Faculty Bibliography

Basic investigations link a Val158Met polymorphism (rs4680) in the catechol-O-methyltransferase (COMT) gene to not only its enzymatic activity, but also to its dopaminergic tone in the prefrontal cortex. Previous PET studies have documented the relationship between COMT Val158Met polymorphism and D1 and D2/3 receptor binding potential (BP), and interpreted them in terms of dopaminergic tone. The use of baseline dopamine D1 and D2/3 receptor binding potential (BPND) as a proxy for dopaminergic tone is problematic because they reflect both endogenous dopamine levels (a change in radiotracer's apparent affinity) and receptor density. In this analysis of 31 healthy controls genotyped for the Val158Met polymorphism (Val/Val, Val/Met, and Met/Met), we used amphetamine-induced displacement of [11C]FLB 457 as a direct measure of dopamine release. Our analysis failed to show a relationship between COMT genotype status and prefrontal cortical dopamine release. COMT genotype was also not predictive of baseline dopamine D2/3 receptor BPND.

OBJECTIVE: Postmortem studies in schizophrenia reveal alterations in gene products that regulate the release and extracellular persistence of GABA. However, results of in vivo studies of schizophrenia measuring total tissue GABA with magnetic resonance spectroscopy (MRS) have been inconsistent. Neither the postmortem nor the MRS studies directly address the physiological properties of GABA neurotransmission. The present study addresses this question through an innovative positron emission tomography (PET) paradigm. METHOD: The binding of [(11)C]flumazenil, a benzodiazepine-specific PET radiotracer, was measured before and after administration of tiagabine (0.2 mg/kg of body weight), a GABA membrane transporter (GAT1) blocker, in 17 off-medication patients with schizophrenia and 22 healthy comparison subjects. Increased extracellular GABA, through GAT1 blockade, enhances the affinity of GABAA receptors for benzodiazepine ligands, detected as an increase in [(11)C]flumazenil tissue distribution volume (VT). RESULTS: [(11)C]Flumazenil VT was significantly increased across all cortical brain regions in the healthy comparison group but not in the schizophrenia group. This lack of effect was most prominent in the antipsychotic-naive schizophrenia group. In this subgroup, [(11)C]flumazenil DeltaVT in the medial temporal lobe was correlated with positive symptoms, and baseline [(11)C]flumazenil VT in the medial temporal lobe was negatively correlated with visual learning. In the healthy comparison group but not the schizophrenia group, [(11)C]flumazenil DeltaVT was positively associated with gamma-band oscillation power. CONCLUSIONS: This study demonstrates, for the first time, an in vivo impairment in GABA transmission in schizophrenia, most prominent in antipsychotic-naive individuals. The impairment in GABA transmission appears to be linked to clinical symptoms, disturbances in cortical oscillations, and cognition.

Changes in endogenous dopamine levels can be detected in humans using positron emission tomography scans by measuring the amount by which a specific D2/3 radioligand is displaced. In some cases, a challenge drug such as amphetamine is introduced to increase the amount of dopamine released into the synaptic cleft. Although intravenous amphetamine is often utilized, oral amphetamine has been shown to be just as effective in increasing endogenous dopamine levels. Based on our own use of oral amphetamine as a challenge drug, we have retroactively reviewed our study charts to determine the cardiovascular safety of 0.5 mg kg(-1) oral d-amphetamine. Of 172 amphetamine administrations in 144 individuals, only 2.8% of subjects experienced any transient adverse effects. In addition, we found no clinically relevant differences in increases of vital signs between healthy controls and patients. We therefore reaffirm the safety of 0.5 mg kg(-1) oral amphetamine in subjects previously screened for cardiovascular risk factors.

OBJECTIVE: Basic studies have demonstrated that optimal levels of prefrontal cortical dopamine are critical to various executive functions such as working memory, attention, inhibitory control, and risk/reward decisions, all of which are impaired in addictive disorders such as alcoholism. Based on this and imaging studies of alcoholism that have demonstrated less dopamine in the striatum, the authors hypothesized decreased dopamine transmission in the prefrontal cortex in persons with alcohol dependence. METHOD: To test this hypothesis, amphetamine and [11C]FLB 457 positron emission tomography were used to measure cortical dopamine transmission in 21 recently abstinent persons with alcohol dependence and 21 matched healthy comparison subjects. [11C]FLB 457 binding potential, specific compared to nondisplaceable uptake (BPND), was measured in subjects with kinetic analysis using the arterial input function both before and after 0.5 mg kg-1 of d-amphetamine. RESULTS: Amphetamine-induced displacement of [11C]FLB 457 binding potential (DeltaBPND) was significantly smaller in the cortical regions in the alcohol-dependent group compared with the healthy comparison group. Cortical regions that demonstrated lower dopamine transmission in the alcohol-dependent group included the dorsolateral prefrontal cortex, medial prefrontal cortex, orbital frontal cortex, temporal cortex, and medial temporal lobe. CONCLUSIONS: The results of this study, for the first time, unambiguously demonstrate decreased dopamine transmission in the cortex in alcoholism. Further research is necessary to understand the clinical relevance of decreased cortical dopamine as to whether it is related to impaired executive function, relapse, and outcome in alcoholism.

In a recent human positron emission tomography (PET) study we demonstrated the ability to detect amphetamine-induced dopamine (DA) release in the prefrontal cortex as a reduction in the binding of the DA D(2/3) radioligand [(11)C]FLB 457. A key requirement for validating this paradigm for use in clinical studies is demonstrating that the changes in [(11)C]FLB 457 binding observed with PET following amphetamine are related to changes in dialysate DA concentration as measured with microdialysis. Microdialysis and PET experiments were performed to compare, in five rhesus monkeys, amphetamine-induced DA release and [(11)C]FLB 457 displacement in the frontal cortex after three doses of amphetamine (0.3 mg kg(-1), 0.5 mg kg(-1) and 1.0 mg kg(-1)). Amphetamine led to a significant dose-dependent increase in dialysate (0.3 mg kg(-1): 999+/-287%; 0.5 mg kg(-1): 1320+/-432%; 1.0 mg kg(-1): 2355+/-1026%) as measured with microdialysis and decrease in [(11)C]FLB 457 binding potential (BP(ND), 0.3 mg kg(-1): -6+/-6%; 0.5 mg kg(-1): -16+/-4%; 1.0 mg kg(-1): -24+/-2%) as measured with PET. The relationship between amphetamine-induced peak DeltaDA and Delta[(11)C]FLB 457 BP(ND) in the frontal cortex was linear. The results of this study clearly demonstrate that the magnitude of dialysate DA release is correlated with the magnitude of the reduction in [(11)C]FLB 457 BP(ND) in the frontal cortex. The use of the [(11)C]FLB 457-amphetamine imaging paradigm in humans should allow for characterization of prefrontal cortical DA release in neuropsychiatric disorders such as schizophrenia and addiction.

3,4-Methylenedioxymethamphetamine (MDMA), the main psychoactive component of the recreational drug ecstasy, is a potent serotonin (5-HT) releaser. In animals, MDMA induces 5-HT depletion and toxicity in 5-HT neurons. The aim of this study was to investigate both presynaptic (5-HT transporter, SERT) and postsynaptic (5-HT(2A) receptor) markers of 5-HT transmission in recently abstinent chronic MDMA users compared with matched healthy controls. We hypothesized that MDMA use is associated with lower SERT density and concomitant upregulation of 5-HT(2A) receptors. Positron emission tomography studies using the SERT ligand [(1)(1)C]DASB and the 5-HT(2A) receptor ligand [(1)(1)C]MDL 100907 were evaluated in 13 current and recently detoxified MDMA users and 13 matched healthy controls. MDMA users reported a mean duration of ecstasy use of 8 years, regular exposure, and at least 2 weeks of abstinence before the scans. SERT and 5-HT(2A) receptor availability (binding potential, BP(ND)) were analyzed with a two-tissue compartment model with arterial input function. Current recreational MDMA use was significantly associated with lower SERT BP(ND) and higher 5-HT(2A) receptor BP(ND) in cortical, but not subcortical regions. Decreased SERT BP(ND) was regionally associated with upregulated 5-HT(2A) receptor BP(ND). In light of the animal literature, the most parsimonious interpretation is that repeated exposure to MDMA in humans, even in moderate amounts, leads to damage in 5-HT neuron terminals innervating the cortex. Alterations in mood, cognition, and impulse control associated with these changes might contribute to sustain MDMA use. The reversibility of these changes upon abstinence remains to be firmly established.

OBJECTIVE: Genetic, pharmacologic, and physiological data suggest that individuals with anorexia nervosa (AN) have altered striatal dopamine (DA) function. METHOD: We used an amphetamine challenge and positron emission tomography [(11) C]raclopride paradigm to explore DA striatal transmission in 10 recovered (REC) AN compared with 9 control women (CW). RESULTS: REC AN and CW were similar for baseline, postamphetamine [(11) C]raclopride binding potential (BP(ND) ) and change (Delta) in BP(ND) for all regions. In CW, ventral striatum Delta BP(ND) was associated with euphoria (r = -0.76; p = 0.03), which was not found for REC AN. Instead, REC AN showed a significant relationship between anxiety and Delta BP(ND) in the precommissural dorsal caudate (r = -0.62, p = 0.05). DISCUSSION: REC AN have a positive association between endogenous DA release and anxiety in the dorsal caudate. This finding could explain why food-related DA release produces anxiety in AN, whereas feeding is pleasurable in healthy participants.

PURPOSE: We measure the whole-body distribution of IV injected [(1)(1)C]Flumazenil (FMZ) as a function of time in adult subjects and determine the absorbed radiation doses. PROCEDURES: After injection with 770 MBq of [(1)(1)C]FMZ (nominal), each of six subjects underwent nine consecutive whole body PET scans. Twelve source organs were identified using PET attenuation and emission images. Activity within each organ as a function of time was determined from the sequence of the nine PET scans. Source organ time activity curves were integrated and normalized by the injected dose to yield source organ residence times for the no voiding situation. Separate bladder residence-time calculations were performed for the cases of a 1- and a 2-h voiding interval. Using the source organ residence times as input, the program OLINDA/EXM (Stabin et al. in J Nucl Med. 46:1023-1027, 2005) was used to perform dosimetry calculations for the various body organs and for the whole body. RESULTS: For the no voiding situation, the average whole-body radiation equivalent dose was 3.02 x 10(-)(3) mSv/MBq of injected [(1)(1)C]FMZ. The average effective dose and effective dose equivalent was 7.57 x 10(-)(3) and 1.12 x 10(-)(2) mSv MBq(-)(1), respectively. The organ receiving the highest equivalent dose was the urinary bladder wall with an average of 6.32 x 10(-)(2) mSv MBq(-)(1). CONCLUSION: On average, the administration of less than 790 MBq (21 mCi) of [(1)(1)C]FMZ yields (no voiding model) an organ equivalent dose of under 50 mSv [the single dose limit for research studies under US regulations (21CFR361.1) to body organs other than blood forming organs, gonads or the lens of the eye] to all organs. Equivalent dose to the blood forming organs and gonads from a 790 MBq administered FMZ dose is well under the 30 mSv limit provided under 21CFR361.1. Additionally, administration of less than 1320 MBq (35.7 mCi) yields an effective dose [International Commission on Radiation Protection (ICRP) 60 tissue weighting scheme] of under 10 mSv, which is the ICRP IIb (minor to intermediate) risk category limit.

OBJECTIVE: Positron emission tomography (PET) imaging studies in cocaine abusers have shown that low dopamine release in the striatum following an amphetamine challenge is associated with higher relapse rates. One possible mechanism that might lead to lower amphetamine-induced dopamine release is low availability of dopamine storage vesicles in the presynaptic terminals for release. Consistent with this hypothesis, postmortem studies have shown low levels of vesicular monoamine transporter, type 2 (VMAT2), the membrane protein that regulates the size of the vesicular dopamine pool, in cocaine abusers relative to healthy subjects. To confirm the postmortem findings, the authors used PET and the VMAT2 radioligand [(1)(1)C]-(+)-dihydrotetrabenazine (DTBZ) to assess the in vivo VMAT2 availability in a group of 12 recently abstinent cocaine-dependent subjects and matched healthy comparison subjects. METHOD: [(1)(1)C]DTBZ nondisplaceable binding potential (BP(ND)) was measured by kinetic analysis using the arterial input function or, if arterial input was unavailable, by the simplified reference tissue method. RESULTS: [(1)(1)C]DTBZ BP(ND) was significantly lower in the cocaine abusers than in the comparison subjects in the limbic striatum (10.0% lower), associative striatum (-13.4%), and sensorimotor striatum (-11.5%). CONCLUSIONS: The results of this in vivo PET study confirm previous in vitro reports of low VMAT2 availability in the striatum of cocaine abusers. It also suggests a compensatory down-regulation of the dopamine storage vesicles in response to chronic cocaine abuse and/or a loss of dopaminergic terminals. Further research is necessary to understand the clinical relevance of this observation to relapse and outcome in abstinent cocaine abusers.