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.     

Occupancy of dopamine D<Subscript>1</Subscript>, D<Subscript>2</Subscript> and serotonin<Subscript>2A</Subscript> receptors in schizophrenic patients treated with flupentixol in comparison with risperidone and haloperidol

Rationale Flupentixol (FLX) has been used as a neuroleptic for nearly 4 decades. In vitro data show comparable affinity to dopamine D₂, D₁ and 5-HT_2A receptors and recently, FLX showed to be not inferior to risperidone in schizophrenic patients with predominant negative symptomatology, which was implicated with flupentixol’s interaction with 5-HT_2A and/or D₁ receptors. Objectives To assess in vivo receptor occupancy (RO) in patients clinically treated with FLX (n = 13, 5.7 ± 1.4 mg/day) in comparison with risperidone (RIS, n = 11, 3.6 ± 1.3 mg/day) and haloperidol (HAL, n = 11, 8.5 ± 5.5 mg/day). Materials and methods Each patient underwent two PET scans with 3-N-[¹¹C]methylspiperone (target: frontal 5-HT_2A), [¹¹C]SCH23390 (striatal D₁) or [¹¹C]raclopride (striatal D₂). RO was calculated as the percentage reduction of specific binding in comparison with healthy controls. Results D₂-RO under FLX was between 50% and 70%, indicating an ED₅₀ of about 0.7 ng/ml serum. 5-HT_2A and D₁-RO was 20 ± 10% and 20 ± 5% (mean, SEM). Under HAL, D₁-RO was 14 ± 6% and under RIS not significantly different from zero. Conclusions We were able to demonstrate a moderate 5-HT_2A and D₁ occupancy under clinically relevant doses of flupentixol, albeit lower than expected from in vitro data and clearly below saturation. Therefore, if flupentixol’s efficacy on negative symptoms is based on its interaction with 5-HT_2A and/or D₁ receptors, it should be highly dependent on serum concentration and thus on dosage and metabolism. However, these data suggest that mechanisms other than D₁ or 5-HT_2A antagonism may contribute to flupentixol’s efficacy on negative symptoms.     

Antipsychotics possessing antidepressive efficacy increase G<Subscript>olf</Subscript> protein in rat striatum

Rationale Paliperidone ER is a novel antipsychotic drug in an extended-release (ER) formulation. As with all antipsychotics, careful dose setting is necessary to avoid side effects. Objectives In this study, we measured striatal and extrastriatal dopamine D₂ receptor occupancy during paliperidone ER treatment in patients with schizophrenia using positron emission tomography (PET) to compare regional occupancy and to estimate the optimal dose. Materials and methods Thirteen male patients with schizophrenia participated in this 6-week multiple-dose study. Six of them took 3 mg of paliperidone ER per day, four took 9 mg, and three took 15 mg. Two to 6 weeks after first drug intake, two PET scans, one with [¹¹C]raclopride and one with [¹¹C]FLB 457, were performed in each patient on the same day. The relationship between the dose or plasma concentration of paliperidone and dopamine D₂ receptor occupancy was calculated. Results The dopamine D₂ receptor occupancies in the striatum measured with [¹¹C]raclopride and the temporal cortex measured with [¹¹C]FLB 457 were 54.2–85.5% and 34.5–87.3%, respectively. ED₅₀ values of the striatum and temporal cortex were 2.38 and 2.84 mg/day, respectively. There was no significant difference in dopamine D₂ receptor occupancy between the striatum and the temporal cortex. Conclusions The data from this study suggest that paliperidone ER at 6–9 mg provides an estimated level of dopamine D₂ receptor occupancy between 70–80% and that the magnitude of dopamine D₂ receptor occupancy is similar between the striatum and temporal cortex.     

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.     

Imaging human reward processing with positron emission tomography and functional magnetic resonance imaging

Functional neuroimaging (fMRI) studies show activation in mesolimbic circuitry in tasks involving reward processing, like the Monetary Incentive Delay Task (MIDT). In voltammetry studies in animals, mesolimbic dopamine release is associated with reward salience. This study examined the relationship between fMRI activation and magnitude of dopamine release measured with Positron emission tomography study (PET) in the same subjects using MIDT in both modalities to test if fMRI activation is related to dopamine release. Eighteen healthy subjects were scanned with [¹¹ C]raclopride PET at baseline and after MIDT. Binding potential (BP_ND) was derived by equilibrium analysis in striatal subregions and percent change across conditions (∆BP_ND) was measured. Blood oxygen level dependence (BOLD) signal changes with MIDT were measured during fMRI using voxelwise analysis and ROI analysis and correlated with ∆BP_ND. ∆BP_ND was not significant in the ventral striatum (VST) but reached significance in the posterior caudate. The fMRI BOLD activation was highest in VST. No significant associations between ∆BP_ND and change in fMRI BOLD were observed with VST using ROI analysis. Voxelwise analysis showed positive correlation between BOLD activation in anticipation of the highest reward and ∆BP_ND in VST and precommissural putamen. Our study indicates that endogenous dopamine release in VST is of small magnitude and is related to BOLD signal change during performance of the MIDT in only a few voxels when rewarding and nonrewarding conditions are interspersed. The lack of correlation at the ROI level may be due to the small magnitude of release or to the particular dependence of BOLD on glutamatergic signaling.     

In vivo affinity of [<Superscript>18</Superscript>F]fallypride for striatal and extrastriatal dopamine D<Subscript>2</Subscript> receptors in nonhuman primates

Rationale [¹⁸F]Fallypride is a new and promising radiotracer, suitable for imaging D₂ receptors with Positron Emission Tomography (PET) in both striatal and extrastriatal regions. The high signal to noise ratio of [¹⁸F]fallypride has been attributed to its high affinity for D₂ receptors (K_D of 0.03 nM, measured in vitro at room temperature).Objectives We sought to further characterize this tracer in terms of its in vivo affinity, possible affinity differences between brain regions and dependence of in vitro affinity on temperature.Methods PET scans were performed in baboons over a wide range of concentrations to measure the in vivo K_D of [¹⁸F]fallypride in striatal and extrastriatal regions. Several analytical approaches were used, including nonlinear kinetic modeling and equilibrium methods. Also, in vitro assays were performed at 22 and 37°C.Results No significant differences in the in vivo K_D were detected between regions. In vivo K_D of [¹⁸F]fallypride was 0.22±0.05 nM in striatum, 0.17±0.05 nM in thalamus, and 0.21±0.07 nM in hippocampus. These values were intermediate between in vitro K_D measured at 22 (0.04±0.03 nM) and 37 degrees (2.03±1.07 nM).Conclusion The in vivo affinity of [¹⁸F]fallypride was not as high as previously estimated from in vitro values. This property might contribute to the favorable kinetic properties of the tracer. The in vivo affinity was similar between striatal and extrastriatal regions. This result indicates that the measured regional in vivo affinities of this tracer are not affected by putative regional differences in endogenous dopamine, and that [¹⁸F]fallypride is an appropriate tool to provide unbiased estimates of the occupancy of D₂ receptors by antipsychotic drugs in striatal and extrastriatal regions.     

Imaging apomorphine stimulation of brain arachidonic acid signaling <Emphasis Type="Italic">via</Emphasis> D<Subscript>2</Subscript>-like receptors in unanesthetized rats

Rationale and objective Because of the important role of dopamine in neurotransmission, it would be useful to be able to image brain dopamine receptor-mediated signal transduction in animals and humans. Administering the D₁–D₂ receptor agonist apomorphine may allow us to do this, as the D₂-like receptor is reported to be coupled to cytosolic phospholipase A₂ activation and arachidonic acid (AA) release from membrane phospholipid. Methods Unanesthetized adult rats were given intraperitoneally apomorphine (0.5 mg/kg) or saline, with or without pretreatment with 6 mg/kg intravenous raclopride, a D₂/D₃ receptor antagonist. [1–¹⁴C]AA was injected intravenously, then AA incorporation coefficients k*—brain radioactivity divided by integrated plasma radioactivity—markers of AA signaling, were measured using quantitative autoradiography in 62 brain regions. Results Apomorphine significantly elevated k* in 26 brain regions, including the frontal cortex, motor and somatosensory cortex, caudate-putamen, thalamic nuclei, and nucleus accumbens. Raclopride alone did not change baseline values of k*, but raclopride pretreatment prevented the apomorphine-induced increments in k*. Conclusions A mixed D₁–D₂ receptor agonist, apomorphine, increased the AA signal by activating only D₂-like receptors in brain circuits containing regions with high D₂-like receptor densities. Thus, apomorphine might be used with positron emission tomography to image brain D₂-like receptor-mediated AA signaling in humans in health and disease.     

Effects of age on dopamine D2 receptor availability in striatal subdivisions: A high-resolution positron emission tomography study

The purpose of the present study was to examine the relationship between age and dopamine D₂ receptor availability in striatal subdivisions of young and middle-aged healthy subjects using high-resolution positron emission tomography (PET) with [¹¹C]raclopride to better characterize the nature of age-related decrements in striatal D₂ receptor availability. Twenty-four healthy volunteers completed 3-Tesla magnetic resonance imaging and high-resolution [¹¹C]raclopride PET scans. The analyses using linear and exponential models revealed that age had a significant negative correlation with D₂ receptor availability in the post-commissural putamen (postPU) and that D₂ receptor binding in the postPU decreased significantly more with age than in the ventral striatum, suggesting subregional differences in age-related changes in D₂ receptor binding. The postPU, which belongs to the sensorimotor striatum, may be particularly vulnerable to the effects of age in young and middle-aged subjects.     

D<Subscript>2</Subscript> but not D<Subscript>1</Subscript> dopamine receptor stimulation augments brain signaling involving arachidonic acid in unanesthetized rats

Rationale and objectives Signal transduction involving the activation of phospholipase A₂ (PLA₂) to release arachidonic acid (AA) from membrane phospholipids, when coupled to dopamine D₁- and D₂-type receptors, can be imaged in rats having a chronic unilateral lesion of the substantia nigra. It is not known, however, if the signaling responses occur in the absence of a lesion. To determine this, we used our in vivo fatty acid method to measure signaling in response to D₁ and D₂ receptor agonists given acutely to unanesthetized rats. Methods [1-¹⁴C]AA was injected intravenously in unanesthetized rats, and incorporation coefficients k* for AA (brain radioactivity/integrated plasma radioactivity) were measured using quantitative autoradiography in 61 brain regions. The animals were administered i.v. the D₂ receptor agonist, quinpirole (1 mg kg⁻¹, i.v.), the D₁ receptor agonist SKF-38393 (5 mg kg⁻¹, i.v.), or vehicle/saline. Results Quinpirole increased k* significantly in multiple brain regions rich in D₂-type receptors, whereas SKF-38393 did not change k* significantly in any of the 61 regions examined. Conclusions In the intact rat brain, D₂ but not D₁ receptors are coupled to the activation of PLA₂ and the release of AA.     

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.     

A positron emission tomography (PET) study of cerebral dopamine D<Subscript>2</Subscript> and serotonine 5-HT<Subscript>2A</Subscript> receptor occupancy in patients treated with cyamemazine (Tercian)

Rationale Cyamemazine (Tercian) is an antipsychotic drug with anxiolytic properties. Recently, an in vitro study showed that cyamemazine possesses high affinity for serotonin 5-HT_2A receptors, which was fourfold higher than its affinity for dopamine D₂ receptors (Hameg et al. 2003).Objectives The aim of this study is to confirm these previous data in vivo in patients treated with clinically relevant doses of Tercian.Methods Eight patients received 37.5, 75, 150 or 300 mg/day of Tercian depending on their symptomatology. Dopamine D₂ and serotonin 5-HT_2A receptor occupancies (RO) were assessed at steady-state plasma levels of cyamemazine with positron emission tomography (PET), using [¹¹C]raclopride and [¹¹C]N-methyl-spiperone, respectively. The effective plasma level of the drug leading to 50% of receptor occupancy was estimated by fitting RO with plasma levels of cyamemazine at the time of the PET scan.Results Cyamemazine induced near saturation of 5-HT_2A receptors (RO=62.1–98.2%) in the frontal cortex even at low plasma levels of the drug. On the contrary, occupancy of striatal D₂ receptors increased with plasma levels, and no saturation was obtained even at high plasma levels (RO=25.2–74.9%). The effective plasma level of cyamemazine leading to 50% of D₂ receptor occupancy was fourfold higher than that for 5-HT_2A receptors. Accordingly, individual 5-HT_2A/D₂ RO ratios ranged from 1.26 to 2.68. No patients presented relevant increased prolactin levels, and only mild extrapyramidal side effects were noticed on Simpson and Angus Scale.Conclusion This in vivo binding study conducted in patients confirms previous in vitro findings indicating that cyamemazine has a higher affinity for serotonin 5-HT_2A receptors compared to dopamine D₂ receptors. In the dose range 37.5–300 mg, levels of dopamine D₂ occupancy remained below the level for motor side effects observed with typical antipsychotics and is likely to explain the low propensity of the drug to induce extrapyramidal side effects.     

Imaging Nicotine- and Amphetamine-Induced Dopamine Release in Rhesus Monkeys with [11C]PHNO vs [11C]raclopride PET

The radiotracer [¹¹C]PHNO may have advantages over other dopamine (DA) D₂/D₃ receptor ligands because, as an agonist, it measures high-affinity, functionally active D₂/D₃ receptors, whereas the traditionally used radiotracer [¹¹C]raclopride measures both high- and low-affinity receptors. Our aim was to take advantage of the strength of [¹¹C]PHNO for measuring the small DA signal induced by nicotine, which has been difficult to measure in preclinical and clinical neuroimaging studies. Nicotine- and amphetamine-induced DA release in non-human primates was measured with [¹¹C]PHNO and [¹¹C]raclopride positron emission tomography (PET) imaging. Seven adult rhesus monkeys were imaged on a FOCUS 220 PET scanner after injection of a bolus of [¹¹C]PHNO or [¹¹C]raclopride in three conditions: baseline; preinjection of nicotine (0.1 mg/kg bolus+0.08 mg/kg infusion over 30 min); preinjection of amphetamine (0.4 mg/kg, 5 min before radiotracer injection). DA release was measured as change in binding potential (BP_ND). Nicotine significantly decreased BP_ND in the caudate (7±8%), the nucleus accumbens (10±7%), and in the globus pallidus (13±15%) measured with [¹¹C]PHNO, but did not significantly decrease BP_ND in the putamen or the substantia nigra or in any region when measured with [¹¹C]raclopride. Amphetamine significantly reduced BP_ND in all regions with both radiotracers. In the striatum, larger amphetamine-induced changes were detected with [¹¹C]PHNO compared with [¹¹C]raclopride (52–64% vs 33–35%, respectively). We confirmed that [¹¹C]PHNO is more sensitive than [¹¹C]raclopride to nicotine- and amphetamine-induced DA release. [¹¹C]PHNO PET may be more sensitive to measuring tobacco smoking-induced DA release in human tobacco smokers.     

Non-uniform blockade of intrastriatal D<Subscript>2</Subscript>/D<Subscript>3</Subscript> receptors by risperidone and amisulpride

Rationale Atypical antipsychotic drugs have been shown to preferentially affect extrastriatal (mesolimbic) D₂/D₃ receptors over those within the striatum (nigrostriatal). The striatum does not contain exclusively nigrostriatal dopamine tracts, however. The caudate nucleus and ventral parts of the striatum primarily contain limbic and associative dopamine pathways more relevant to psychosis. Objectives We tested the hypothesis that two pharmacologically distinct atypical antipsychotic drugs, amisulpride and risperidone, would preferentially occupy of D₂/D₃ dopamine receptors in limbic and associative regions of the striatum. Methods Eight amisulpride-treated patients, six risperidone-treated patients and six age- and sex-matched healthy controls were recruited. Dynamic SPET studies were performed after bolus injection of [¹²³I]epidepride. Binding potential (BP) images were generated using a modified Logan method and aligned between subjects. Regions of interest (ROIs) were placed around head of caudate and putamen bilaterally on an average BP map derived from aligned control images. These ROIs were then applied user-independently to the BP maps for each subject to calculate BP for head of caudate and putamen. Mean occupancy of D₂/D₃ receptors in each ROI was determined by reference to the drug-free healthy volunteer group. Occupancy values for head of caudate and putamen were compared using paired Student’s t test. Results D₂/D₃ receptor occupancy was 42% in caudate and 31% in putamen for risperidone (t=5.9, df=11, p=0.0001) and 51% in caudate and 37% in putamen for amisulpride (t=11.1, df=15, p<0.0001). Conclusions Amisulpride and risperidone both show selective occupancy for limbic and associative D₂/D₃ receptors within the striatum.     

Effects of acute detoxification of the herbal blend ‘Spice Gold’ on dopamine D2/3 receptor availability: A [18F]fallypride PET study

We carried out dynamic [¹⁸F]fallypride PET scans to measure cerebral dopamine D_2/3 receptor availability in a 23-year old patient experiencing a severe withdrawal syndrome upon voluntary abstinence from “Spice”, a pre-packaged herbal smoking thought to contain synthetic cannabinoids.Upon admission to the clinic, the patient experienced craving, affective symptoms and a range of somatic complaints, which resolved after several days' monitored abstinence. PET scans were performed on the day of admission, and one week later. Estimates of [¹⁸F]fallypride binding potential (BP_ND) were obtained in striatal and extrastriatal brain regions, and compared to results of age-matched healthy control subjects. Upon admission, [¹⁸F]fallypride BP_ND was reduced by 20% in the patient's striatum and also in extra-striatal regions. During short-term follow-up upon detoxification, the BP_ND increased to normal values.This study shows substantial short-term alterations of dopamine D_2/3 receptor availability in a patient before and after acute detoxification from “Spice Gold”, thus providing first evidence of reversible effects on dopamine receptors of heavy use of a herbal smoking blend.     

Clozapine binds preferentially to cortical D1-like dopamine receptors in the primate brain: a PET study

Rationale The D₁-like dopamine receptors have been suggested to play a role in the pathophysiology and treatment of schizophrenia. Previous positron emission tomography studies have demonstrated that the atypical antipsychotic clozapine occupies D₁-like dopamine receptors in the striatum in clozapine-treated patients. Objectives The aim of the present study was to compare striatal and cortical D₁-like dopamine receptor occupancy by clozapine in the primate brain. Methods Three monkeys were each examined three times at the same day with the radioligand (+)−[¹¹C]NNC 112. The first measurement was at baseline conditions, the second after 1.5 mg/kg and the third after 6 mg/kg clozapine IV. To compare regional levels of nonspecific binding in brain regions, an additional monkey was examined using the inactive enantiomer (−)−[¹¹C]NNC 112. Receptor occupancy was calculated using both the equilibrium–ratio analysis and the simplified reference tissue model. Results After 1.5 mg/kg the D₁-like dopamine receptor occupancy ranged from 30 to 38% in the striatum, whereas the range was 51 to 57% in the frontal cortex. After 6.0 mg/kg the occupancy was 53 to 64% in the striatum and 63 to 83% in the frontal cortex. The differences between striatal and cortical D₁-like receptors occupancy were between 12 and 25%. The study with (−)−[¹¹C]NNC 112 did not show regional differences in nonspecific binding that might explain the regional differences in occupancy. Conclusions The higher D₁-like dopamine receptor occupancy in the frontal cortex may reflect a different distribution of the D₁ and D₅ dopamine receptor subtypes among brain regions and different affinity of clozapine for the two subtypes. The finding supports the suggestion that binding to D₁-like dopamine receptors may explain clozapine’s atypical drug actions.     

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.     

Striatal D2 dopamine receptor binding characteristics in vivo in patients with alcohol dependence

Striatal D₂ dopamine receptor characteristics of nine male patients with alcohol dependence abstinent for 1–68 weeks and eight healthy male volunteers were studied in vivo with positron emission tomography. The selective D₂ receptor ligand [¹¹C]raclopride and equilibrium model was used for D₂ receptor density (B_max) and affinity (K_d) measurements. A trend for a decreased striatal D₂ receptor density and for reduced D₂ receptor affinity was observed in patients with alcohol dependence. These parameters were not statistically significantly different between alcoholics and controls, but the ratio between D₂ receptor density and affinity (B_max/K_d or the striatum/cerebellum ratio from the high specific activity scan) was highly significantly lower in alcoholics than that of controls. In conclusion, the low D₂ dopamine receptor B_max/K_d ratio (striatum/cerebellum ratio) indicates that specific aspects of striatal [¹¹C]raclopride binding in vivo are deviant in alcoholics compared to controls. The result is compatible with a reduced avidity of striatal dopamine D₂ receptors in alcoholics, which is in line with the idea that D₂ dopaminergic mechanisms are involved in the biology of alcohol dependence in man.     

A cross-validation study on the relationship between central D<Subscript>2</Subscript> receptor occupancy and serum perphenazine concentration

Rationale There is a need for laboratory measures to guide clinical treatment with antipsychotic drugs. For serum concentration of the classical antipsychotic drug perphenzine an optimal therapeutic interval has been identified between 2 and 6 nmol/l. Positron emission tomography (PET) studies have suggested an optimal interval in central dopamine D₂ receptor occupancy of between 65 and 80%.Objectives The aim of the present cross-validation study in clinically stable schizophrenic patients was to examine the relationship between the optimal interval in central D₂ receptor occupancy and the therapeutic window for serum perphenazine concentration.Methods Six patients who had responded to maintenance treatment with perphenazine decanoate were examined with PET and [¹¹C]raclopride during steady-state conditions. Blood sampling was carried out for minimum serum perphenazine concentration and during the PET examination.Results The serum perphenazine concentration was between 1.8 and 9 nmol/l and the D₂ receptor occupancy varied between 66 and 82%. The relationship between central receptor occupancy and serum drug concentration was curvilinear. Mild extrapyramidal symptoms were present in the patient with the highest D₂ receptor occupancy.Conclusions The previously suggested therapeutic window in serum perphenazine concentration is in good agreement with the optimal interval suggested for central D₂ receptor occupancy. Serum concentrations at low dose levels may therefore serve as a useful tool in clinical monitoring of antipsychotic drug treatment.     

Locomotor and discriminative-stimulus effects of cocaine in dopamine D<Subscript>5</Subscript> receptor knockout mice

Rationale Dopamine D₁-like antagonists block several effects of cocaine, including its locomotor-stimulant and discriminative-stimulus effects. Because these compounds generally lack selectivity among the dopamine D₁ and D₅ receptors, the specific roles of the subtypes have not been determined. Objectives Dopamine D₅ receptor knockout (DA D₅R KO), heterozygous (HET) and wild-type (WT) mice were used to study the role of D₅ dopamine receptors in the effects of cocaine. In addition, effects of the D₁-like antagonist, SCH 39166 were also studied to further clarify the roles of D₁ and D₅ dopamine receptors in the discriminative-stimulus effects of cocaine. Methods DA D₅R KO, HET and WT mice were treated with cocaine (3–30 mg/kg) or vehicle and their horizontal locomotor activity was assessed. The mice were also trained to discriminate IP injections of saline from cocaine (10 mg/kg) using a two-lever food-reinforcement (FR10) procedure. Doses of cocaine (1.0–10 mg/kg) were administered 5 min before 15-min test-sessions. Results Cocaine dose-dependently stimulated activity in each genotype, with the highest level of activity induced in the DA D₅R WT mice. Both DA D₅R KO and HET mice showed reduced levels of horizontal activity compared to WT mice. All three genotypes acquired the discrimination of 10 mg/kg cocaine; doses of 1.0–10.0 mg/kg produced dose-related increases in the number of cocaine-appropriate responses. SCH 39166, at inactive to fully active doses (0.01–0.1 mg/kg) produced predominately saline-appropriate responding. SCH 39166 produced a dose-dependent rightward shift in the cocaine dose-effect curve in all genotypes, with similar apparent affinities. Conclusions The present data suggest an involvement of DA D₅R in the locomotor stimulant effects of cocaine. In addition, the data indicate that there is little involvement of the DA D₅R in the discriminative-stimulus effects of cocaine. In addition, the antagonism data suggest a role of the D₁ receptor in the behavioral effects of cocaine.     

Prolactinemia is uncoupled from central D<Subscript>2</Subscript>/D<Subscript>3</Subscript> dopamine receptor occupancy in amisulpride treated patients

Rationale Atypical antipsychotic drugs are classically associated with lower propensity to extrapyramidal symptoms (EPS) and hyperprolactinemia than typical antipsychotic drugs. It has not been clarified why some atypical antipsychotic drugs, such as amisulpride, induce prolactin plasma concentration (PRL) elevation, but little EPS. Previous studies have found an association between striatal D₂/D₃ receptor occupancy and PRL in typical antipsychotic treated patients suggesting that PRL is a marker of central D₂/D₃ receptors blockade.Objective We have evaluated the relationship between PRL and central (striatum, temporal cortex and thalamus) D₂/D₃ receptor occupancy in amisulpride treated schizophrenic patients.Methods Single photon emission tomography (SPET) and [¹²³I]-epidepride were used to determine D₂/D₃ receptor occupancy in eight amisulpride treated patients. PRL was measured concurrently with the scans.Results The mean PRL was 1166 (range 499–1892 mIU/l) for a mean amisulpride dose of 406 mg/day (range 150–600 mg/day). Amisulpride plasma concentration and central D₂/D₃ receptor occupancy were positively correlated (r=0.83–0.89, df=4, P<0.05). No significant correlations were observed between PRL and amisulpride (daily dose or plasma concentration, P>0.05), or between PRL and central D₂/D₃ receptor occupancy (P>0.05).Conclusions Our findings show that amisulpride-induced hyperprolactinemia is uncoupled from central D₂/D₃ receptor occupancy. Amisulpride has poor blood–brain barrier penetration and reaches much higher concentration at the pituitary, which is outside the blood–brain barrier. Higher D₂/D₃ receptor occupancy at the pituitary gland than at central regions is a possible explanation for amisulpride PRL elevation with low EPS. Further studies evaluating pituitary D₂/D₃ receptor occupancy in vivo are necessary to confirm this hypothesis.This study was partially presented (poster) at the International Congress on Schizophrenia Research, Colorado Springs, USA, 2003 and received the Young Investigator Award.