Allegra Broft

Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and precision of D2 receptor parameter measurements in ventral striatum

Dopamine transmission in the ventral striatum (VST), a structure which includes the nucleus accumbens, ventral caudate, and ventral putamen, plays a critical role in the pathophysiology of psychotic states and in the reinforcing effects of virtually all drugs of abuse. The aim of this study was to assess the accuracy and precision of measurements of D2 receptor availability in the VST obtained with positron emission tomography on the high-resolution ECAT EXACT HR+ scanner (Siemens Medical Systems, Knoxville, TN, U.S.A.). A method was developed for identification of the boundaries of the VST on coregistered high-resolution magnetic resonance imaging scans. Specific-to-nonspecific partition coefficient (V3″) and binding potential (BP) of [11C]raclopride were measured twice in 10 subjects, using the bolus plus constant infusion method. [11C]Raclopride V3″ in the VST (1.86 ± 0.29) was significantly lower than in the dorsal caudate (DCA, 2.33 ± 0.28) and dorsal putamen (DPU, 2.99 ± 0.26), an observation consistent with postmortem studies. The reproducibility of V3″ and BP were appropriate and similar in VST (V3″ test–retest variability of 8.2% ± 6.2%, intraclass correlation coefficient = 0.83), DCA (7.7% ± 5.1%, 0.77), DPU (6.0% ± 4.1%, 0.71), and striatum as a whole (6.3% ± 4.1%, 0.78). Partial volume effects analysis revealed that activities in the VST were significantly contaminated by counts spilling over from the adjacent DCA and DPU: 70% ± 5% of the specific binding measured in the VST originated from D2 receptors located in the VST, whereas 12% ± 3% and 18% ± 3% were contributed by D2 receptors in the DCA and DPU, respectively. Thus, accuracy of D2 receptor measurement is improved by correction for partial voluming effects. The demonstration of an appropriate accuracy and precision of D2 receptor measurement with [11C]raclopride in the VST is the first critical step toward the use of this ligand in the study of synaptic dopamine transmission at D2 receptors in the VST using endogenous competition techniques.

Imaging Human Mesolimbic Dopamine Transmission with Positron Emission Tomography. Part II: Amphetamine-Induced Dopamine Release in the Functional Subdivisions of the Striatum

The human striatum is functionally organized into limbic, associative, and sensorimotor subdivisions, which process information related to emotional, cognitive, and motor function. Dopamine projections ascending from the midbrain provide important modulatory input to these striatal subregions. The aim of this study was to compare activation of dopamine D2 receptors after amphetamine administration in the functional subdivisions of the human striatum. D2 receptor availability (V3″) was measured with positron emission tomography and [11C]raclopride in 14 healthy volunteers under control conditions and after the intravenous administration of amphetamine (0.3 mg/kg). For each condition, [11C]raclopride was administered as a priming bolus followed by constant infusion, and measurements of D2 receptor availability were obtained under sustained binding equilibrium conditions. Amphetamine induced a significantly larger reduction in D2 receptor availability (ΔV3″) in limbic (ventral striatum, −15.3 ± 11.8%) and sensorimotor (postcommissural putamen, −16.1 ± 9.6%) regions compared with associative regions (caudate and precommissural putamen, −8.1 ± 7.2%). Results of this region-of-interest analysis were confirmed by a voxel-based analysis. Correction for the partial volume effect showed even greater differences in ΔV3″ between limbic (−17.8 ± 13.8%), sensorimotor (−16.6 ± 9.9%), and associative regions (−7.5 ± 7.5%). The increase in euphoria reported by subjects after amphetamine was associated with larger ΔV3″ in the limbic and sensorimotor regions, but not in the associative regions. These results show significant differences in the dopamine response to amphetamine between the functional subdivisions of the human striatum. The mechanisms potentially accounting for these regional differences in amphetamine-induced dopamine release within the striatum remain to be elucidated, but may be related to the asymmetrical feed-forward influences mediating the integration of limbic, cognitive, and sensorimotor striatal function via dopamine cell territories in the ventral midbrain.

Cocaine dependence and d2 receptor availability in the functional subdivisions of the striatum: relationship with cocaine-seeking behavior.

Striatal dopamine D2 receptors have been implicated in the neurobiology of cocaine addiction. Previous imaging studies showed reduced striatal D2 receptor availability in chronic cocaine abusers, and animal studies suggested that low D2 receptor availability promotes cocaine self-administration. Here, D2 receptor availability was assessed with positron emission tomography (PET) and [11C]raclopride in the limbic, associative, and sensori-motor subdivisions of the striatum in 17 recently detoxified chronic cocaine-dependent (CCD) subjects and 17 matched healthy control (HC) subjects. In addition, the relationship between regional D2 receptor availability and behavioral measures obtained in cocaine self-administration sessions was investigated in CCD subjects. [11C]Raclopride binding potential was significantly reduced by 15.2% in the limbic striatum, 15.0% in the associative striatum, and 17.1% in the sensori-motor striatum in CCD subjects compared to HC subjects. In CCD subjects, no relationship was detected between D2 availability in striatal regions and either the positive effects of smoked cocaine or the choice of cocaine over an alternative reinforcer (money) following a priming dose of cocaine (a laboratory model of relapse). Thus, this study confirms previous reports of a modest decrease in D2 receptor availability in CCD subjects, and establishes that this decrease is generalized throughout the striatum. However, this study failed to demonstrate a relationship between D2 receptor availability and cocaine-induced cocaine-taking behavior. Additional research is warranted to unravel potential neurobiological traits that might confer vulnerability to relapse in detoxified CCD subjects.

Imaging dopamine transmission in cocaine dependence: link between neurochemistry and response to treatment.

OBJECTIVE Previous research has shown that dopamine signaling in the limbic striatum is crucial for selecting adaptive, motivated behavior and that disrupted dopamine transmission is associated with impulsive and maladaptive behavior. In humans, positron emission tomography (PET) imaging studies have shown that cocaine dependence is associated with the dysregulation of striatal dopamine signaling, which is linked to cocaine-seeking behavior. The goal of the present study was to investigate whether this association applies to the treatment setting. The authors hypothesized that dopamine signaling in the limbic striatum would be associated with response to a behavioral treatment that uses positive reinforcement to replace impulsive cocaine use with constructive personal goals. METHOD Prior to treatment, cocaine-dependent subjects underwent two PET scans using [(11)C]raclopride, before and after the administration of a stimulant (methylphenidate), for measurement of striatal dopamine D(2/3) receptor binding and presynaptic dopamine release. RESULTS Both of the outcome measures were lower in the volunteers who did not respond to treatment than in those who experienced a positive treatment response. CONCLUSIONS These findings provide insight into the neurochemistry of treatment response and show that low dopamine transmission is associated with treatment failure. In addition, these data suggest that the combination of behavioral treatment with methods that increase striatal dopamine signaling might serve as a therapeutic strategy for cocaine dependence.

Lower Level of Endogenous Dopamine in Patients With Cocaine Dependence: Findings From PET Imaging of D 2 /D 3 Receptors Following Acute Dopamine Depletion

OBJECTIVE Previous positron emission tomography (PET) imaging studies have demonstrated that cocaine dependence is associated with a decrease in dopamine type 2 and 3 (D(2)/D(3)) receptor binding in cocaine-dependent individuals relative to healthy comparison subjects. However, given the nature of PET imaging, it is possible that the measured decrease in radiotracer binding results from an increase in baseline dopamine levels. The purpose of this study was to measure D(2)/D(3) receptors following acute dopamine depletion in cocaine-dependent volunteers relative to healthy comparison subjects. METHOD Cocaine-dependent volunteers (N=15) and healthy matched comparison subjects (N=15) were scanned using PET, with the dopamine receptor radiotracer [(11)C]raclopride, at baseline and again following acute depletion of endogenous dopamine via alpha-methyl-para-tyrosine (AMPT) administration. Changes in radiotracer binding were measured in the subdivisions of the striatum (caudate, putamen, and ventral striatum) in addition to the striatum as a whole. RESULTS Findings revealed that cocaine-dependent volunteers exhibited lower levels of endogenous dopamine relative to comparison subjects, which was measured as an increase in [(11)C]raclopride binding following AMPT administration. The increase in [(11)C]raclopride binding in the striatum was 11.1% (SD=4.4%) in healthy comparison subjects and 5.7% (SD=5.9%) in cocaine-dependent volunteers. Similar differences were seen in the subdivisions of the striatum. CONCLUSIONS The decrease in striatal D(2)/D(3 )receptors associated with cocaine dependence cannot be attributed to higher levels of endogenous dopamine.

Deficits in Dopamine D2 Receptors and Presynaptic Dopamine in Heroin Dependence: Commonalities and Differences with Other Types of Addiction

BACKGROUND Positron emission tomography (PET) imaging studies have shown that addiction to a number of substances of abuse is associated with a decrease in dopamine D(2/3) receptor binding and decreased presynaptic dopamine release in the striatum. Some studies have also shown that these reductions are associated with the severity of addiction. For example, in cocaine dependence, low dopamine release is associated with the choice to self-administer cocaine. The goal of the present study was to investigate these parameters of striatal dopamine transmission in heroin dependence and their association with drug seeking behavior. METHODS Heroin-dependent and healthy control subjects were scanned with [(11)C]raclopride before and after stimulant administration (methylphenidate) to measure striatal D(2/3) receptor binding and presynaptic dopamine release. After the PET scans, the heroin-dependent subjects performed heroin self-administration sessions. RESULTS Both striatal D(2/3) receptor binding and dopamine release were reduced in the heroin-dependent subjects compared with healthy control subjects. However, neither PET measure of dopamine transmission predicted the choice to self-administer heroin. CONCLUSIONS These findings show that heroin addiction, like addiction to other drugs of abuse, is associated with low D(2/3) receptor binding and low presynaptic dopamine. However, neither of these outcome measures was associated with the choice to self-administer heroin.

Dopamine type 2/3 receptor availability in the striatum and social status in human volunteers.

BACKGROUND Previous positron emission tomography (PET) imaging studies in nonhuman primates have shown that striatal dopamine type 2/3 (D(2/3)) receptors correlate with social hierarchy in monkeys and that dominant animals exhibit higher levels of D(2/3) receptor binding. The goal of the present study was to examine this phenomena in human subjects using PET and the radiotracer [(11)C]raclopride. METHODS Fourteen healthy volunteers were scanned with [(11)C]raclopride to measure D(2/3) receptor binding potential (BP). Social status was assessed using the Barratt Simplified Measure of Social Status. In addition, participants were asked to assess their level of social support using the Multidimensional Scale of Perceived Social Support (MSPSS). RESULTS A correlation was seen between social status and dopamine D(2/3) receptors, where volunteers with the higher status had higher values for [(11)C]raclopride BP. A similar correlation was seen with the perceived social support, where higher [(11)C]raclopride BP correlated with higher scores on the MSPSS. CONCLUSIONS The results of this study support the hypothesis that social status and social support is correlated with D(2/3) receptor binding.

Dopamine D1 Receptors in Cocaine Dependence Measured with PET and the Choice to Self-Administer Cocaine

The goal of this study was to determine D1 receptor availability in human cocaine-dependent (CD) subjects and matched healthy controls (HCs). In addition, the CD subjects performed cocaine self-administration sessions in order to explore the association between D1 receptor availability and cocaine-seeking behavior. Twenty-five CD subjects (40±4 years, 19M/6 F) and 23 matched HCs (38±4 years, 19M/4F) were scanned with PET and the radiotracer [11C]NNC 112. During the cocaine self-administration sessions, CD volunteers were given the choice to self-administer cocaine (0, 6, and 12 mg) or to receive a monetary voucher worth

Pindolol augmentation of antidepressant treatment: recent contributions from brain imaging studies

5. D1 receptor availability was measured in the limbic, associative, and sensori-motor striatum in addition to cortical brain regions. No difference in D1 receptor availability was seen between the two groups. A negative association was seen between D1 receptor BPND in the limbic striatum and the choice for the 6 mg dose of cocaine (r=−0.47, p=0.02, corrected for age). These results do not support the hypothesis that cocaine dependence is associated with a reduction in D1 receptor availability in the striatum. However, within the CD subjects, low D1 receptor availability in the ventral striatum was associated with the choice to self-administer cocaine, suggesting that low D1 receptor availability may be associated with an increased risk of relapse in cocaine dependence.

Regional cerebral metabolic patterns demonstrate the role of anterior forebrain mesocircuit dysfunction in the severely injured brain

Preclinical studies suggest that augmentation of selective serotonin (5-HT) reuptake inhibitors by the 5-HT(1A) receptor agent pindolol might reduce the delay between initiation of treatment and antidepressant response, an effect largely mediated by blockade of 5-HT(1A) autoreceptors in the dorsal raphe nuclei. Although some controlled clinical trials suggest that pindolol might reduce latency to selective serotonin reuptake inhibitor response in acute depressive episodes, the effect is moderate and highly variable. Recent positron emission tomography studies investigating the occupancy of 5-HT(1A) receptors in humans by pindolol have shown that at the dose used most often in clinical trials the occupancy is low and variable, which might explain the inconsistent clinical results. Positron emission tomography studies also suggest that pindolol might be more potent at blocking 5-HT(1A) autoreceptors than at blocking postsynaptic receptors, a property that may be useful in this pharmacologic strategy. Thus, the positron emission tomography data support the potential of pindolol to augment the antidepressant response of selective serotonin reuptake inhibitors, but also imply that this potential has not been fully evaluated. Here we review the clinical trials, the positron emission tomography studies, and the possible mechanisms of pindolol augmentation. It is also suggested that positron emission tomography may be used to define therapeutic dosing early on in the process of clinical evaluation of new treatment strategies.