Heightened D3 Dopamine Receptor Levels in Cocaine Dependence and Contributions to the Addiction Behavioral Phenotype: A Positron Emission Tomography Study with [11C]-(+)-PHNO

The dopamine system is a primary treatment target for cocaine dependence (CD), but research on dopaminergic abnormalities (eg, D₂ receptor system deficiencies) has so far failed to translate into effective treatment strategies. The D₃ receptor system has recently attracted considerable clinical interest, and D₃ antagonism is now under investigation as a novel avenue for addiction treatment. The objective here was to evaluate the status and behavioral relevance of the D₃ receptor system in CD, using the positron emission tomography (PET) radiotracer [¹¹C]-(+)-PHNO. Fifteen CD subjects (many actively using, but all abstinent 7–240 days on scan day) and fifteen matched healthy control (HC) subjects completed two PET scans: one with [¹¹C]-(+)-PHNO to assess D₃ receptor binding (BP_ND; calculated regionally using the simplified reference tissue model), and for comparison, a second scan with [¹¹C]raclopride to assess D_2/3 binding. CD subjects also completed a behavioral battery to characterize the addiction behavioral phenotype. CD subjects showed higher [¹¹C]-(+)-PHNO BP_ND than HC in the substantia nigra, which correlated with behavioral impulsiveness and risky decision making. In contrast, [¹¹C]raclopride BP_ND was lower across the striatum in CD, consistent with previous literature in ⩾2 week abstinence. The data suggest that in contrast to a D₂ deficiency, CD individuals may have heightened D₃ receptor levels, which could contribute to addiction-relevant traits. D₃ upregulation is emerging as a biomarker in preclinical models of addiction, and human PET studies of this receptor system can help guide novel pharmacological strategies for treatment.     

Dopamine Response to Psychosocial Stress in Chronic Cannabis Users: A PET Study With [11C]-(+)-PHNO

A number of addictions have been linked with decreased striatal dopamine (DA) receptor availability and DA release. Stress has a key role in cannabis craving, as well as in modulation of dopaminergic signaling. The present study aimed to assess DA release in response to a laboratory stress task with [¹¹C]-(+)-PHNO positron emission tomography in cannabis users (CU). Thirteen healthy CU and 12 healthy volunteers (HV) were scanned during a sensorimotor control task (SMCT) and under a stress condition using the validated Montreal imaging stress task (MIST). The simplified reference tissue model (SRTM) was used to obtain binding potential (BP_ND) in striatal subdivisions: limbic striatum (LST), associative striatum (AST), and sensorimotor striatum (SMST). Stress-induced DA release (indexed as a percentage of reduction in [¹¹C]-(+)-PHNO BP _ND) between CU and HV was tested with analysis of variance. SMCT BP_ND was significantly higher in CU compared with HV in the AST (F=10.38, p=0.003), LST (F=4.95, p=0.036), SMST (F=4.33, p=0.048), and whole striatum (F=9.02, p=0.006). Percentage of displacement (change in BP_ND between SMCT and MIST PET scans) was not significantly different across groups in any brain region, except in the GP (−5.03±14.6 in CU, compared with 6.15±12.1 in HV; F=4.39, p=0.049). Duration of cannabis use was significantly associated with stress-induced [¹¹C]-(+)-PHNO displacement by endogenous DA in the LST (r=0.566, p=0.044), with no effect in any other brain region. In conclusion, despite an increase in striatal BP_ND observed during the control task, chronic cannabis use is not associated with alterations in stress-induced DA release.     

Postpartum and Depression Status are Associated With Lower [11C]raclopride BPND in Reproductive-Age Women

The early postpartum period is associated with increased risk for affective and psychotic disorders. Because maternal dopaminergic reward system function is altered with perinatal status, dopaminergic system dysregulation may be an important mechanism of postpartum psychiatric disorders. Subjects included were non-postpartum healthy (n=13), postpartum healthy (n=13), non-postpartum unipolar depressed (n=10), non-postpartum bipolar depressed (n=7), postpartum unipolar (n=13), and postpartum bipolar depressed (n=7) women. Subjects underwent 60 min of [¹¹C]raclopride–positron emission tomography imaging to determine the nondisplaceable striatal D_2/3 receptor binding potential (BP_ND). Postpartum status and unipolar depression were associated with lower striatal D_2/3 receptor BP_ND in the whole striatum (p=0.05 and p=0.02, respectively) that reached a maximum of 7–8% in anteroventral striatum for postpartum status (p=0.02). Unipolar depression showed a nonsignificant trend toward being associated with 5% lower BP_ND in dorsal striatum (p=0.06). D_2/3 receptor BP_ND did not differ significantly between unipolar depressed and healthy postpartum women or between bipolar and healthy subjects; however, D_2/3 receptor BP_ND was higher in dorsal striatal regions in bipolar relative to unipolar depressives (p=0.02). In conclusion, lower striatal D_2/3 receptor BP_ND in postpartum and unipolar depressed women, primarily in ventral striatum, and higher dorsal striatal D_2/3 receptor BP_ND in bipolar relative to unipolar depressives reveal a potential role for the dopamine (DA) system in the physiology of these states. Further studies delineating the mechanisms underlying these differences in D_2/3 receptor BP_ND, including study of DA system responsivity to rewarding stimuli, and increasing power to assess unipolar vs bipolar-related differences, are needed to better understand the affective role of the DA system in postpartum and depressed women.     

Measuring Cigarette Smoking-Induced Cortical Dopamine Release: A [11C]FLB-457 PET Study

Striatal dopamine (DA) is thought to have a fundamental role in the reinforcing effects of tobacco smoking and nicotine. Microdialysis studies indicate that nicotine also increases DA in extrastriatal brain areas, but much less is known about its role in addiction. High-affinity D_2/3 receptor radiotracers permit the measurement of cortical DA in humans using positron emission tomography (PET). [¹¹C]FLB-457 PET scans were conducted in 10 nicotine-dependent daily smokers after overnight abstinence and reinstatement of smoking. Voxel-wise [¹¹C]-FLB-457-binding potential (BP_ND) in the frontal lobe, insula, and limbic regions was estimated in the two conditions. Paired t-tests showed BP_ND values were reduced following smoking (an indirect index of DA release). The overall peak t was located in the cingulate gyrus, which was part of a larger medial cluster (BP_ND change −12.1±9.4%) and this survived false discovery rate correction for multiple comparisons. Clusters were also identified in the left anterior cingulate cortex/medial frontal gyrus, bilateral prefrontal cortex (PFC), bilateral amygdala, and the left insula. This is the first demonstration of tobacco smoking-induced cortical DA release in humans; it may be the result of both pharmacological (nicotine) and non-pharmacological factors (tobacco cues). Abstinence increased craving but had minimal cognitive effects, thus limiting correlation analyses. However, given that the cingulate cortex, PFC, insula, and amygdala are thought to have important roles in tobacco craving, cognition, and relapse, these associations warrant investigation in a larger sample. [¹¹C]FLB-457 PET imaging may represent a useful tool to investigate individual differences in tobacco addiction severity and treatment response.     

In Vivo Binding of Antipsychotics to D3 and D2 Receptors: A PET Study in Baboons with [11C]-(+)-PHNO

Measuring the in vivo occupancy of antipsychotic drugs at dopamine D₂ and D₃ receptors separately has been difficult because of the lack of selective radiotracers. The recently developed [¹¹C]-(+)-PHNO is D₃-preferring, allowing estimates of the relative D₂ and D₃ binding of antipsychotic drugs. We used positron emission tomography (PET) imaging in baboons with [¹¹C]-(+)-PHNO to examine the binding of clozapine and haloperidol to D₂ and D₃ receptors. Four animals were scanned with dynamically acquired PET and arterial plasma input functions. Test and retest scans were acquired in single scanning sessions for three subjects to assess the reproducibility of [¹¹C]-(+)-PHNO scans. Four additional scans were acquired in each of three subjects following single doses of antipsychotic drugs (clozapine 0.5534 mg/kg, haloperidol 0.0109 mg/kg, two administrations per drug per subject) and compared with baseline scans. The percent change in binding (ΔBP_ND) following challenges with antipsychotic drugs was measured. A regression model, based on published values of regional D₂ and D₃ fractions of [¹¹C]-(+)-PHNO BP_ND in six brain regions, was used to infer occupancy at D₂ and D₃ receptors. BP_ND following antipsychotic challenge decreased in all regions. Estimated D₂ : D₃ selectivity was 2.38 for haloperidol and 5.25 for clozapine, similar to published in vitro values for haloperidol (3.03), but slightly higher for clozapine (2.82). These data suggest that acute doses of clozapine and haloperidol bind to D₃ receptors in vivo, and that the lack of D₃ occupancy by antipsychotics observed in some recent imaging studies may be because of other phenomena.     

Long-Term Exposure to Oral Methylphenidate or dl-Amphetamine Mixture in Peri-Adolescent Rhesus Monkeys: Effects on Physiology,Behavior, and Dopamine System Development

The stimulants methylphenidate and amphetamine are used to treat children with attention deficit/hyperactivity disorder over important developmental periods, prompting concerns regarding possible long-term health impact. This study assessed the effects of such a regimen in male, peri-adolescent rhesus monkeys on a variety of cognitive/behavioral, physiological, and in vivo neurochemical imaging parameters. Twice daily (0900 and 1200 hours), for a total of 18 months, juvenile male monkeys (8 per group) consumed either an unadulterated orange-flavored solution, a methylphenidate solution, or a dl-amphetamine mixture. Doses were titrated to reach blood/plasma levels comparable to therapeutic levels in children. [¹¹C]MPH and [¹¹C]raclopride dynamic PET scans were performed to image dopamine transporter and D₂-like receptors, respectively. Binding potential (BP_ND), an index of tracer-specific binding, and amphetamine-induced changes in BP_ND of [¹¹C]raclopride were estimated by kinetic modeling. There were no consistent differences among groups on the vast majority of measures, including cognitive (psychomotor speed, timing, inhibitory control, cognitive flexibility), general activity, physiological (body weight, head circumference, crown-to-rump length), and neurochemical (ie, developmental changes in dopamine transporter, dopamine D₂ receptor density, and amphetamine-stimulated dopamine release were as expected). Cytogenetic studies indicated that neither drug was a clastogen in rhesus monkeys. Thus, methylphenidate and amphetamine at therapeutic blood/plasma levels during peri-adolescence in non-human primates have little effect on physiological or behavioral/cognitive development.     

The Dopamine Stabilizer (?)-OSU6162 Occupies a Subpopulation of Striatal Dopamine D2/D3 Receptors: An [11C]Raclopride PET Study in Healthy Human Subjects

(−)-OSU6162 is a dopamine stabilizer that can counteract both hyperdopaminergic and hypodopaminergic states. In this study, D2/D3 receptor occupancy of (−)-OSU6162 in the human brain was investigated using positron emission tomography (PET). Twelve male healthy volunteers underwent [¹¹C]raclopride PET scanning before and 1 h after a single oral dose of (−)-OSU6162 (15–90 mg). Blood samples for determination of (−)-OSU6162 and prolactin plasma levels were collected at T_max. Parametric images of [¹¹C]raclopride binding potential relative to nondisplaceable tissue (cerebellar grey matter) uptake (BP_ND) at baseline and after (−)-OSU6162 administration were generated using the simplified reference tissue model. MRI-based regions of interest were defined for the striatum, composed of caudate nucleus and putamen, and projected onto the co-registered parametric [¹¹C]raclopride BP_ND image. Furthermore, three striatal subregions, ie, anterior dorsal caudate, anterior dorsal putamen, and ventral striatum, were defined manually and additionally analyzed. Plasma concentrations of (−)-OSU6162, ranging from 0.01 to 0.9 μM, showed a linear relationship with prolactin levels, reflecting blockade of pituitary D2 receptors. A concentration-dependent increase in striatal D2/D3 receptor occupancy was observed, reaching a value of about 20% at an (−)-OSU6162 plasma level of 0.2 μM, and which for higher concentrations leveled off to a maximal occupancy of about 40%. Findings were similar in the striatal subregions. The present data corroborate the notion that (−)-OSU6162 binds preferentially to a subpopulation of D2/D3 receptors, possibly predominantly extrasynaptic, and this may form the basis for the dopamine-stabilizing properties of (−)-OSU6162.     

Striatal dopamine D<Subscript>2</Subscript> receptors in medication-naive patients with major depressive disorder as assessed with [<Superscript>11</Superscript>C]raclopride PET

Rationale Among other monoamine neurotransmitters, dopamine is implicated in the pathophysiology of major depression. Experimental studies suggest the involvement of the mesolimbic dopamine system in the mechanism of action of antidepressant drugs. Previous in vivo imaging studies have studied striatal dopamine D₂ receptor availability in depression but the results are equivocal thus far. Objective To study the striatal and thalamic dopamine D₂ receptor availability in drug-naive patients with major depression was the aim of this study. Materials and methods Caudate, putamen, and thalamic dopamine D₂ receptor availability was estimated using positron emission tomography and [¹¹C]raclopride in 25 treatment-seeking drug-free patients (of whom 24 were drug-naive) with major depression (primary care patients) as well as in 19 demographically similar healthy control subjects. Receptor availability was expressed as the binding potential (BP_ND), and analyses were carried out based on both regional and voxel-level BP_ND estimates. Results No statistically significant differences in [¹¹C]raclopride BP_ND were observed between the groups either in the caudate nucleus (+1.7%, CI −4.8% to +8.3%), putamen (−1.0%, CI −7.2% to 5.1%), thalamus (−2.4%, CI −8.7% to 4.0%), or ventral striatum (−3.8%, CI −9.3% to +1.6%). In the patients, depressive symptoms were not associated with [¹¹C]raclopride BP_ND in any region. Conclusions The findings in this sample of treatment-seeking, drug-naive and predominantly first-episode patients with major depression do not support the involvement of striatal dopamine D₂ receptors in the pathophysiology of the illness, but do not exclude the potential importance of dopaminergic mechanisms in antidepressant drug action.     

Estimating Endogenous Dopamine Levels at D2 and D3 Receptors in Humans using the Agonist Radiotracer [11C]-(+)-PHNO

Using positron emission tomography (PET) and an acute dopamine depletion challenge it is possible to estimate endogenous dopamine levels occupying dopamine D_2/3 receptors (D_2/3R) in humans in vivo. Our group has developed [¹¹C]-(+)-PHNO, the first agonist radiotracer with preferential in vivo affinity for D₃R. Thus, the use of [¹¹C]-(+)-PHNO offers the novel possibility of (i) estimating in vivo endogenous dopamine levels at D_2/3R using an agonist radiotracer, and (ii) estimating endogenous dopamine levels at D₃R in extrastriatal regions such as the substantia nigra, hypothalamus, and ventral pallidum. Ten healthy participants underwent a [¹¹C]-(+)-PHNO PET scan under baseline conditions and another under acute endogenous dopamine depletion achieved via oral administration of alpha-methyl-para-tyrosine (64 mg/kg). [¹¹C]-(+)-PHNO binding was sensitive to acute dopamine depletion, allowing in vivo estimates of endogenous dopamine in D₂R-rich regions (caudate and putamen), mixed D_2/3R-rich regions (ventral striatum and globus pallidus), and extrastriatal D₃R-rich regions (hypothalamus and ventral pallidum). Dopamine depletion decreased self-reported vigor, which was correlated with the reduction in dopamine levels in the globus pallidus. [¹¹C]-(+)-PHNO is a suitable radiotracer for use in estimating endogenous dopamine levels at D₂R and D₃R in neuropsychiatric populations.     

Sustained Recreational Use of Ecstasy Is Associated with Altered Pre and Postsynaptic Markers of Serotonin Transmission in Neocortical Areas: A PET Study with [11C]DASB and [11C]MDL 100907

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 [¹¹C]DASB and the 5-HT_2A receptor ligand [¹¹C]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.     

Blunted Endogenous Opioid Release Following an Oral Amphetamine Challenge in Pathological Gamblers

Pathological gambling is a psychiatric disorder and the first recognized behavioral addiction, with similarities to substance use disorders but without the confounding effects of drug-related brain changes. Pathophysiology within the opioid receptor system is increasingly recognized in substance dependence, with higher mu-opioid receptor (MOR) availability reported in alcohol, cocaine and opiate addiction. Impulsivity, a risk factor across the addictions, has also been found to be associated with higher MOR availability. The aim of this study was to characterize baseline MOR availability and endogenous opioid release in pathological gamblers (PG) using [¹¹C]carfentanil PET with an oral amphetamine challenge. Fourteen PG and 15 healthy volunteers (HV) underwent two [¹¹C]carfentanil PET scans, before and after an oral administration of 0.5 mg/kg of d-amphetamine. The change in [¹¹C]carfentanil binding between baseline and post-amphetamine scans (ΔBP_ND) was assessed in 10 regions of interest (ROI). MOR availability did not differ between PG and HV groups. As seen previously, oral amphetamine challenge led to significant reductions in [¹¹C]carfentanil BP_ND in 8/10 ROI in HV. PG demonstrated significant blunting of opioid release compared with HV. PG also showed blunted amphetamine-induced euphoria and alertness compared with HV. Exploratory analysis revealed that impulsivity positively correlated with caudate baseline BP_ND in PG only. This study provides the first evidence of blunted endogenous opioid release in PG. Our findings are consistent with growing evidence that dysregulation of endogenous opioids may have an important role in the pathophysiology of addictions.     

Amphetamine-Induced Dopamine Release and Neurocognitive Function in Treatment-Naive Adults with ADHD

Converging evidence from clinical, preclinical, neuroimaging, and genetic research implicates dopamine neurotransmission in the pathophysiology of attention deficit hyperactivity disorder (ADHD). The in vivo neuroreceptor imaging evidence also suggests alterations in the dopamine system in ADHD; however, the nature and behavioral significance of those have not yet been established. Here, we investigated striatal dopaminergic function in ADHD using [¹¹C]raclopride PET with a d-amphetamine challenge. We also examined the relationship of striatal dopamine responses to ADHD symptoms and neurocognitive function. A total of 15 treatment-free, noncomorbid adult males with ADHD (age: 29.87±8.65) and 18 healthy male controls (age: 25.44±6.77) underwent two PET scans: one following a lactose placebo and the other following d-amphetamine (0.3 mg/kg, p.o.), administered double blind and in random order counterbalanced across groups. In a separate session without a drug, participants performed a battery of neurocognitive tests. Relative to the healthy controls, the ADHD patients, as a group, showed greater d-amphetamine-induced decreases in striatal [¹¹C]raclopride binding and performed more poorly on measures of response inhibition. Across groups, a greater magnitude of d-amphetamine-induced change in [¹¹C]raclopride binding potential was associated with poorer performance on measures of response inhibition and ADHD symptoms. Our findings suggest an augmented striatal dopaminergic response in treatment-naive ADHD. Though in contrast to results of a previous study, this finding appears consistent with a model proposing exaggerated phasic dopamine release in ADHD. A susceptibility to increased phasic dopamine responsivity may contribute to such characteristics of ADHD as poor inhibition and impulsivity.     

Elevation of Dopamine Induced by Cigarette Smoking: Novel Insights from a [11C]-(+)-PHNO PET Study in Humans

Positron emission tomography (PET) has convincingly provided in vivo evidence that psychoactive drugs increase dopamine (DA) levels in human brain, a feature thought critical to their reinforcing properties. Some controversy still exists concerning the role of DA in reinforcing smoking behavior and no study has explored whether smoking increases DA concentrations at the D3 receptor, speculated to have a role in nicotine''s addictive potential. Here, we used PET and [¹¹C]-(+)-PHNO ([¹¹C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol) to test the hypothesis that smoking increases DA release (decreases [¹¹C]-(+)-PHNO binding) in D2-rich striatum and D3-rich extra-striatal regions and is related to craving, withdrawal and smoking behavior. Ten participants underwent [¹¹C]-(+)-PHNO scans after overnight abstinence and after smoking a cigarette. Motivation to smoke (smoking topography), mood, and craving were recorded. Smoking significantly decreased self-reported craving, withdrawal, and [¹¹C]-(+)-PHNO binding in D2 and D3-rich areas (−12.0 and −15.3%, respectively). We found that motivation to smoke (puff rate) predicted magnitude of DA release in limbic striatum, and the latter was correlated with decreased craving and withdrawal symptoms. This is the first report suggesting that, in humans, DA release is increased in D3-rich areas in response to smoking. Results also support the preferential involvement of the limbic striatum in motivation to smoke, anticipation of pleasure from cigarettes and relief of withdrawal symptoms. We propose that due to the robust effect of smoking on [¹¹C]-(+)-PHNO binding, this radiotracer represents an ideal translational tool to investigate novel therapeutic strategies targeting DA transmission.     

PET examination of [11C]NNC 687 and [11C]NNC 756 as new radioligands for the D1-dopamine receptor

The benzazepines NNC 687 and NNC 756 have in animal studies been described as selective D₁-dopamine receptor antagonists. Both compounds have been labeled with¹¹C for examination by positron emission tomography (PET). In the present study central receptor binding was studied in monkeys and healthy men. After IV injection of both radioligands in Cynomolgus monkeys radioactivity accumulated markedly in the striatum, a region with a high density of D₁-dopamine receptors. This striatal uptake was displaced by high doses of the selective D₁-antagonist SCH 23390 (2 mg/kg) but not by the 5HT₂-antagonist ketanserin (1.5 mg/kg) or the selective D₂-antagonist raclopride (3 mg/kg). The cortical uptake after injection of [¹¹C]NNC 687 was not reduced in displacement experiments with ketanserin. The cortical uptake of [¹¹C]NNC 756 was reduced in displacement and protection experiments with ketanserin by 24–28% (1.5 mg/kg), whereas no reduction could be demonstrated on striatal uptake. In healthy males both compounds accumulated markedly in the striatum. For [¹¹C]NNC 687 the ratio of radioactivity in the putamen to cerebellum was about 1.5. For [¹¹C]NNC 756 the ratio was about 5. This ratio of 5 for [¹¹C]NNC 756 is the highest obtained so far for PET radioligands for the D₁-dopamine receptor.     

Dopaminergic activity in Tourette syndrome and obsessive-compulsive disorder

Tourette syndrome (TS) and obsessive-compulsive disorder (OCD) both are neuropsychiatric disorders associated with abnormalities in dopamine neurotransmission. Aims of this study were to quantify striatal D_2/3 receptor availability in TS and OCD, and to examine dopamine release and symptom severity changes in both disorders following amphetamine challenge.Changes in [¹¹C]raclopride binding potential (BP_ND) were assessed using positron emission tomography before and after administration of d-amphetamine (0.3 mg kg^?1) in 12 TS patients without comorbid OCD, 12 OCD patients without comorbid tics, and 12 healthy controls. Main outcome measures were baseline striatal D_2/3 receptor BP_ND and change in BP_ND following amphetamine as a measure of dopamine release.Voxel-based analysis revealed significantly decreased baseline [¹¹C]raclopride BP_ND in bilateral putamen of both patient groups vs. healthy controls, differences being more pronounced in the TS than in the OCD group. Changes in BP_ND following amphetamine were not significantly different between groups. Following amphetamine administration, tic severity increased in the TS group, which correlated with BP_ND changes in right ventral striatum. Symptom severity in the OCD group did not change significantly following amphetamine challenge and was not associated with changes in BP_ND.This study provides evidence for decreased striatal D_2/3 receptor availability in TS and OCD, presumably reflecting higher endogenous dopamine levels in both disorders. In addition, it provides the first direct evidence that ventral striatal dopamine release is related to the pathophysiology of tics.     

Immediate and Persistent Effects of Salvinorin A on the Kappa Opioid Receptor in Rodents,Monitored In Vivo with PET

Monitoring changes in opioid receptor binding with positron emission tomography (PET) could lead to a better understanding of tolerance and addiction because altered opioid receptor dynamics following agonist exposure has been linked to tolerance mechanisms. We have studied changes in kappa opioid receptor (KOR) binding availability in vivo with PET following kappa opioid agonist administration. Male Sprague–Dawley rats (n=31) were anesthetized and treated with the (KOR) agonist salvinorin A (0.01–1.8 mg/kg, i.v.) before administration of the KOR selective radiotracer [¹¹C]{"type":"entrez-nucleotide","attrs":{"text":"GR103545","term_id":"238230768","term_text":"GR103545"}}GR103545. When salvinorin A was administered 1 min prior to injection of the radiotracer, [¹¹C]{"type":"entrez-nucleotide","attrs":{"text":"GR103545","term_id":"238230768","term_text":"GR103545"}}GR103545 binding potential (BP_ND) was decreased in a dose-dependent manner, indicating receptor binding competition. In addition, the unique pharmacokinetics of salvinorin A (half-life ~8 min in non-human primates) allowed us to study the residual impact on KOR after the drug had eliminated from the brain. Salvinorin A was administered up to 5 h prior to [¹¹C]{"type":"entrez-nucleotide","attrs":{"text":"GR103545","term_id":"238230768","term_text":"GR103545"}}GR103545, and the changes in BP_ND were compared with baseline, 2.5 h, 1 h, and 1 min pretreatment times. At lower doses (0.18 mg/kg and 0.32 mg/kg) we observed no prolonged effect on KOR binding but at 0.60 mg/kg salvinorin A induced a sustained decrease in KOR binding (BP_ND decreased by 40–49%) which persisted up to 2.5 h post administration, long after salvinorin A had been eliminated from the brain. These data point towards an agonist-induced adaptive response by KOR, the dynamics of which have not been previously studied in vivo with PET.     

Synthesis of [11C]Am80 via Novel Pd(0)-Mediated Rapid [11C]Carbonylation Using Arylboronate and [11C]Carbon Monoxide

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Selective D1- and D2-dopamine receptor blockade both induces akathisia in humans — a PET study with [11C]SCH 23390 and [11C]raclopride

Pharmacological effects were recorded and time course for receptor binding in brain was followed by positron emission tomography after IV injection of the selective D₁-dopamine receptor antagonist SCH 23390 in four healthy subjects in doses of 310–810 µg. Akathisia, the syndrome of motor restlessness, appeared after the three highest doses. The akathisia was transient and occurred only when [¹¹C]SCH 23390 binding in the basal ganglia was at a high level with a central D₁-dopamine receptor occupancy of 45–59%. The D₂-dopamine receptor antagonist [¹¹C]raclopride was injected IV into 20 healthy subjects and 13 schizophrenic patients. Akathisia appeared in 14 healthy subjects and 7 patients and coincided with maximal [¹¹C]raclopride binding in the basal ganglia. The findings for [¹¹C]raclopride and [¹¹C]SCH 23390 are the first demonstration of a relationship between time courses for radioligand binding in the human brain and simultaneously induced pharmacological effects.     

Stress-Induced Dopamine Response in Subjects at Clinical High Risk for Schizophrenia with and without Concurrent Cannabis Use

Research on the environmental risk factors for schizophrenia has focused on either psychosocial stress or drug exposure, with limited investigation of their interaction. A heightened dopaminergic stress response in patients with schizophrenia and individuals at clinical high risk (CHR) supports the dopaminergic sensitization hypothesis. Cannabis is believed to contribute to the development of schizophrenia, possibly through a cross-sensitization with stress. Twelve CHR and 12 cannabis-using CHR (CHR-CU, 11 dependent) subjects underwent [¹¹C]-(+)-PHNO positron emission tomography scans, while performing a Sensorimotor Control Task (SMCT) and a stress condition (Montreal Imaging Stress task). The simplified reference tissue model was used to obtain binding potential relative to non-displaceable binding (BP_ND) in the whole striatum, its functional subdivisions (limbic striatum (LST), associative striatum (AST), and sensorimotor striatum (SMST)), globus pallidus (GP), and substantia nigra (SN). Changes in BP_ND, reflecting alterations in synaptic dopamine (DA) levels, were tested with analysis of variance. SMCT BP_ND was not significantly different between groups in any brain region (p>0.21). Although stress elicited a significant reduction in BP_ND in the CHR group, CHR-CU group exhibited an increase in BP_ND. Stress-induced changes in regional BP_ND between CHR-CU and CHR were significantly different in AST (p<0.001), LST (p=0.007), SMST (p=0.002), SN (p=0.021), and whole striatum (p=0.001), with trend level in the GP (p=0.099). All subjects experienced an increase in positive (attenuated) psychotic symptoms (p=0.001) following the stress task. Our results suggest altered DA stress reactivity in CHR subjects who concurrently use cannabis, as compared with CHR subjects. Our finding does not support the cross-sensitization hypothesis, which posits greater dopaminergic reactivity to stress in CHR cannabis users, but adds to the growing body of literature showing reduced DA (stress) response in addiction.     

Synthesis of [11C]Bexarotene by Cu-Mediated [11C]Carbon Dioxide Fixation and Preliminary PET Imaging

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