicated depressed patients with high scores on the Dysfunctional Attitudes Scale. The purpose of the present study was to use the highly selective 5-HT 2A receptor ligand [ 11 C]MDL 100,907 in a PET imaging paradigm to assess 1) 5-HT 2A receptor binding potential in euthymic subjects with a history of recurrent depression and 2) the relationship between receptor binding and scores on the Dysfunctional Attitudes Scale. Method: Cortical 5-HT 2A receptor binding was measured in 20 unmedicated, fully recovered unipolar depressed patients and 20 age- and gender-matched comparison subjects. Regional estimates of binding potential were obtained using a reversible plasma input function compartmental model and the cerebellum as a reference region to estimate the free and non-specifically bound [ 11 C]MDL 100,907 in brain tissue. Results: Relative to the comparison subjects, the recovered depressed patients demonstrated significantly higher 5-HT 2A receptor binding potential in the frontal cortex (mean increase: 19%), parietal cortex (mean increase: 25%), and occipital cortex (mean increase: 19%). 5-HT 2A receptor binding potential correlated negatively with age in both patients and comparison subjects and positively with the Dysfunctional Attitudes Scale in the recovered patients. Conclusions: These findings should be considered preliminary but suggest that recovered subjects with a history of recurrent major depression have elevated binding potential of cortical 5-HT 2A receptors. The correlation of increased 5-HT 2A receptor binding potential with increased scores on Dysfunctional Attitudes Scale supports earlier work suggesting that increased 5-HT 2A receptor availability characterizes a group of depressed patients with high levels of dysfunctional attitudes.

Widespread increases of cortical serotonin type 2A receptor availability after hormone therapy in euthymic postmenopausal women

Objective To use statistical parametric mapping to determine the extent of previously reported serotonin type 2A (5HT 2A) receptor binding potential (BP) increases in postmenopausal women following hormone therapy. Design Repeated measures positron emission tomography (PET) study. Setting Academic research environment. Patient(s) Five healthy, postmenopausal women. Intervention(s) Serial PET images of [ 18F]altanserin uptake were acquired to measure 5HT 2A receptor BP at menopausal baseline, following estradiol (E 2), and following combined E 2 + micronized progesterone (P 4). Main outcome measure(s) 5HT 2A receptor BP. Result(s) Combined E 2 + P 4 treatment was associated with significant increases in the 5HT 2A receptor BP increases in widespread areas of cerebral cortex. Treatment with E 2 alone was also associated with widespread cortical BP increases, although these changes reached statistical significance in fewer regions. The rate of [ 18F]altanserin metabolism was significantly decreased in the E 2 + P 4 condition relative to menopausal baseline, but this difference did not appear to correlate with changes in 5HT 2A receptor BP. Conclusion(s) Estradiol priming followed by combined E 2 + P 4 is associated with widespread increases in 5HT 2A receptor BP in the cerebral cortex, consistent with the E 2-associated increases in 5HT 2A receptor density previously observed in experimental animals.