Biological psychiatry. Cognitive neuroscience and neuroimaging, Jan 21, 2018
We used positron emission tomography imaging with [C]raclopride to examine the effects of consump... more We used positron emission tomography imaging with [C]raclopride to examine the effects of consumption of alcohol or placebo beverage by participants with alcohol use disorder (AUD) compared with healthy participants with and without family history of AUD. We sought to assess dopamine release following alcohol exposure in relation to AUD risk. Three groups were enrolled: participants with AUD (n = 15) and healthy participants with family history negative (n = 34) or positive (n = 16) for AUD. Participants consumed a placebo (n = 65) or alcohol (n = 63) beverage in counterbalanced order before positron emission tomography scanning (128 scans). Binding potential (BP) in the two drink conditions and the percent change in BP between conditions were evaluated across striatal subregions. Subjective effects of beverage consumption were rated. Effects of group, drink order, and sex were evaluated. Alcohol resulted in greater dopamine release than did placebo in the ventral striatum (p < ....
All currently available antipsychotic medications bind to both the dopamine-2 (D2) and dopamine-3... more All currently available antipsychotic medications bind to both the dopamine-2 (D2) and dopamine-3 (D3) receptors in vitro. However, there is conflicting evidence from in vivo studies about whether or not antipsychotic medications bind to the D3 receptor (D3R). The purpose of this study was to determine whether acute doses of risperidone bind to the D3R in humans. We performed PET scans on an mCT scanner with [(11)C]-(+)-PHNO injected as a bolus, before and after a 2mg oral dose of risperidone in five medication free subjects with schizophrenia. The subjects were scanned for 120min and underwent an MRI scan for region of interest delineation and coregistration. Cerebellum was used as a reference region. Simplified reference tissue modeling (SRTM) was used to calculate BPND. We observed binding to the D3R receptor by risperidone as evidenced by observable occupancy in regions in which the [(11)C]-(+)-PHNO signal is almost exclusively from the D3R (i.e., substantia nigra/ventral tegmen...
Purpose: Pharmacological evidence suggests abnormalities in the brain serotonin (5-HT) system in ... more Purpose: Pharmacological evidence suggests abnormalities in the brain serotonin (5-HT) system in obsessive–compulsive disorder (OCD) involving cortical 5-HT2A receptors. However, recent animal and human studies have also implicated the glutamate system in OCD. Animal studies found that disrupting glutamatergic signaling at cortico-striatal synapses leads to OCD-like behaviors, human genetic studies demonstrated associations between the glutamate transporter SLC1A1 and OCD, and case studies and open label trials demonstrated efficacy of glutamatergic agents in reducing OCD symptoms. This has led to the hypothesis that OCD symptoms result either directly or indirectly from increased glutamatergic signaling in cortico-striatal pathways. As 5-HT2A receptors are located on both pyramidal cells and interneurons and may modulate glutamate and GABA transmission, we measured 5-HT2A receptor availability with PET, and Glx (glutamate plus glutamine) and GABA levels with MRS in OCD patients and matched controls.
Introduction: Low striatal dopamine 2 receptor (D2) availability and low ventrostriatal (VST) dop... more Introduction: Low striatal dopamine 2 receptor (D2) availability and low ventrostriatal (VST) dopamine (DA) release have been observed in alcoholism, cocaine and heroin dependence. Less is known about the DAergic system in cannabis dependence. We assessed D2 availability and DA release in cannabis dependence and explored the effects of early age of onset (AOO) on these parameters, using [11C]raclopride PET and the amphetamine challenge paradigm.
D1 receptors are the main mediators of dopamine transmission in the cortex and subserve cognitive... more D1 receptors are the main mediators of dopamine transmission in the cortex and subserve cognitive functions that are affected in patients with schizophrenia. Prior imaging studies have suggested abnormalities in the expression of these receptors in schizophrenia, but no conclusive picture has emerged yet. One source of discrepancy may have been prior antipsychotic exposure. The goal of this study was to determine D1 receptor expression in separate groups of patients with schizophrenia, with or without prior antipsychotic exposure, compared to respectively matched controls.
Purpose: 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-C-methyl-oxime ([C]-ABP688) is a hig... more Purpose: 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-C-methyl-oxime ([C]-ABP688) is a highly-selective antagonist PET tracer for imaging the metabotropic glutamate receptor subtype 5 (mGluR5). The aims of this study were to test the reproducibility of outcome measures using this tracer with anesthetized baboons and to test the effect of challenge with the glutamate releaser N-acetylcysteine (NAC) on [C]-ABP688 specific binding.
Introduction:Dopamine (DA)plays a role in thepathophysiologyof both schizophrenia and addiction. ... more Introduction:Dopamine (DA)plays a role in thepathophysiologyof both schizophrenia and addiction. Imaging studies have shown thatDA is increased in the associative striatum(AST), and specifically in the precommissural caudate, in schizophrenia,while it is blunted in addiction, predominantly in the ventral striatum(VST).Wehypothesized that subjects suffering fromboth schizophrenia and addictionmayhave both alterations. Here,we assessedD2 receptors and DA transmission in striatal subregions with [C]raclopride PET and the amphetamine challenge paradigm.
Journal of Cerebral Blood Flow & Metabolism, 2007
The dopamine D1 receptor antagonist radioligand [11C]NNC 112 has previously been reported to have... more The dopamine D1 receptor antagonist radioligand [11C]NNC 112 has previously been reported to have 100-fold selectivity for the D1 receptor compared with the serotonin 5-HT2A receptor. In this study, we tested the selectivity by scanning seven healthy human research volunteers with [11C]NNC 112 before and after 2mg of the antipsychotic drug risperidone, a dose that putatively blocks all 5-HT2A receptors with negligible effect on D1 receptors. We found that specific binding in cortical regions was reduced by 20% to 30%, whereas the striatum showed no change. Based on the known relative densities of these receptors in humans, our results suggest 5- to 10-fold selectivity of [11C]NNC 112 for D1 versus 5-HT2A as opposed to 100-fold selectivity. These results suggest caution in interpreting data from studies using this tracer to measure cortical D1 receptors as well as the need for more selective radioligands to assess cortical D1 receptors.
Journal of psychopharmacology (Oxford, England), 2011
D(1) receptors are the main mediators of dopamine transmission in the cortex and subserve cogniti... more D(1) receptors are the main mediators of dopamine transmission in the cortex and subserve cognitive functions that are affected in patients with schizophrenia. Prior imaging studies have suggested abnormalities in the expression of these receptors in schizophrenia, but no conclusive picture has emerged yet. One source of discrepancy may have been prior antipsychotic exposure. We used positron emission tomography (PET) and a D1 radiotracer, [(11)C]NNC112, in drug naïve (DN, n = 12) and drug free (DF, n = 13) patients with schizophrenia and 40 healthy control subjects (HC, n = 40 total, n = 24 per comparison group) matched for age, gender, ethnicity, parental socioeconomic status and cigarette smoking. We measured the binding potential BPP, corrected for partial volume effects. The outcome measure was obtained in cortical and striatal subregions outlined on coregistered individual MRIs. Partial volume effect corrected BPP measures were significantly higher in DN vs controls in cortica...
Biological psychiatry. Cognitive neuroscience and neuroimaging, Jan 21, 2018
We used positron emission tomography imaging with [C]raclopride to examine the effects of consump... more We used positron emission tomography imaging with [C]raclopride to examine the effects of consumption of alcohol or placebo beverage by participants with alcohol use disorder (AUD) compared with healthy participants with and without family history of AUD. We sought to assess dopamine release following alcohol exposure in relation to AUD risk. Three groups were enrolled: participants with AUD (n = 15) and healthy participants with family history negative (n = 34) or positive (n = 16) for AUD. Participants consumed a placebo (n = 65) or alcohol (n = 63) beverage in counterbalanced order before positron emission tomography scanning (128 scans). Binding potential (BP) in the two drink conditions and the percent change in BP between conditions were evaluated across striatal subregions. Subjective effects of beverage consumption were rated. Effects of group, drink order, and sex were evaluated. Alcohol resulted in greater dopamine release than did placebo in the ventral striatum (p < ....
All currently available antipsychotic medications bind to both the dopamine-2 (D2) and dopamine-3... more All currently available antipsychotic medications bind to both the dopamine-2 (D2) and dopamine-3 (D3) receptors in vitro. However, there is conflicting evidence from in vivo studies about whether or not antipsychotic medications bind to the D3 receptor (D3R). The purpose of this study was to determine whether acute doses of risperidone bind to the D3R in humans. We performed PET scans on an mCT scanner with [(11)C]-(+)-PHNO injected as a bolus, before and after a 2mg oral dose of risperidone in five medication free subjects with schizophrenia. The subjects were scanned for 120min and underwent an MRI scan for region of interest delineation and coregistration. Cerebellum was used as a reference region. Simplified reference tissue modeling (SRTM) was used to calculate BPND. We observed binding to the D3R receptor by risperidone as evidenced by observable occupancy in regions in which the [(11)C]-(+)-PHNO signal is almost exclusively from the D3R (i.e., substantia nigra/ventral tegmen...
Purpose: Pharmacological evidence suggests abnormalities in the brain serotonin (5-HT) system in ... more Purpose: Pharmacological evidence suggests abnormalities in the brain serotonin (5-HT) system in obsessive–compulsive disorder (OCD) involving cortical 5-HT2A receptors. However, recent animal and human studies have also implicated the glutamate system in OCD. Animal studies found that disrupting glutamatergic signaling at cortico-striatal synapses leads to OCD-like behaviors, human genetic studies demonstrated associations between the glutamate transporter SLC1A1 and OCD, and case studies and open label trials demonstrated efficacy of glutamatergic agents in reducing OCD symptoms. This has led to the hypothesis that OCD symptoms result either directly or indirectly from increased glutamatergic signaling in cortico-striatal pathways. As 5-HT2A receptors are located on both pyramidal cells and interneurons and may modulate glutamate and GABA transmission, we measured 5-HT2A receptor availability with PET, and Glx (glutamate plus glutamine) and GABA levels with MRS in OCD patients and matched controls.
Introduction: Low striatal dopamine 2 receptor (D2) availability and low ventrostriatal (VST) dop... more Introduction: Low striatal dopamine 2 receptor (D2) availability and low ventrostriatal (VST) dopamine (DA) release have been observed in alcoholism, cocaine and heroin dependence. Less is known about the DAergic system in cannabis dependence. We assessed D2 availability and DA release in cannabis dependence and explored the effects of early age of onset (AOO) on these parameters, using [11C]raclopride PET and the amphetamine challenge paradigm.
D1 receptors are the main mediators of dopamine transmission in the cortex and subserve cognitive... more D1 receptors are the main mediators of dopamine transmission in the cortex and subserve cognitive functions that are affected in patients with schizophrenia. Prior imaging studies have suggested abnormalities in the expression of these receptors in schizophrenia, but no conclusive picture has emerged yet. One source of discrepancy may have been prior antipsychotic exposure. The goal of this study was to determine D1 receptor expression in separate groups of patients with schizophrenia, with or without prior antipsychotic exposure, compared to respectively matched controls.
Purpose: 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-C-methyl-oxime ([C]-ABP688) is a hig... more Purpose: 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-C-methyl-oxime ([C]-ABP688) is a highly-selective antagonist PET tracer for imaging the metabotropic glutamate receptor subtype 5 (mGluR5). The aims of this study were to test the reproducibility of outcome measures using this tracer with anesthetized baboons and to test the effect of challenge with the glutamate releaser N-acetylcysteine (NAC) on [C]-ABP688 specific binding.
Introduction:Dopamine (DA)plays a role in thepathophysiologyof both schizophrenia and addiction. ... more Introduction:Dopamine (DA)plays a role in thepathophysiologyof both schizophrenia and addiction. Imaging studies have shown thatDA is increased in the associative striatum(AST), and specifically in the precommissural caudate, in schizophrenia,while it is blunted in addiction, predominantly in the ventral striatum(VST).Wehypothesized that subjects suffering fromboth schizophrenia and addictionmayhave both alterations. Here,we assessedD2 receptors and DA transmission in striatal subregions with [C]raclopride PET and the amphetamine challenge paradigm.
Journal of Cerebral Blood Flow & Metabolism, 2007
The dopamine D1 receptor antagonist radioligand [11C]NNC 112 has previously been reported to have... more The dopamine D1 receptor antagonist radioligand [11C]NNC 112 has previously been reported to have 100-fold selectivity for the D1 receptor compared with the serotonin 5-HT2A receptor. In this study, we tested the selectivity by scanning seven healthy human research volunteers with [11C]NNC 112 before and after 2mg of the antipsychotic drug risperidone, a dose that putatively blocks all 5-HT2A receptors with negligible effect on D1 receptors. We found that specific binding in cortical regions was reduced by 20% to 30%, whereas the striatum showed no change. Based on the known relative densities of these receptors in humans, our results suggest 5- to 10-fold selectivity of [11C]NNC 112 for D1 versus 5-HT2A as opposed to 100-fold selectivity. These results suggest caution in interpreting data from studies using this tracer to measure cortical D1 receptors as well as the need for more selective radioligands to assess cortical D1 receptors.
Journal of psychopharmacology (Oxford, England), 2011
D(1) receptors are the main mediators of dopamine transmission in the cortex and subserve cogniti... more D(1) receptors are the main mediators of dopamine transmission in the cortex and subserve cognitive functions that are affected in patients with schizophrenia. Prior imaging studies have suggested abnormalities in the expression of these receptors in schizophrenia, but no conclusive picture has emerged yet. One source of discrepancy may have been prior antipsychotic exposure. We used positron emission tomography (PET) and a D1 radiotracer, [(11)C]NNC112, in drug naïve (DN, n = 12) and drug free (DF, n = 13) patients with schizophrenia and 40 healthy control subjects (HC, n = 40 total, n = 24 per comparison group) matched for age, gender, ethnicity, parental socioeconomic status and cigarette smoking. We measured the binding potential BPP, corrected for partial volume effects. The outcome measure was obtained in cortical and striatal subregions outlined on coregistered individual MRIs. Partial volume effect corrected BPP measures were significantly higher in DN vs controls in cortica...
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