Effect of endogenous dopamine on endogenous dopamine on extrastriated [11C]FLB 457 binding measured by PET

Central dopaminergic systems are known to be implicated in the pathophysiology of schizophrenia and recent in vivo dopamine receptor imaging studies have focused on the measurement of extrastriatal dopamine receptor. However, there are only a limited number of ligands that can measure the low-density D2 receptor in extrastriatal regions and their sensitivity to endogenous dopamine in extrastriatal regions has not yet been fully examined. In this study, the effect of endogenous dopamine on the extrastriatal binding of [(11)C]FLB 457 was examined in the rhesus monkey after facilitation with 1 mg/kg of methamphetamine (MAP) and was compared with the effect on the striatal binding of [(11)C]raclopride. The indices of receptor binding were obtained by four methods using cerebellum as a reference region. The bindings of [(11)C]FLB 457 in the frontal cortex, temporal cortex, and thalamus were not significantly changed after MAP treatment, while the striatal binding of [(11)C]raclopride was decreased by more than 20%. These results suggest that [(11)C]FLB 457 is not sensitive to endogenous dopamine in the extrastriatal regions of rhesus monkeys, despite a sufficient dose of MAP to decrease the binding of [(11)C]raclopride in the striatum.     

In vivo vulnerability to competition by endogenous dopamine: comparison of the D2 receptor agonist radiotracer (-)-N-[11C]propyl-norapomorphine ([11C]NPA) with the D2 receptor antagonist radiotracer [11C]-raclopride

(-)-N-Propyl-norapomorphine (NPA) is a full dopamine (DA) D2 receptor agonist and [11C]NPA is a suitable radiotracer to image D2 receptors configured in a state of high affinity for agonists with positron emission tomography (PET). In this study the vulnerability of the in vivo binding of [11C]NPA to acute fluctuation in synaptic DA was assessed with PET in baboons and compared to that of the reference D2 receptor antagonist radiotracer [11C]raclopride. Three male baboons were studied with [11C]raclopride and [11C]NPA under baseline conditions and following administration of the potent DA releaser amphetamine (0.3, 0.5, and 1.0 mg kg(-1) i.v.). Kinetic modeling with an arterial input function was used to derive the striatal specific-to-nonspecific equilibrium partition coefficient (V3"). [11C]Raclopride V3" was reduced by 24 +/- 10%, 32 +/- 6%, and 44 +/- 9% following amphetamine doses of 0.3, 0.5, and 1.0 mg kg(-1), respectively. [11C]NPA V3" was reduced by 32 +/- 2%, 45 +/- 3%, and 53 +/- 9% following amphetamine doses of 0.3, 0.5, and 1.0 mg kg(-1), respectively. Thus, endogenous DA was more effective at competing with [11C]NPA binding compared to [11C]raclopride binding, a finding consistent with the pharmacology of these tracers (agonist vs. antagonist). These results also suggest that 71% of D2 receptors are configured in a state of high affinity for agonists in vivo. In conclusion, [11C]NPA might provide a superior radiotracer to probe presynaptic DA function with PET in health and disease.     

Striatal dopaminergic system in dopa-responsive dystonia: a multi-tracer PET study shows increased D2 receptors

Summary. We investigated the integrity of striatal dopaminergic system in seven patients with dopa-responsive dystonia (DRD). Dopamine transporter function ([¹¹C]CFT) and D1 ([¹¹C]NNC 756) and D2 receptors ([¹¹C]raclopride) were studied in same patients using positron emission tomography. Compared to age-adjusted control values the dopamine D2 receptor availability was increased in DRD. The mean age-adjusted [¹¹C]raclopride uptake was 116% of the control mean in the putamen (p=0.004) and 114% in the caudate nucleus (p=0.007). The mean [¹¹C]NNC 756 uptake was not different between DRD patients and controls, the age-adjusted uptake in DRD being 93% of mean control value in the putamen (p=0.20) and 95% in the caudate nucleus (p=0.40).The dopamine transporter binding was not altered. The [¹¹C]CFT uptake in DRD was 96% of the control value in the putamen (p=0.64), and 95% in the caudate nucleus (p=0.44).In conclusion, striatal dopamine D2 receptors availability is increased in DRD whereas dopamine D1 receptors and dopamine transporter ligand binding is unchanged. The pattern of changes in striatal dopaminergic system in DRD is different from that reported in juvenile Parkinsons disease. The increased D2 receptor availability may be due to reduced competition by endogenous dopamine or a compensatory response to dopamine deficiency, or both.     

Differential effects of stress on [11C]raclopride and [11C]MNPA binding to striatal D2/D3 dopamine receptors: A PET study in conscious monkeys

It has been reported that stress and facilitation of dopamine neuronal system are closely related. In the present study, the effects of stress on the binding of antagonist‐based [¹¹C]raclopride and agonist‐based (R)‐2‐CH3O‐N‐n‐ propylnorapomorphine ([¹¹C]MNPA) to D₂/D₃ receptors were evaluated in the striatum of conscious monkey brain. The stress state assessed from plasma cortisol level was negatively correlated with [¹¹C]raclopride binding as expected. It was noteworthy that [¹¹C]MNPA binding exhibited a positive correlation with stress state; thus, the animals with higher cortisol levels showed higher binding to D₂/D₃ receptors. Synapse 65:84–89, 2011. © 2010 Wiley‐Liss, Inc.     

The effect of nicotine on striatal dopamine release in man: A [11C]raclopride PET study

In common with many addictive substances and behaviors nicotine activates the mesolimbic dopaminergic system. Brain microdialysis studies in rodents have consistently shown increases in extrasynaptic DA levels in the striatum after administration of nicotine but PET experiments in primates have given contradicting results. A recent PET study assessing the effect of smoking in humans showed no change in [(11)C]raclopride binding in the brain, but did find that "hedonia" correlated with a reduction in [(11)C]raclopride binding suggesting that DA may mediate the positive reinforcing effects of nicotine. In this experiment we measured the effect of nicotine, administered via a nasal spray, on DA release using [(11)C]raclopride PET, in 10 regular smokers. There was no overall change in [(11)C]raclopride binding after nicotine administration in any of the striatal regions examined. However, the individual change in [(11)C]raclopride binding correlated with change in subjective measures of "amused" and "happiness" in the associative striatum (AST) and sensorimotor striatum (SMST). Nicotine concentration correlated negatively with change in BP in the limbic striatum. Nicotine had significant effects on cardiovascular measures including pulse rate, systolic blood pressure (BPr), and diastolic BPr. Baseline [(11)C]raclopride binding potential (BP) in the AST correlated negatively with the Fagerstr?m score, an index of nicotine dependence. These results support a role for the DA system in nicotine addiction, but reveal a more complex relationship than suggested by studies in animals.     

Dopamine (D2/3) receptor agonist positron emission tomography radiotracer [11C]-(+)-PHNO is a D3 receptor preferring agonist in vivo

[11C]PHNO is a recently introduced agonist to image DA D2-like receptors with Positron Emission Tomography (PET). In cats and humans, [11C]PHNO revealed an atypical distribution compared to radiolabeled D2-like antagonists (such as [11C]raclopride) or other D2-like agonists (such as [11C]NPA), as it displayed unusual high binding in the globus pallidus (GP). The goal of this study was to assess the pharmacological nature of the binding of [11C]PHNO in the GP in nonhuman primates. As previously reported in humans, [11C]PHNO equilibrium specific to nonspecific equilibrium partition coefficients (V3') in baboons was much higher in GP (3.88 +/- 1.15) than in the dorsal striatum (DST, 2.07 +/- 0.43), whereas the reverse was true for [11C]raclopride (1.48 +/- 0.41 in GP, 2.56 +/- 0.91 in DST) and [11C]NPA (0.87 +/- 0.19 in GP, 1.02 +/- 0.13 in DST). Administration of unlabeled raclopride resulted in similar reductions of [11C] PHNO V3' and [11C]raclopride V3' in both the GP and the DST. This observation demonstrated that the [11C]PHNO binding in the GP was specific to D2-like receptors. To evaluate the respective contribution of D3 and D2 receptors to the binding potential (BP) of [11C]PHNO and [11C]raclopride, experiments were carried out with the selective D3 partial agonist 1-(4(2-Napthoylamino)butyl)-4-(2-methoxyphenyl)-1A-piperazine HCL (BP897). BP897 reduced [11C]raclopride V3' by 29% +/- 9%, 19% +/- 8%, and 10% +/- 7% in GP, VST, and DST, respectively, a result consistent with expectation from postmortem studies (D3/D2 ratio in GP > VST > DST). BP897 reduced [11C]PHNO V3' by 57% +/- 11%, 30% +/- 11%, and 13% +/- 8% in GP, VST, and DST, respectively, indicating that the D3 receptor contribution to [11C]PHNO signal is higher than that of [11C]raclopride. From these experiments we conclude that [11C]PHNO is a D3 preferring agonist, and that this property explains the high GP signal not observed with [11C]raclopride or [11C]NPA. This property might contribute to its higher vulnerability to endogenous DA compared to [11C]raclopride and [11C]NPA.     

NMDA antagonist effects on striatal dopamine release: positron emission tomography studies in humans.

Previous brain imaging studies with [(11)C]raclopride have suggested that the psychotogenic effects of the noncompetitive N-methyl-D-aspartate antagonist ketamine in humans might be mediated by increased dopamine (DA) release and increased stimulation of DA D(2) receptors in the striatum. The goal of the present study was to assess the effect of ketamine on D(2) receptor availability in subregions of the striatum (dorsal caudate, DCA; dorsal putamen, DPU; ventral striatum, VST) in humans. Ten healthy subjects were studied twice. In a first group of five subjects, PET scanning was obtained twice for 90 min during bolus plus constant infusion of [(11)C]raclopride. No significant differences were observed in [(11)C]raclopride specific-to-nonspecific activity ratios (V(")(3)) measured during an early interval (30-50 min) and late interval (70-90 min), confirming that a state of sustained equilibrium had been established from 30-90 min (end of infusion). In a second group of five subjects, a similar experiment was performed twice, except that ketamine was administered beginning at 50 min (0.12 mg/kg i.v. bolus followed by 0.65 mg/kg/h i.v. infusion for 70 min). Raclopride V(")(3) measured before ketamine (30-50-min interval) was compared to [(11)C]raclopride V(")(3) measured during ketamine infusion (70-90-min interval). Ketamine induced a robust dissociative state. However, no significant differences were observed in D(2) receptor availability measured before and during the ketamine infusion (n = 10) in any of the regions examined (DCA, DPU, and VST). These data fail to demonstrate an effect of ketamine on [(11)C]raclopride BP and are consistent with microdialysis studies in rodents and nonhuman primates which reported only small effects of acute NMDA receptor blockade on extracellular striatal DA concentration.     

Dopaminergic activity in depressed smokers: A positron emission tomography study

Tobacco dependence is highly prevalent in depressed patients. We assessed changes in [¹¹C]‐raclopride binding potential (BP) using positron emission tomography (PET) before and after the oral administration of d‐amphetamine in healthy controls and unmedicated patients with current depression with and without current tobacco dependence. Over a single study day 2 [¹¹C]‐raclopride positron emission tomography scans were taken in 38 subjects: at baseline and 2 h following oral d‐amphetamine 30 mg. Twenty controls (9 smokers, 11 nonsmokers) and 18 subjects with current major depressive episode (8 smokers, 10 non‐smokers). Striatal [¹¹C]‐raclopride binding potential was measured before and after d‐amphetamine administration. Depressed smokers had a lower baseline [¹¹C]‐raclopride binding potential compared with both control non‐smokers (P < 0.007) and depressed non‐smokers (P < 0.001). There was a main effect of smoking status on amphetamine‐induced change in [¹¹C]‐raclopride binding potential (P < 0.02), but no main effect of depression. This may be due to a floor effect because of the low BP at baseline. Depressed subjects reported significant increase of positive mood after d‐amphetamine administration compared with controls (depressed smokers vs. control smokers: P < 0.05; depressed non‐smokers vs. controls: P < 0.055). Tobacco dependence appears to decrease d‐amphetamine‐induced changes in [¹¹C]‐raclopride binding potential as measured by positron emission tomography. Comorbid major depression and tobacco dependence exacerbates this effect, suggesting an altered dopamine system in comorbid patients. Synapse 63:681–689, 2009. © 2009 Wiley‐Liss, Inc.     

Intravenous ethanol increases dopamine release in the ventral striatum in humans: PET study using bolus-plus-infusion administration of [11C]raclopride

Ethanol increases the interstitial dopamine (DA) concentration in the nucleus accumbens (NAcc) of experimental animals, but positron emission tomography (PET) studies using the single-bolus protocol of the [¹¹C]-raclopride competition paradigm have yielded conflicting results in humans. To resolve disparate previous findings, we utilized the bolus-plus-infusion (B/I) method, allowing both baseline and intervention quantification of [¹¹C]raclopride binding during a single 105-minute PET scan, to investigate possible ethanol-induced DA release in nine healthy male subjects. A 25-minute intravenous ethanol (7.6%) infusion, resulting in a 1.3 g/L mean blood ethanol concentration, was administered using masked timing during the PET scan. Automated region-of-interest analysis testing the difference between baseline (40–50 minutes) and intervention (60–85 minutes) revealed an average 12.6% decrease in [¹¹C]raclopride binding in the ventral striatum (VST, P=0.003) including the NAcc. In addition, a shorter time interval from the start of ethanol infusion to the first subjective effect was associated with a greater binding potential decrease bilaterally in the VST (r=0.92, P=0.004), and the feeling of pleasure was associated with a decrease in binding potential values in both the caudate nucleus (r=−0.87, P=0.003) and putamen (r=−0.74; P=0.02). These results confirm that ethanol induces rapid DA release in the limbic striatum, which can be reliably estimated using the B/I method in one imaging session.     

Decreased dopamine D receptor binding in essential blepharospasm

Objectives – The purpose of this study was to investigate whether dopamine D₂ receptor binding was altered in the striatum of essential blepharospasm patients. Methods – Striatal dopamine D₂ receptor binding was measured with positron emission tomography and [¹¹C]raclopride. We studied eight drug‐naive patients with bilateral blepharospasm and eight age‐matched normal controls. Results – The uptake indices in the blepharospasm group were significantly reduced by 11.7% in the caudate (P < 0.005), 11.6% in the anterior putamen (P < 0.0001), and 10.3% in the posterior putamen (P < 0.005) relative to the control group. Conclusions – This study indicates decreased dopamine D₂ receptor binding in the entire striatal region of blepharospasm patients. The findings suggest that decreased dopamine D₂ receptor binding might be one of the predisposing factors that leads to the dysfunction of the motor circuit, resulting in the loss of broad inhibition of unwanted movements during an intended movement in blepharospasm patients.     

Comparative effects of methamphetamine and nicotine on the striatal [(11)C]raclopride binding in unanesthetized monkeys

Although a very large literature exists on the in vitro, ex vivo, and in vivo effects of nicotine on dopamine release in rodents, similar data in primates are scant. This study was initiated to compare methamphetamine to nicotine given i.v. to normal unanesthetized monkeys using positron emission tomography (PET) techniques. Release of dopamine in the striatum using [¹¹C]raclopride was determined indirectly in four nicotine‐naïve adult Macaca mulatta monkeys under conscious and isoflurane‐anesthetized conditions using high‐resolution PET. [¹¹C]Raclopride was given i.v. as a bolus injection followed by continuous infusion with steady state over 30–45 min. Nicotine bitartrate was then given as a bolus plus infusion for 30 min in doses of 32 μg/kg + 0.8 μg/kg/min or 100 μg/kg + 2.53 μg/kg/min as base. The larger doses of nicotine caused significant cardiovascular effects; these doses did not displace [¹¹C]raclopride binding in either dorsal or ventral striatum under the anesthetized conscious condition. In contrast, isoflurane‐anesthesia induced a slight but significant dose‐dependent reduction of [¹¹C]raclopride binding by nicotine even at the same doses used in the anesthetized condition. Methamphetamine in bolus doses of 0.1, 0.3, and 1.0 mg/kg i.v. under conscious condition caused a significant displacement of [¹¹C]raclopride and isoflurane‐anesthesia facilitated the displacement induced by nicotine. These results indicate that nicotine, in high tobacco‐smoking‐related doses, does not release sufficient brain dopamine to displace [¹¹C]raclopride in the striatum in the awake and fully conscious state, in contrast to small doses of methamphetamine. Synapse 45:207–212, 2002. © 2002 Wiley‐Liss, Inc.     

MDMA‐evoked changes in the binding of dopamine D2 receptor ligands in striatum of rats with unilateral serotonin depletion

We earlier reported an anomalous 50% decrease in [¹¹C]N‐methylspiperone ([¹¹C]NMSP) binding to dopamine D₂‐like receptors in living pig striatum after challenge with 3,4‐methylenedioxymethamphetamine (MDMA, “Ecstasy”), suggesting either (1) a species peculiarity in the vulnerability of butyrophenone binding to competition from dopamine or (2) a novel consequence of synergistic actions of serotonin and dopamine at dopamine receptors. To distinguish these possibilities, we used microPET to test the vulnerability of [¹¹C]NMSP binding in striatum of rats with unilateral telencephalic serotonin lesions, later verified by [¹²⁵I]RTI‐55 autoradiography. Baseline [¹¹C]NMSP microPET recordings were followed by either saline or MDMA‐HCl (4 mg/kg) injections (i.v.), and a second [¹¹C]NMSP recording, culminating with injection of [³H]raclopride for autoradiography ex vivo. Neither MDMA‐challenge nor serotonin lesion had any detectable effect on [¹¹C]NMSP binding. In contrast, MDMA challenge increased receptor occupancy by [³H]raclopride ex vivo (relative to the B_max in vitro) from 8% to 12%, and doubled the free ligand concentration in cerebral cortex, apparently by blocking hepatic CYP2D6. Assuming a single binding‐site model, the increased [³H]raclopride binding indicated doubling of the apparent equilibrium dissociation constant in vivo (K), revealing a 2‐fold increase in competition from endogenous dopamine at [³H]raclopride binding sites. The results favor hypothesis (1) that the remarkable vulnerability of [¹¹C]NMSP binding in pig striatum to MDMA challenge does not generalize to the rodent. Synapse 64:70–82, 2010. © 2009 Wiley‐Liss, Inc.     

Temporal characterisation of amphetamine-induced dopamine release assessed with [11C]raclopride in anaesthetised rodents

Competition between endogenous neurotransmitters and radiolabelled tracers, as measured by positron emission tomography (PET), may provide a measure of endogenous neurotransmitter flux in vivo. For example, carbon-11 labelled raclopride has been effectively used to monitor dopamine release following pharmacological and behavioural manipulations. The current study describes a rodent model of amphetamine-induced [11C]raclopride reduction, which allowed the characterisation of the dose-response and temporal dynamics of this reduction over a 24-h time course. Over the range studied, a monotonic dose-response relationship between amphetamine dose and [11C]raclopride reduction was observed. When compared with previously published microdialysis data, an approximate 16% reduction in [11C]raclopride binding potential was associated with a approximately 25-fold increase in extracellular dopamine. A reduction of 20-30% in raclopride binding was observed 30 min after amphetamine injection (4 mg/kg i.p.). This reduction in [11C]raclopride binding persisted for 4 h but returned to baseline by 8 h. The data suggest a persistent amphetamine-induced raclopride displacement in rodents and reinforce findings from nonhuman primates that a simple competitive occupancy model may not adequately explain the temporal characteristics of the amphetamine-induced decrease in radiotracer binding.     

Positron emission tomography imaging of amphetamine‐induced dopamine release in the human cortex: A comparative evaluation of the high affinity dopamine D2/3 radiotracers [11C]FLB 457 and [11C]fallypride

The use of PET and SPECT endogenous competition binding techniques has contributed to the understanding of the role of dopamine in several neuropsychiatric disorders. An important limitation of these imaging studies is the fact that measurements of acute changes in synaptic dopamine have been restricted to the striatum. The ligands previously used, such as [¹¹C]raclopride and [¹²³I]IBZM, do not provide sufficient signal to noise ratio to quantify D₂ receptors in extrastriatal areas, such as cortex, where the concentration of D₂ receptors is much lower than in the striatum. Given the importance of cortical DA function in cognition, a method to measure cortical dopamine function in humans would be highly desirable. The goal of this study was to compare the ability of two high affinity DA D₂ radioligands [¹¹C]FLB 457 and [¹¹C]fallypride to measure amphetamine‐induced changes in DA transmission in the human cortex. D₂ receptor availability was measured in the cortical regions of interest with PET in 12 healthy volunteers under control and postamphetamine conditions (0.5 mg kg^?1, oral), using both [¹¹C]FLB 457 and [¹¹C]fallypride (four scans per subjects). Kinetic modeling with an arterial input function was used to derive the binding potential (BP_ND) in eight cortical regions. Under controlled conditions, [¹¹C]FLB 457 BP_ND was 30–70% higher compared with [¹¹C]fallypride BP_ND in cortical regions. Amphetamine induced DA release led to a significant decrease in [¹¹C]FLB 457 BP_ND in five out the eight cortical regions evaluated. In contrast, no significant decrease in [¹¹C]fallypride BP_ND was detected in cortex following amphetamine. The difference between [¹¹C]FLB 457 and [¹¹C]fallypride ability to detect changes in the cortical D₂ receptor availability following amphetamine is related to the higher signal to noise ratio provided by [¹¹C]FLB 457. These findings suggest that [¹¹C]FLB 457 is superior to [¹¹C]fallypride for measurement of changes in cortical synaptic dopamine. Synapse 63:447–461, 2009. © 2009 Wiley‐Liss, Inc.     

Imaging of dopamine D2/3 agonist binding in cocaine dependence: a [11C]NPA positron emission tomography study

Objective: Positron emission tomography (PET) studies performed with [¹¹C]raclopride have consistently reported lower binding to D_2/3 receptors and lower amphetamine‐induced dopamine (DA) 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 DA 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) (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. Synapse, 2011. © 2011 Wiley‐Liss, Inc.     

Age differences in phosphodiesterase type-IV and its functional response to dopamine D1 receptor modulation in the living brain: a PET study in conscious monkeys

The present study demonstrated the age-related changes in the striatal dopamine D1 receptor binding and its related cAMP second-messenger system in the living brains of conscious young (6.4 +/- 1.8 years old) and aged (19.5 +/- 3.3 years old) monkeys (Macaca mulatta) using positron emission tomography (PET). For quantitative analysis of D1 receptors, [11C]SCH23390 was used and phosphodiesterase type-IV (PDE-IV) activity, as an index of cAMP system, was estimated by two scans with R- and S-[11C]rolipram. Significant age-related decreases in D1 receptor binding were observed in the striatum and frontal cortex. Analysis of uptake of R- and S-[11C]rolipram indicated age-related decreases in PDE-IV activity showing 22.0 and 25.2% decreases in the striatum and frontal cortex, respectively, while no significant changes were observed in the cerebellum. With systemic preadministration of the dopamine D1 receptor antagonist SCH23390 (0.2, 0.6, and 2 mg/kg), the PDE-IV activities in the striatum and frontal cortex were dose-dependently suppressed in both age groups. However, the degree of suppression by SCH23390 was more marked in young than in aged monkeys. These results demonstrate that the striatal cAMP second-messenger system activity as well as its functional response to dopamine D1 antagonist showed age-related impairment in the brain.     

Upregulation of dopamine D2 receptors in dopaminergic drug-naive patients with Parkin gene mutations.

Medicated patients with Parkinsonism and parkin gene mutations have been reported to show a significant decrease in striatal dopamine D2 receptors (D2R) in comparison to medicated idiopathic Parkinson's disease (IPD) patients with similar age and disease severity. The aim of this study was to verify whether the genetic defect per se is responsible for this decrease. We have studied with [11C]raclopride (RAC) positron emission tomography (PET) in a group of 14 sporadic patients with parkin-linked Parkinsonism, 6 of whom had never received levodopa or dopamine agonists. The remaining 8 patients had been treated with levodopa for at least 5 years. Presynaptic striatal [18F]dopa storage was not significantly different between these two groups of patients. In untreated parkin-positive patients, significant putaminal increases in RAC-binding potential (BP) were found in comparison to an age-matched healthy control group by using a classical region of interest approach and statistical parametric mapping. In contrast, levodopa-treated parkin-positive patients showed significant decreases in RAC-BP in the caudate and putamen when compared to an age-matched healthy control group. The RAC PET findings revealed that striatal D2R upregulation occurs in dopaminergic drug-naive parkin-positive patients, in a similar fashion to the upregulation reported in drug-naive IPD. D2R downregulation observed in medicated parkin-positive patients, therefore, is not caused primarily by the genetic defect itself. Parkin-positive patients appear to have a greater susceptibility to the exposure to dopaminergic medication than IPD patients, which in turn might be an indirect effect of their genetic mutation.     

L-DOPA modulates striatal dopaminergic function in vivo: Evidence from PET investigations in nonhuman primates

Significant increases in striatal L-[¹¹C]DOPA retention were observed in adult female rhesus monkeys with positron emission tomography (PET) following administration of drugs that increase cerebral L-DOPA concentrations. The monkeys were scanned twice: at baseline (using 10–50 μg of tracer substance) and during continuous administration of L-DOPA (3 or 15 mg/kg/h) and 6-R-Erythro-4,5,6,7-tetrahydrobiopterin (6R-BH₄) (5 mg/kg/h) and during combined administration of both drugs. PET scans of L-[¹¹C]DOPA distribution were obtained in GE2048-15B or GE4096-15WB Plus positron tomographs. In all studies the specific striatal L-[¹¹C]DOPA influx rate increased by an average of 17–20%. These increases were significantly higher than the retest variability obtained with saline infusions under identical experimental conditions. In individual monkeys the magnitude of increase in the striatal L-[¹¹C]DOPA influx rate varied from no effect of the drug infusion to a 45% increase. Taken together, the results of this study demonstrate that L-DOPA in itself can affect dopaminergic neurotransmission in vivo and also adds further evidence that the neuromodulatory effects of the amino acid are predominantly autoreceptor antagonist-like. The findings most likely have importance for the further understanding of the dopaminergic system in neurodegenerative and psychiatric disorders. Synapse 25:56–61, 1997. © 1997 Wiley-Liss, Inc.