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• G G Alvarez
• Bioinformatics

Abstract

Objective

PET studies performed with [¹¹C]raclopride have consistently reported lower binding to D_2/3 receptors and lower amphetamine-induced dopamine release in cocaine abusers relative to healthy controls. A limitation of these studies that were performed with D_2/3 antagonist radiotracers such as [¹¹C]raclopride is the failure to provide information that is specific to D_2/3 receptors configured in a state of high affinity for the agonists (i.e., D_2/3 receptors coupled to G- proteins, D_{2/3 HIGH}). As the endogenous agonist dopamine binds with preference to D_{2/3 HIGH} relative to D_{2/3 LOW} receptors (i.e., D_2/3 receptors uncoupled to G-proteins) it is critical to understand the in vivo status of D_{2/3 HIGH} receptors in cocaine dependence. Thus, we measured the available fraction of D_{2/3 HIGH} receptors in 10 recently abstinent cocaine abusers (CD) and matched healthy controls (HC) with the D_2/3 antagonist and agonist PET radiotracers [¹¹C]raclopride and [¹¹C]NPA

Methods

[¹¹C]raclopride and [¹¹C]NPA binding potential (BP_ND) in the striatum were measured with kinetic analysis using the arterial input function. The available fraction of D_{2/3 HIGH} receptors, i.e., % R_HIGH available=D_{2/3 HIGH}/(D_{2/3 HIGH} + D_{2/3 LOW}) was then computed as the ratio of [¹¹C]NPA BP_ND/[¹¹C]raclopride BP_ND.

Results

No differences in striatal [¹¹C]NPA BP_ND (HC = 1.00 ± 0.17; CD = 0.97 ± 0.17, p =0.67) or available % R_HIGH (HC= 39% ± 5%; CD = 41% ± 5%, p = 0.50) was observed between cocaine abusers and matched controls

Conclusions

The results of this [¹¹C]NPA PET study do not support alterations in D_{2/3 HIGH} binding in the striatum in cocaine dependence.

INTRODUCTION

Previous imaging studies using endogenous competition techniques and PET have unequivocally demonstrated that the amphetamine (or methylphenidate)-induced displacement of [¹¹C]raclopride binding in the striatum is significantly less (or blunted) in cocaine abusers than healthy controls (; ). A fundamental question unanswered by the previous imaging studies is whether the blunted displacement of [¹¹C]raclopride following amphetamine in cocaine abusers is caused by pre-synaptic (i.e., less dopamine) or post-synaptic (i.e., lesser affinity of D_2/3 receptors for dopamine) factors. A possible explanation for the decreased occupancy of D_2/3 receptors by dopamine in chronic cocaine abusers is a reduced activity of dopaminergic neurons following amphetamine exposure. This interpretation is supported by a previous [¹⁸F]-6-L-fluorodopa imaging study reporting decreased availability of the dopamine synthesis enzyme DOPA decarboxylase in patients with cocaine abuse relative to controls (). An alternative explanation for the same phenomenon is that the presynaptic dopamine release is essentially normal, but the affinity of D_2/3 receptors for dopamine is decreased in chronic cocaine users. In this scenario, relatively normal or even exaggerated release of dopamine following amphetamine in cocaine dependence would be associated with decreased occupancy of D_2/3 receptors by dopamine. The available imaging data do not distinguish between pre- and post-synaptic factors, and it is also conceivable that both factors might play a role. This issue is important to the understanding of dopamine transmission abnormalities in cocaine dependence.

As D_2/3 receptors are configured in inter-convertible states of high or low affinity for agonists, the affinity of a pool of D_2/3 receptors for dopamine will depend not only on the affinity of the high (K_HIGH) and low (K_LOW) configuration sites, but also on the respective proportion of sites present in high and low configuration. If we assume that the total number of sites in the D_{2/3 HIGH} and D_{2/3 LOW} configurations are R_HIGH and R_LOW, then R_HIGH + R_LOW = B_MAX, where B_MAX is the total number of D_2/3 receptors. Under this scenario, the binding potential (BP) of a population of D_2/3 receptors for a given antagonist radiotracer such as [¹¹C]raclopride is BP_ANTAGONIST =BP_HIGH + BP_LOW = R_HIGH/K_HIGH + R_LOW/K_LOW because antagonists do not distinguish between the D_{2 HIGH} and D_{2 LOW} configurations. In contrast the BP for an agonist such as dopamine is BP_AGONIST = BP_HIGH= R_HIGH/K_HIGH. Therefore a decrease in the proportion of sites configured in the high-affinity state (% R_HIGH) in cocaine dependence would result in a smaller BP for dopamine and lead to a blunted response to amphetamine. To investigate this hypothesis that a lower % R_HIGH (=BP_AGONIST/BP_ANTAGONIST) for dopamine contributes to the blunted displacement of [¹¹C]raclopride after amphetamine in cocaine dependence, we measured D_2/3 antagonist and D_2/3 agonist BP in cocaine abusers and matched controls with the PET radiotracers [¹¹C]raclopride and [¹¹C]NPA.

MATERIALS AND METHODS

Human Subjects

Twenty subjects were enrolled in this study who were either cocaine dependent (n=10) or healthy comparison (n=10) subjects. The study was conducted under the University of Pittsburgh Institutional Review Board. All subjects provided written informed consent. Cocaine abusers were recruited through flyers displayed at local community centers, buses, and addiction medicine clinics. Study criteria for cocaine abusers were [1] males or females between 18 and 50 years old, of all ethnic and racial origins; [2] fulfill DSM-IV criteria for cocaine dependence as assessed by SCID; [3] a positive urine screen for cocaine; [4] no DSM IV Axis I disorder other than cocaine abuse or dependence including abuse or dependence to alcohol or other drugs (nicotine dependence was allowed); [5] no current (as confirmed by urine drug screen at screening) use of opiates, cannabis, sedative-hypnotics, amphetamines, MDMA, and PCP [6] not currently on any prescription or over the counter medications; [7] no current or past severe medical or neurological illnesses (including glaucoma, seizure disorders) as assessed by a complete medical history and physical; [8] not currently pregnant; [9] no history of significant radioactivity exposure (nuclear medicine studies or occupational exposure); [10] no metallic objects in the body that are contraindicated for MRI. All eligible cocaine dependent subjects completed a minimum of twelve days of outpatient abstinence monitored with witnessed urine toxicology (all subjects underwent urine drug screens for cocaine and other recreational drugs three times/week for two consecutive weeks). Following the twelve-day outpatient abstinence period subjects were admitted to an inpatient research unit for two days prior to the PET scan. This combined outpatient and inpatient monitoring protocol ensured that all subjects were abstinent for a minimum of two weeks prior to the PET scan. Healthy control subjects with no past or present neurological or psychiatric illnesses including substance abuse (confirmed by urine drug screen both at screening and the day of the PET scan) underwent the PET scan as outpatients.

Imaging methods

MRI acquisition

Prior to PET imaging, a spoiled gradient recalled sequence (SPGR) magnetic resonance imaging (MRI) scan was obtained using a GE Signa 1.5 Tesla scanner for determination of regions of interest as previously described (; )

PET acquisition

[¹¹C]raclopride and [¹¹C]NPA were synthesized using the methodology reported previously (; ). PET imaging sessions were conducted with the ECAT EXACT HR+ camera. The [¹¹C]raclopride PET scan was always followed by the [¹¹C]NPA PET scan in both patients and controls. Following a 10 minute transmission scan, [¹¹C]raclopride or [¹¹C]NPA was injected intravenously over a 45 second period and emission data were collected in the 3D mode for 60 minutes consistent with previous studies for these radiotracers in humans (; ). Also, consistent with previous evaluations the maximum injected mass for [¹¹C]raclopride and [¹¹C]NPA were restricted to 6 μg and 2 μg (; ) to be at tracer dose, i.e., less than 5% receptor occupancy.

Input function measurement

Following radiotracer injection, arterial samples were collected manually approximately every 6s for the first two min and thereafter at longer intervals. A total of 35 samples were obtained per scan. Following centrifugation, plasma was collected in 200 μL aliquots and activities were counted in a gamma counter. To determine the plasma activity representing unmetabolized parent compound for [¹¹C]raclopride (collected at 8, 12, 20, 30, 40, 50 and 60 min) and [¹¹C]NPA (collected at 4, 8, 12, 16, 20, 40, 50) seven samples were further processed using high performance liquid chromatogram methods described previously for both the radiotracers (; ). For [¹¹C]raclopride, the seven measured parent fractions were fitted using a sum of two exponentials (). For [¹¹C]NPA the parent fractions were fitted to a Hill Plot model (). The input function was then calculated as the product of total counts and interpolated parent fraction at each time point. The measured input function values were fitted to a sum of three exponentials from the time of peak plasma activity and the fitted values were used as the input to the kinetic analysis. The clearance of the parent compound (C_L expressed in liter/hour) was calculated as the ratio of the injected dose to the area under the curve of the input function (). The determination of the plasma free fraction (f_P) for both [¹¹C]raclopride and [¹¹C]NPA were performed using ultrafiltration units ().

Image analysis

All region drawing and image analysis was performed blind to the subject diagnosis with MEDx (Sensor Systems, Inc., Sterling, Virginia) and SPM2 (Statistical parametric mapping). The primary region of interest (ROI), the striatum was divided into five anatomical ROIs and three functional subdivisions using published criteria (). The three functional subdivisions of the striatum include the limbic striatum, LST (includes the ventral striatum VST), the associative striatum, AST (includes the precommisural caudate preDCA, precommisural putamen preDPU and postcommisural caudate postCA) and sensorimotor striatum, SMST (included the postcommisural putamen, postPU). The cerebellum was used as a reference region for both radiotracers (). Correction for head movement and co-registration of the PET data to the MR were done using previously described methods ().

Outcome measures

In this section we describe outcome variables using the consensus nomenclature for in vivo imaging of reversibly binding radioligands (). Baseline D_2/3 receptor availability for the antagonist and agonist radiotracers, [¹¹C]raclopride and [¹¹C]NPA were estimated using the PET outcome measure BP_ND, i.e., binding potential relative to non-displaceable uptake. As the concentration of D_2/3 receptors in the cerebellum is relatively low compared to the striatum, we assumed that the V_T in the cerebellum (V_{T CER}) is largely representative of the free and nonspecifically bound radiotracer. In other words, we assumed that V_{T CER} is equal to the non-displaceable distribution volume (V_ND).

[¹¹C]raclopride and [¹¹C]NPA regional distribution volumes (V_T, mL of plasma/cm³ of tissue) were derived with kinetic analysis and the arterial input function. A one and two-tissue compartment model was used to describe the kinetics in the cerebellum and striatal subdivisions for [¹¹C]raclopride (). A two-tissue compartment model described the kinetics in both the cerebellum and striatal subdivisions for [¹¹C]NPA (). Following, which the [¹¹C]raclopride or [¹¹C]NPA BP_ND was derived using the formula

The primary outcome measure for the study, which was computed as the ratio of [¹¹C]NPA BP_ND to [¹¹C]raclopride BP_ND in cocaine abusers and healthy controls provided an estimate of the fraction of the D_2HIGH sites not occupied by dopamine at baseline (or available for endogenous competition), that is

Statistical analysis

Group differences in baseline scan parameters (such as injected dose, mass, plasma clearance, V_ND) and dependent variables ([¹¹C]raclopride BP_ND, [¹¹C]NPA BP_ND and [¹¹C]NPA/[¹¹C]raclopride ratio) were performed with unpaired t tests. A probability value of 0.05 was selected as significance level for all analyses.

RESULTS

Ten cocaine dependent subjects (3 women and 7 men, mean age 44 ± 8 years) and 10 healthy comparison subjects (3 women and 7 men, mean age 42 ± 8 years) were enrolled in this study. All twenty individuals completed the [¹¹C]raclopride scan, but only 9/10 individuals in both the patient and control groups completed the [¹¹C]NPA scans (n=1 radiochemistry failure; n=1 dropped out because of back spasms). Subjects were matched on smoking status (5 smokers/group) and ethnicity (cocaine abusers: 7 African American and 3 Caucasian; healthy controls: 4 African American and 6 Caucasian) as best as possible. The cocaine abusers reported smoking crack cocaine on average of 17 ± 8 years and were spending $728 ± 650 weekly.

Scan parameters

Critical PET scan parameters are listed in Table 1(n=10 subjects/group for [¹¹C]raclopride and n=9 subjects/group for [¹¹C]NPA). The mean injected dose, specific activity at time of injection, and injected mass did not differ between the cocaine dependent and healthy comparison groups for both [¹¹C]raclopirde and [¹¹C]NPA. In addition, no significant between-group differences were observed in [¹¹C]raclopride and [¹¹C]NPA rate of clearance from the plasma compartment, or cerebellum distribution volume (V_ND)

G G Alvarez

Table 1

Comparisons between controls and cocaine abusers for both scan parameters all p > 0.05, two-tailed, unpaired t-test

Regional volumes

No significant between-group differences were found in ROI or reference region volumes (Table 2) suggesting lack of measurable volumetric changes in the human striatum after chronic cocaine abuse.

Table 2

LST-limbic striatum; AST-associative striatum; SMST-sensorimotor striatum; STR-Striatum; VST-ventral striatum; pre-DCA-precommisural caudate; post-CA postcommisural caudate; pre-DPU-precommisural putamen; post-PU-postcommisural putamen

D_2/3 receptor binding potential as measured using [¹¹C]raclopride and [¹¹C]NPA

The results of [¹¹C]raclopride BP_ND and [¹¹C]NPA BP_ND in cocaine abusers in the striatal subdivisions relative to healthy controls are shown in Table 3. Also shown in Table 3 are the the effect sizes (d) for between group difference for [¹¹C]raclopride BP_ND and [¹¹C]NPA BP_ND in the striatal subdivisions.

Table 3

Regional [¹¹C]raclopride and [¹¹C]NPA binding potential (BP_ND)in healthy controls and chronic cocaine abusers

LST-limbic striatum; AST-associative striatum; SMST-sensorimotor striatum; STR-Striatum; VST-ventral striatum; pre-DCA-precommisural caudate; post-CA postcommisural caudate; pre-DPU-precommisural putamen; post-PU-postcommisural putamen

Effect size is Cohen’s d derived using pooled standard deviation for two independent samples

Bioinformatics

Fraction of D_2/3 high receptors available (% R_HIGH available)

No between-group differences were observed for the available % R_HIGH in the striatal subdivisions (Figure 1).

Shows no significant difference between controls (white bars) and cocaine abusers (black bars) in the available fraction of D_2/3 high receptors (% R_HIGH) in the striatal subdivisions.

DISCUSSION

Previous PET studies performed with the D_2/3 antagonist radiotracers [¹¹C]raclopride and [¹⁸F]NMSP have consistently reported decreased D_2/3 receptor availability in the striatum of cocaine abusers (11–38%) which persisted following abstinence (; ; ; ; ). The [¹¹C]raclopride results of this study were consistent with these previous data in suggesting both trend level and significant decreases in the subdivisions of the striatum in cocaine abusers relative to healthy controls (Table 3). Thus, the overall data on this topic are in agreement that there is less D_2/3 antagonist (D_{2/3 HIGH} and D_{2/3 LOW}) binding in cocaine abusers relative to healthy comparison subjects. No previous in vitro postmortem or in vivo imaging studies have investigated and reported on the availability of the physiologically more relevant D_2/3 agonist binding (as D_{2/3 HIGH}, and not D_{2 LOW} are the sites accessed by dopamine) in cocaine dependent humans. We were interested in this particular issue for two reasons (1) it was critical to understand whether the blunted displacement of [¹¹C]raclopride after amphetamine in cocaine dependence can be attributed to post-synaptic factors, i.e., a lower fraction of D_2/3 receptors configured in a state of high affinity for the agonists and (2) previous reports in rodents suggest that chronic exposure to psychostimulant drugs such as cocaine and amphetamine lead to a higher (~ 150%), not lower fraction of D_{2/3 HIGH} receptors (; ; ; ), which was contradictory to our predicted hypothesis. Thus, in this human imaging study, we investigated both the D_2/3 antagonist and D_2/3 agonist binding potential in a group of subjects who regularly abused cocaine for nearly two decades and found neither an increase nor a decrease in the available % R_HIGH relative to healthy comparison subjects. This particular observation was a consequence of the lack of difference in D_2/3 agonist BP_ND rather than D_2/3 antagonist BP_ND as shown in Table 3. Furthermore, as the effect size for [¹¹C]NPA in the striatal subdivisions was relatively small (0.06 to 0.47; Table 3), we found no reason to continue with the study. For example, at the observed effect size of 0.86 in the striatum for [¹¹C]raclopride, the study would have required a sample size of 22 subjects/group to detect a significant difference between cocaine abusers and controls (p < 0.05; power 0.8). In contrast, at the observed effect size of only 0.22 in the striatum for [¹¹C]NPA, the same clinical study would have required us to recruit and scan 325 subjects/group to detect a between-group difference.

One reason for the failure to observe an increase in the available % R _HIGH in chronic cocaine exposed humans may be related to the differences in baseline dopamine levels between the control and cocaine groups that impact the in vivo PET measures in humans but not necessarily the in vitro binding measures in rodents (). Nevertheless, a more likely explanation is that chronic cocaine exposure leads to paradoxical changes in dopamine transmission and associated parameters (such as D_2/3 receptors, D_{2/3 HIGH} receptors, dopamine transporters, vesicular monoamine transporter, type 2, etc.,) in rodents and humans for unclear reasons as reviewed in (). Future [¹¹C]NPA PET studies following the depletion of synaptic dopamine with alpha-methyl-para-tyrosine (AMPT) in cocaine abusers and micro-PET studies in rodents exposed to chronic cocaine are necessary to clarify these issues. Another factor that needs to be considered in the interpretation of the available % R_HIGH that was arrived at via comparison of the agonist [¹¹C]NPA and antagonist [¹¹C]raclopride in this study is the difference in D₃/D₂ affinity ratio between these radiotracers. For example, a decrease or increase in D₃ receptor availability in cocaine dependent patients compared to controls may have masked an abnormally higher or lower % R_HIGH as [¹¹C]NPA demonstrates modest preference for D₃ over D₂ receptors compared to [¹¹C]raclopride (). Future studies with the D₃-receptor preferring agonist radiotracer [¹¹C]PHNO and a selective D₃ antagonist drug in cocaine dependence are necessary to investigate this issue (). Finally, recent PET imaging studies with both D_2/3 antagonist (such as [¹¹C]raclopride and [¹¹C]FLB 457) and agonist radiotracers (such as [¹¹C]NPA and [¹¹C]PHNO) suggest a small but significant fraction of D_2/3 specific binding in the cerebellum (; ; ; ; ), the region that is typically used as an estimate of free plus non-specific binding for the derivation of BP_ND. Thus, one cannot discount the possibility that differences in the fraction of D_2/3 specific binding between the agonist and antagonist radiotracer could have biased the % R_HIGH measured in this clinical study as we assumed that there is no specific binding in the cerebellum for both these radiotracers. In summary, despite the limitations of the imaging paradigm used we found no evidence for abnormal D_{2/3 HIGH} binding in cocaine abusers relative to healthy controls, thereby raising questions as to whether it plays a critical role in cocaine dependence in humans.

Acknowledgments

The project described was supported by Award Numbers R21 DA023450, R03 DA024704 and CTSA-UL1 RR024153 from the National Institute On Drug Abuse (NIDA), the American Reinvestment and Recovery Act of 2009 (ARRA) and National Center for Research Resources (NCRR). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute On Drug Abuse or the National Institutes of Health.

Footnotes

DISCLOSURES

The authors report no competing interests

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