The purpose of this study was to determine the binding sites of pramipexole in extrastriatal dopaminergic regions because its antidepressive effects have been speculated to occur by activating the dopamine D2 receptor subfamily in extrastriatal areas. Dynamic positron emission tomography (PET) scanning using 11C-FLB 457 for quantification of D2/D3 receptor subtype was performed on 15 healthy volunteers. Each subject underwent two PET scans before and after receiving a single dose of pramipexole (0, 0.125, or 0.25 mg). The study demonstrated that pramipexole significantly binds to D2/D3 receptors in the prefrontal cortex, amygdala, and medial and lateral thalamus at a dose of 0.25 mg. These regions have been indicated to have some relation to depression and may be part of the target sites where pramipexole exerts its antidepressive effects.
Citation: Ishibashi K, Ishii K, Oda K, Mizusawa H, Ishiwata K (2011) Binding of Pramipexole to Extrastriatal Dopamine D2/D3 Receptors in the Human Brain: A Positron Emission Tomography Study Using 11C-FLB 457. PLoS ONE 6(3): e17723. https://doi.org/10.1371/journal.pone.0017723
Editor: Kenji Hashimoto, Chiba University Center for Forensic Mental Health, Japan
Received: November 30, 2010; Accepted: February 13, 2011; Published: March 9, 2011
Copyright: © 2011 Ishibashi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: Funding for this work was supported by a Grant-in-Aid for Scientific Research (B) No. 20390334 (Ishiwata K) by the Japan Society for the Promotion of Science (JSPS). JSPS had no further role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Pramipexole is a dopamine D2 receptor (D2R) subfamily agonist. It was introduced for treating motor symptoms in patients with idiopathic Parkinson's disease (PD)  and has been shown to be effective by various clinical trials , . In addition, various studies have recently found antidepressive effects of pramipexole not only in patients with PD complicated by depressive state , , , , but also in depressive patients without parkinsonian symptoms , , , , , , , , . Its antidepressive effects have been also shown in animal experiments , .
The D2R subfamily consists of D2, D3, and D4 receptor subtypes . Pramipexole is active mainly at D2 and D3 receptors, and compared with other dopamine agonists, it is unique in that the binding affinity for D3 receptors is higher than that for D2 receptors , , , . Kvernmo et al. reported that binding affinities (inhibition constant; Ki) for cloned human D2 and D3 receptors of pramipexole were 3.9 and 0.5 nmol/L, respectively . The distribution of D3 receptors in the brain is different from that of D2 receptors , , , , , . Compared with D2 receptors, D3 receptors are predominantly located in extrastriatal regions including the mesolimbic dopamine system involved in mood and behavior. On the other hand, although both D2 and D3 receptors in the striatum are much more abundant than those in other regions, the D2 receptor density is higher than the D3 receptor density in the striatum. Stimulation of D2 and D3 receptors appears to induce different effects.
There are growing evidences that D3 receptors may play a role in the pathogenesis of depression because of their pharmacology and distribution in the brain , , , although the exact mechanism remains unknown. The mechanism of antidepressive effects and extrastriatal binding sites of pramipexole are also unknown, and no study has investigated this issue. These effects have been speculated to occur by means of activation of D2R subfamily, especially the D3 receptor subtype, in the mesolimbic dopamine system . Therefore, we aimed to determine the binding sites of pramipexole in the extrastriatal dopaminergic regions by using 11C-FLB 457 positron emission tomography (PET) scanning for quantification of D2/D3 receptors in extrastriatal brain regions. In addition, we discussed whether the regional sites occupied by pramipexole may be target sites where pramipexole exerts its antidepressive effects on the basis of previous anatomical and functional reports on depression.
Materials and Methods
This study protocol was approved by the Ethics Committee of the Tokyo Metropolitan Institute of Gerontology. Written informed consent was obtained from all participants. A total of 15 healthy volunteers (7 men and 8 women; mean age = 50.2 years, SD = 11.7, range = 30–77) participated in the study. All subjects underwent two 11C-FLB 457 PET scans and magnetic resonance imaging (MRI) of the brain. They were classified into 3 groups according to the dose of pramipexole (0.25, 0.125, or 0 mg). The 5 subjects in the high-dose group (2 men and 3 women, 57.2±12.8 years) received a single oral 0.25 mg dose of pramipexole. Another 5 subjects in the low-dose group (2 men and 3 women, 51.4±9.4 years) received a single oral 0.125 mg dose of pramipexole. The drug was administered between the two PET scans. The other 5 subjects were in the control group (3 men and 2 women, 42.0±6.3 years) and received no medication. Significant difference was not found in age between the 3 groups with one-way ANOVA test. All volunteers were free of any current or past mental disorders, and defined as healthy on the basis of their medical history, the results of their physical and neurological examinations and routine mental health interview performed by a neurologist, and the findings of the MRI. None had been receiving any other medications at the time of this study.
Doses of pramipexole
Previous studies have shown that administration of more than approximately 1 mg of pramipexole exerts antidepressive effects , , , , , , , , , , , , ; compared with these studies, the doses of pramipexole used in our study were low. We chose these low doses to ensure the safety of the participants in this study.
According to unpublished data on file in Nippon Boehringer Ingelheim (Tokyo, Japan), a single administration of pramipexole 0.4 mg caused orthostatic hypotension in an early clinical trial of German volunteers. On the basis of these results, the doses of pramipexole were set at 0.1, 0.2, and 0.3 mg in the Phase one clinical trial of Japanese volunteers, and no one developed more than moderate adverse effects. After oral administration of a single dose of pramipexole 0.1 mg, Cmax, Tmax, and t1/2 were 294.6±46.3 pg/mL, 1.5±0.5 h and 7.71±1.90 h (mean ± SD), respectively. After administration of pramipexole 0.2 mg, the values were 583.2±69.9 pg/mL, 1.4±0.5 h, and 6.36±1.46 h, respectively; after a dose of 0.3 mg, the values were 766.3±88.8 pg/mL, 2.3±1.2 h, and 6.94±1.09 h, respectively. One tablet of pramipexole equals 0.125 mg. Therefore, the doses of pramipexole were set at 0.25 and 0.125 mg in this study.
11C-FLB 457 PET imaging
Each volunteer participated in two 11C-FLB 457 PET scans on the same day—one in the morning and another in the afternoon. Of 15 subjects, 10 were administered with either 0.25 or 0.125 mg of pramipexole after the first PET scan; the second PET scan took place 1–1.5 h later because the concentration of pramipexole in plasma reaches its peak in approximately 1–2 hours as described above.
PET imaging was performed at the Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, with a SET-2400W scanner (Shimadzu, Kyoto, Japan). The spatial resolution was 4.4 mm full width at half maximum in the transverse direction and 6.5 mm full width at half maximum in the axial direction. Images with 50 slices were obtained with a 2×2×3.125-mm voxel size and a 128×128 matrix size. The transmission data were acquired by using a rotating 68Ga/68Ge rod as a source for attenuation correction. 11C-FLB 457 was prepared as described previously .
In the first PET experiment, the injected dose, specific activity, and mass of injected ligand were 283±24 MBq, 118±45 GBq/µmol, and 3.0±1.7 µg (mean ± SD), respectively. The respective values in the second PET experiment were 285±19 MBq, 110±38 GBq/µmol, and 3.2±2.0 µg. The time interval between the first and second injections of 11C-FLB 457 was 4–4.5 hours. The mass of injected ligand in each second scan was carefully adjusted to that in each first scan because of potential occupancy effects by unlabelled ligand itself , , and no significant difference was found in the mass of injected ligand as well as the injected dose and specific activity between the first and second scans in each group, using paired Student t test.
A dynamic series of decay-corrected PET data acquisition was performed in the 3D mode for 90 minutes starting at the time of the intravenous injection of 11C-FLB 457. The frame arrangement was 20 s ×6 frames, 60 s ×2 frames, 180 s ×2 frames, and 300 s ×16 frames.
For the 5 subjects in the high-dose group, arterial blood samples were also obtained. Immediately after the intravenous injection of 11C-FLB 457, 18 arterial blood samples were collected at 10-s intervals over 3 min; the next 2 samples were collected at 60-s intervals over 2 min, and the remaining 10 samples were collected at longer intervals, for a total of 30 samples. All samples were manually drawn. Plasma was separated, weighed, and measured for radioactivity with a sodium iodide (Tl) well scintillation counter. Six samples collected at 3, 10, 20, 30, 40, and 60 minutes were further processed by high-performance liquid chromatography to determine the fractions of plasma radioactivity corresponding to unchanged 11C-FLB 457 and labeled metabolites, as described previously .
Image manipulations were performed using Dr. View version R2.0 (AJS, Tokyo, Japan) and statistical parametric mapping 2 (SPM2; Functional Imaging Laboratory, London, UK) implemented in MATLAB version 7.0.1 (The MathWorks, Natick, MA). First, individual two dynamic 11C-FLB 457 images and MRI images were coregistered. Next, regions of interest (ROIs) were defined over the prefrontal, parietal, lateral temporal and anterior cingulate cortices, medial and lateral parts of the thalamus, amygdala, hippocampus, and cerebellum on the individual coregistered MRI. These ROIs were spatially moved on the corresponding coregistered dynamic 11C-FLB 457 images.
11C-FLB 457 binding to extrastriatal D2/D3 receptors was calculated as the binding potential (BP) by the simplified reference tissue model (SRTM) using cerebellum as a reference tissue . BP derived with this method is referred to as BPND_SRTM (ND: nondisplaceable). For the high-dose group with arterial blood samples, the binding was also analyzed by using the linear graphic analysis by Logan et al. . The slope of the linear phase of the obtained plot corresponds to the total distribution volume (VT) of the ligand plus the plasma volume. The regional VT was determined from the slope, and the BP with this method was calculated as follows using cerebellum as a reference region: BPND_Logan = (VT on ROI/VT on cerebellum) - 1.
D2/D3 occupancy rate by pramipexole was calculated for each ROI by using the following equation: occupancy rate (%) = 100× (BP at baseline – BP at pramipexole-loading)/BP at baseline. BP at baseline and BP at pramipexole-loading are obtained from first and second PET scans, respectively. Data were expressed as mean ± SD.
The differences between first and second PET scans were tested by paired Student's t-test. Correlations between BPND_SRTM and BPND_Logan in high-dose group were assessed by means of linear regression analysis with Pearson's correlation test. P values<0.05 were considered statistically significant.
For the high-dose group, BPND_SRTM was found to be significantly correlated with BPND_Logan (r = 0.97; P<0.01) using data of both the first and second experiments, as shown in Figure 1. Although the slope of the regression line was slightly less than one, the BPND_SRTM and BPND_Logan had almost a one-to-one relationship.
The binding potential estimated by Logan plot method and that estimated by the simplified reference tissue model method are represented as BPND_Logan and BPND_SRTM, respectively. The solid line represents the regression line. Linear correlation is significant (r = 0.97, P<0.01, y = 0.95x + 0.17). The dotted line represents the line of “y = x” for reference. ND: nondisplaceable.
Each regional BPND of first and second PET scans for each dose of pramipexole is shown in Figure 2. After administration of pramipexole 0.25 mg, BPND_Logan in the prefrontal cortex (P = 0.03, t = 3.15), medial (P = 0.01, t = 4.56) and lateral (P = 0.01, t = 3.78) thalamus, and amygdala (P = 0.02, t = 3.32) and BPND_SRTM in medial (P = 0.01, t = 4.51) and lateral (P = 0.02, t = 3.33) thalamus decreased significantly. D2/D3 occupancy rates estimated with BPND_Logan in the prefrontal cortex, medial and lateral thalamus, and amygdala were 10.3%±6.8%, 16.7%±6.9%, 14.9%±8.9%, and 20.4%±8.6%, respectively. Occupancy rates estimated with BPND_SRTM in the medial and lateral thalamus were 10.3%±5.0% and 10.8%±6.4%, respectively. No significant difference was found in occupancy rates estimated with either BPND_Logan or BPND_SRTM between the medial and lateral thalamus, using paired Student t test. In the low-dose group with 0.125 mg of pramipexole and in the control group, there was no significant correlation between BPND_SRTM of the two PET scans in all regions.
For 0.25 mg dose group, each BPND was estimated by the Logan plot method and simplified reference tissue model method. For 0.125 mg and 0 mg dose groups, each BPND was estimated only by the simplified reference tissue model method. Pramipexole was orally administered 1–1.5 h before second PET scanning at doses of 0.25 mg, 0.125 mg. Each P value was estimated by paired Student's t-test between first and second PET scans. Significant differences were found only in the high-dose group (* P<0.05). BP: binding potential, ND: nondisplaceable.
The time-activity curves of representative regions before and after administration of pramipexole 0.25 mg are displayed in Figure 3. Visually, the radioactivity levels of the putamen, entire thalamus and amygdala seemed to decrease after administration of pramipexole 0.25 mg. On the other hand, the radioactively level of the cerebellum seemed mostly unchanged between the first and second scans. Actually, VT on the cerebellum estimated by Logan plot method in the first and second PET scans was 4.55±0.68 and 4.67±0.97, respectively, and no significant difference was found between the two.
Pramipexole is a synthetic aminobenzothiazole derivative with selective actions mainly on D2 and D3 receptors, and it binds with the highest affinity to D3 receptors , , , . In the brain, the distribution of D3 receptors is known to be different from that of D2 receptors , , , , , , although there are some differences in the relative proportion of D2 and D3 receptors between the previous studies. The D2 binding sites are widely detected with the highest concentration found in the striatum, followed by the nucleus accumbens, external segment of the globus pallidus, substantia nigra and ventral tegmental area. The distribution of D3 receptors is relatively restricted and D3 binding sites are enriched in the amygdala, nucleus accumbens, ventral striatum, substantia nigra, anteroventral nucleus of the thalamus and internal segment of the globus pallidus. Thus, D2 or D3 binding sites are located in the synapse of the afferent structures as well as the neurons of the efferent structures such as substantia nigra and ventral tegmental area. D2 or D3 receptors in the efferent structures are thought to act as autoreceptors, which could play an important role in regulating the activity of dopaminergic neurons , .
On the other hand, in this study, the BPND in the substantia nigra or ventral tegmental area could not be quantified with reliability, because the structures were too small for usual ROI analysis of the dynamic data on the basis of the resolution of the PET scanner and the number of subjects was relatively small. For the same reasons, the ROIs were drawn over not each small nucleus but medial and lateral parts of the thalamus although the thalamus is known to have a great deal of regional heterogeneity in D2 and D3 expression. Also, the BPND in the striatal and its closely neighbor regions such as the ventral striatum and globus pallidus could not be quantified using 11C-FLB 457 because a long time more than a few hours is needed for reaching equilibration in the striatum . Based on the distribution of D2 and D3 receptors and the technical matters as described above, we investigated the binding sites of pramipexole especially in the limbic system, thalamus and cortical regions. To our knowledge, this is the first in vivo study that has investigated the relationship between a dopamine agonist and its binding sites in extrastriatal regions.
This study showed that a single dose of pramipexole 0.25 mg decreased BPND_Logan significantly in the prefrontal cortex, amygdala, and thalamus. The mesolimbic pathway begins in the ventral tegmental area of the midbrain and projects to the limbic areas, including the nucleus accumbens in the ventral striatum, amygdala, and hippocampus; it also projects to the cortical areas, including the prefrontal and cingulate cortices. The latter cortical pathway is called as the mesocortical pathway. Both pathways are known to be involved in the depressive state , , , . Indeed, the amygdala is important for emotional processing and its functional abnormalities are associated with depression , , , and frontal cortical dopamine function has been reported to be involved in depression , , . In the mesolimbic pathway, D2 and D3 binding sites are predominant in the hippocampus and amygdala, respectively , , , and this difference may be one of the reasons that significant decrease of BPND_Logan was not found in the hippocampus. The mesocortical pathway also has D3 receptors as well as D2 receptors , , although there is no detail report on the relative proportion of D2 and D3 receptors in that area. The thalamic dopaminergic system has been recently identified; this system is speculated to have a prominent role in depression, especially in regard to emotion, attention, cognition, and complex somatosensory and visual processing , , , . Although this study could not find the significant difference between medial and lateral parts of the thalamus, D3 binding sites are relatively abundant and especially tend to be concentrated along the midline in the thalamus, while D2 binding sites are more homogeneously distributed , . On the basis of the relationship between the occupied sites by pramipexole, the distribution of D2 and D3 receptors and previous anatomical and functional reports on depression, it is reasonable to suggest that pramipexole may exert its antidepressive effects by activating D2R subfamily, especially the D3 receptor subtype, in these regions (prefrontal cortex, amygdala, and thalamus).
With regard to the BPND_SRTM method, after administration of a single dose of pramipexole 0.25 mg, binding in the medial and lateral thalamus decreased significantly as shown in the BPND_Logan method, and bindings in both the prefrontal cortex and amygdala showed the tendency to decrease without significant difference. On the other hand, there was no significant difference between first and second PET scans in both the low-dose group and the control group. On the basis of the difference between the high-dose group and the other two groups, we speculate that the effects of pramipexole may be dose dependent, although it is impossible to confirm this finding only with our data. Despite the high correlation between BPND_Logan and BPND_SRTM methods as shown in Figure 1, the discrepancies between the both methods found in the high-dose group could be explained by the interindividual and intraindividual variability of each analytical method , , . However, BPND_Logan estimated with artery blood samples should be regarded as more reliable and accurate than BPND_SRTM estimated without artery blood samples, and the findings for the prefrontal cortex and amygdala, where only the BPND_Logan method showed significance, were considered to be meaningful.
Vilkman et al. conducted a test-retest analysis of 11C-FLB 457 PET scanning with 7 healthy volunteers (mean age ± SD = 29.0±6.9) and suggested that coefficient of variation (COV) of each extrastriatal region in BPND_Logan and BPND_SRTM methods was about 20% and the reproducibility of both methods was good . Consistent with Vilkman et al., our results of the control group corresponding to a test-retest analysis showed no significant difference in BPND_SRTM of each region between first and second PET scans. In the control group, the COV of each region between the first and second experiments was similar, and the ranges of COV in the first and second experiments were 19.3%–33.9% and 16.3%–38.5%, respectively. Thus, the reproducibility of the BPND_SRTM method in this study was good. Compared with previous studies , , , the COV in our control group was somewhat larger. A possible explanation for this difference could be given by following two reasons. One is the relatively smaller number of subjects, and the other is the relatively larger variability in age because D2R subfamily in each extrastriatal region is known to show age-related decline , .
In vitro brain homogenate binding studies have demonstrated that D2R subfamily exists in two affinity states, i.e., high and low affinity states , , . The high affinity state is thought to represent the functional state, and agonists bind preferentially to D2R subfamily in the high affinity state, while antagonists have equal affinity for D2R subfamily in the high and low affinity states. In vivo competition studies between endogenous dopamine and a labeled agonist or antagonist ligand estimated the percentage of high affinity state to be about 60–70% , . On the other hand, some recent in vivo studies indicated that most D2R subfamily is in the high affinity state at living conditions because the binding of exogenous unlabeled agonist to D2R subfamily in high or low affinity states could not be differentiated with either a labeled agonist or antagonist ligand , . Thus, the accurate proportion of the two states remains controversial. In this study, relatively low D2/D3 occupancy rates by pramipexole were mainly due to low dose of pramipexole. However, based on the two states theory, another reason may be because D2/D3 occupancy rates by agonist pramipexole were estimated by antagonist ligand 11C-FLB 457.
One of the drawbacks of this study may be that we used the cerebellum as a reference region, in order to gain smaller variability and better reproducibility for the analysis of the PET data, compared with the two-tissue compartment four-rate constant model . Asselin et al. reported that using the cerebellum as a reference region could lead to underestimation of BPND and occupancy rate . However, we showed no statistical difference in VT on the cerebellum estimated by Logan plot method before and after administration of pramipexole 0.25 mg, and at least our data, especially in the high-dose group, would be appropriate for the purpose of confirming the extrastriatal effects of a dopamine agonist. Other drawbacks of this study may be that we collected arterial blood samples only from the high-dose group, the number of subjects was relatively small and a dose of pramipexole was relatively low for safety, as described previously.
In conclusion, we demonstrated that pramipexole binds to D2/D3 receptors in the prefrontal cortex, amygdala, and medial and lateral thalamus. These regions have been indicated to have some relation to depression and may be part of the target sites where pramipexole exerts its antidepressive effects.
The authors are thankful to Ms. Hiroko Tsukinari and Mr. Kunpei Hayashi for their technical assistance.
Conceived and designed the experiments: K. Ishibashi K. Ishii K. Ishiwata. Performed the experiments: K. Ishibashi K. Ishii KO K. Ishiwata. Analyzed the data: K. Ishibashi KO K. Ishiwat. Contributed reagents/materials/analysis tools: K. Ishibashi K. Ishii KO HM K. Ishiwata. Wrote the paper: K. Ishibashi K. Ishiwata. Discussed the results: K. Ishibashi K. Ishii KO HM K. Ishiwata.
- 1. Bennett JP Jr, Piercey MF (1999) Pramipexole–a new dopamine agonist for the treatment of Parkinson's disease. J Neurol Sci 163: 25–31.JP Bennett JrMF Piercey1999Pramipexole–a new dopamine agonist for the treatment of Parkinson's disease.J Neurol Sci1632531
- 2. Lieberman A, Ranhosky A, Korts D (1997) Clinical evaluation of pramipexole in advanced Parkinson's disease: results of a double-blind, placebo-controlled, parallel-group study. Neurology 49: 162–168.A. LiebermanA. RanhoskyD. Korts1997Clinical evaluation of pramipexole in advanced Parkinson's disease: results of a double-blind, placebo-controlled, parallel-group study.Neurology49162168
- 3. Shannon KM, Bennett JP Jr, Friedman JH (1997) Efficacy of pramipexole, a novel dopamine agonist, as monotherapy in mild to moderate Parkinson's disease. The Pramipexole Study Group. Neurology 49: 724–728.KM ShannonJP Bennett JrJH Friedman1997Efficacy of pramipexole, a novel dopamine agonist, as monotherapy in mild to moderate Parkinson's disease. The Pramipexole Study Group.Neurology49724728
- 4. Barone P, Scarzella L, Marconi R, Antonini A, Morgante L, et al. (2006) Pramipexole versus sertraline in the treatment of depression in Parkinson's disease: a national multicenter parallel-group randomized study. J Neurol 253: 601–607.P. BaroneL. ScarzellaR. MarconiA. AntoniniL. Morgante2006Pramipexole versus sertraline in the treatment of depression in Parkinson's disease: a national multicenter parallel-group randomized study.J Neurol253601607
- 5. Lemke MR, Brecht HM, Koester J, Kraus PH, Reichmann H (2005) Anhedonia, depression, and motor functioning in Parkinson's disease during treatment with pramipexole. J Neuropsychiatry Clin Neurosci 17: 214–220.MR LemkeHM BrechtJ. KoesterPH KrausH. Reichmann2005Anhedonia, depression, and motor functioning in Parkinson's disease during treatment with pramipexole.J Neuropsychiatry Clin Neurosci17214220
- 6. Reichmann H, Brecht MH, Koster J, Kraus PH, Lemke MR (2003) Pramipexole in routine clinical practice: a prospective observational trial in Parkinson's disease. CNS Drugs 17: 965–973.H. ReichmannMH BrechtJ. KosterPH KrausMR Lemke2003Pramipexole in routine clinical practice: a prospective observational trial in Parkinson's disease.CNS Drugs17965973
- 7. Rektorova I, Rektor I, Bares M, Dostal V, Ehler E, et al. (2003) Pramipexole and pergolide in the treatment of depression in Parkinson's disease: a national multicentre prospective randomized study. Eur J Neurol 10: 399–406.I. RektorovaI. RektorM. BaresV. DostalE. Ehler2003Pramipexole and pergolide in the treatment of depression in Parkinson's disease: a national multicentre prospective randomized study.Eur J Neurol10399406
- 8. Lattanzi L, Dell'Osso L, Cassano P, Pini S, Rucci P, et al. (2002) Pramipexole in treatment-resistant depression: a 16-week naturalistic study. Bipolar Disord 4: 307–314.L. LattanziL. Dell'OssoP. CassanoS. PiniP. Rucci2002Pramipexole in treatment-resistant depression: a 16-week naturalistic study.Bipolar Disord4307314
- 9. Corrigan MH, Denahan AQ, Wright CE, Ragual RJ, Evans DL (2000) Comparison of pramipexole, fluoxetine, and placebo in patients with major depression. Depress Anxiety 11: 58–65.MH CorriganAQ DenahanCE WrightRJ RagualDL Evans2000Comparison of pramipexole, fluoxetine, and placebo in patients with major depression.Depress Anxiety115865
- 10. Goldberg JF, Burdick KE, Endick CJ (2004) Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression. Am J Psychiatry 161: 564–566.JF GoldbergKE BurdickCJ Endick2004Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression.Am J Psychiatry161564566
- 11. Zarate CA Jr, Payne JL, Singh J, Quiroz JA, Luckenbaugh DA, et al. (2004) Pramipexole for bipolar II depression: a placebo-controlled proof of concept study. Biol Psychiatry 56: 54–60.CA Zarate JrJL PayneJ. SinghJA QuirozDA Luckenbaugh2004Pramipexole for bipolar II depression: a placebo-controlled proof of concept study.Biol Psychiatry565460
- 12. DeBattista C, Solvason HB, Breen JA, Schatzberg AF (2000) Pramipexole augmentation of a selective serotonin reuptake inhibitor in the treatment of depression. J Clin Psychopharmacol 20: 274–275.C. DeBattistaHB SolvasonJA BreenAF Schatzberg2000Pramipexole augmentation of a selective serotonin reuptake inhibitor in the treatment of depression.J Clin Psychopharmacol20274275
- 13. Ostow M (2002) Pramipexole for depression. Am J Psychiatry 159: 320–321.M. Ostow2002Pramipexole for depression.Am J Psychiatry159320321
- 14. Sporn J, Ghaemi SN, Sambur MR, Rankin MA, Recht J, et al. (2000) Pramipexole augmentation in the treatment of unipolar and bipolar depression: a retrospective chart review. Ann Clin Psychiatry 12: 137–140.J. SpornSN GhaemiMR SamburMA RankinJ. Recht2000Pramipexole augmentation in the treatment of unipolar and bipolar depression: a retrospective chart review.Ann Clin Psychiatry12137140
- 15. Perugi G, Toni C, Ruffolo G, Frare F, Akiskal H (2001) Adjunctive dopamine agonists in treatment-resistant bipolar II depression: an open case series. Pharmacopsychiatry 34: 137–141.G. PerugiC. ToniG. RuffoloF. FrareH. Akiskal2001Adjunctive dopamine agonists in treatment-resistant bipolar II depression: an open case series.Pharmacopsychiatry34137141
- 16. Cassano P, Lattanzi L, Soldani F, Navari S, Battistini G, et al. (2004) Pramipexole in treatment-resistant depression: an extended follow-up. Depress Anxiety 20: 131–138.P. CassanoL. LattanziF. SoldaniS. NavariG. Battistini2004Pramipexole in treatment-resistant depression: an extended follow-up.Depress Anxiety20131138
- 17. Maj J, Rogoz Z, Skuza G, Kolodziejczyk K (1997) The behavioural effects of pramipexole, a novel dopamine receptor agonist. Eur J Pharmacol 324: 31–37.J. MajZ. RogozG. SkuzaK. Kolodziejczyk1997The behavioural effects of pramipexole, a novel dopamine receptor agonist.Eur J Pharmacol3243137
- 18. Willner P, Lappas S, Cheeta S, Muscat R (1994) Reversal of stress-induced anhedonia by the dopamine receptor agonist, pramipexole. Psychopharmacology (Berl) 115: 454–462.P. WillnerS. LappasS. CheetaR. Muscat1994Reversal of stress-induced anhedonia by the dopamine receptor agonist, pramipexole.Psychopharmacology (Berl)115454462
- 19. Missale C, Nash SR, Robinson SW, Jaber M, Caron MG (1998) Dopamine receptors: from structure to function. Physiol Rev 78: 189–225.C. MissaleSR NashSW RobinsonM. JaberMG Caron1998Dopamine receptors: from structure to function.Physiol Rev78189225
- 20. Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, et al. (2002) Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes. J Pharmacol Exp Ther 303: 791–804.MJ MillanL. MaiofissD. CussacV. AudinotJA Boutin2002Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes.J Pharmacol Exp Ther303791804
- 21. Mierau J, Schneider FJ, Ensinger HA, Chio CL, Lajiness ME, et al. (1995) Pramipexole binding and activation of cloned and expressed dopamine D2, D3 and D4 receptors. Eur J Pharmacol 290: 29–36.J. MierauFJ SchneiderHA EnsingerCL ChioME Lajiness1995Pramipexole binding and activation of cloned and expressed dopamine D2, D3 and D4 receptors.Eur J Pharmacol2902936
- 22. Piercey MF (1998) Pharmacology of pramipexole, a dopamine D3-preferring agonist useful in treating Parkinson's disease. Clin Neuropharmacol 21: 141–151.MF Piercey1998Pharmacology of pramipexole, a dopamine D3-preferring agonist useful in treating Parkinson's disease.Clin Neuropharmacol21141151
- 23. Kvernmo T, Hartter S, Burger E (2006) A review of the receptor-binding and pharmacokinetic properties of dopamine agonists. Clin Ther 28: 1065–1078.T. KvernmoS. HartterE. Burger2006A review of the receptor-binding and pharmacokinetic properties of dopamine agonists.Clin Ther2810651078
- 24. Gurevich EV, Joyce JN (1999) Distribution of dopamine D3 receptor expressing neurons in the human forebrain: comparison with D2 receptor expressing neurons. Neuropsychopharmacology 20: 60–80.EV GurevichJN Joyce1999Distribution of dopamine D3 receptor expressing neurons in the human forebrain: comparison with D2 receptor expressing neurons.Neuropsychopharmacology206080
- 25. Murray AM, Ryoo HL, Gurevich E, Joyce JN (1994) Localization of dopamine D3 receptors to mesolimbic and D2 receptors to mesostriatal regions of human forebrain. Proc Natl Acad Sci U S A 91: 11271–11275.AM MurrayHL RyooE. GurevichJN Joyce1994Localization of dopamine D3 receptors to mesolimbic and D2 receptors to mesostriatal regions of human forebrain.Proc Natl Acad Sci U S A911127111275
- 26. Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC (1990) Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347: 146–151.P. SokoloffB. GirosMP MartresML BouthenetJC Schwartz1990Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics.Nature347146151
- 27. Bouthenet ML, Souil E, Martres MP, Sokoloff P, Giros B, et al. (1991) Localization of dopamine D3 receptor mRNA in the rat brain using in situ hybridization histochemistry: comparison with dopamine D2 receptor mRNA. Brain Res 564: 203–219.ML BouthenetE. SouilMP MartresP. SokoloffB. Giros1991Localization of dopamine D3 receptor mRNA in the rat brain using in situ hybridization histochemistry: comparison with dopamine D2 receptor mRNA.Brain Res564203219
- 28. Landwehrmeyer B, Mengod G, Palacios JM (1993) Dopamine D3 receptor mRNA and binding sites in human brain. Brain Res Mol Brain Res 18: 187–192.B. LandwehrmeyerG. MengodJM Palacios1993Dopamine D3 receptor mRNA and binding sites in human brain.Brain Res Mol Brain Res18187192
- 29. Diaz J, Pilon C, Le Foll B, Gros C, Triller A, et al. (2000) Dopamine D3 receptors expressed by all mesencephalic dopamine neurons. J Neurosci 20: 8677–8684.J. DiazC. PilonB. Le FollC. GrosA. Triller2000Dopamine D3 receptors expressed by all mesencephalic dopamine neurons.J Neurosci2086778684
- 30. Joyce JN (2001) Dopamine D3 receptor as a therapeutic target for antipsychotic and antiparkinsonian drugs. Pharmacol Ther 90: 231–259.JN Joyce2001Dopamine D3 receptor as a therapeutic target for antipsychotic and antiparkinsonian drugs.Pharmacol Ther90231259
- 31. Levant B (1997) The D3 dopamine receptor: neurobiology and potential clinical relevance. Pharmacol Rev 49: 231–252.B. Levant1997The D3 dopamine receptor: neurobiology and potential clinical relevance.Pharmacol Rev49231252
- 32. Halldin C, Farde L, Hogberg T, Mohell N, Hall H, et al. (1995) Carbon-11-FLB 457: a radioligand for extrastriatal D2 dopamine receptors. J Nucl Med 36: 1275–1281.C. HalldinL. FardeT. HogbergN. MohellH. Hall1995Carbon-11-FLB 457: a radioligand for extrastriatal D2 dopamine receptors.J Nucl Med3612751281
- 33. Olsson H, Halldin C, Farde L (2004) Differentiation of extrastriatal dopamine D2 receptor density and affinity in the human brain using PET. Neuroimage 22: 794–803.H. OlssonC. HalldinL. Farde2004Differentiation of extrastriatal dopamine D2 receptor density and affinity in the human brain using PET.Neuroimage22794803
- 34. Suhara T, Sudo Y, Okauchi T, Maeda J, Kawabe K, et al. (1999) Extrastriatal dopamine D2 receptor density and affinity in the human brain measured by 3D PET. Int J Neuropsychopharmacol 2: 73–82.T. SuharaY. SudoT. OkauchiJ. MaedaK. Kawabe1999Extrastriatal dopamine D2 receptor density and affinity in the human brain measured by 3D PET.Int J Neuropsychopharmacol27382
- 35. Lammertsma AA, Hume SP (1996) Simplified reference tissue model for PET receptor studies. Neuroimage 4: 153–158.AA LammertsmaSP Hume1996Simplified reference tissue model for PET receptor studies.Neuroimage4153158
- 36. Logan J, Fowler JS, Volkow ND, Wolf AP, Dewey SL, et al. (1990) Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(-)-cocaine PET studies in human subjects. J Cereb Blood Flow Metab 10: 740–747.J. LoganJS FowlerND VolkowAP WolfSL Dewey1990Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(-)-cocaine PET studies in human subjects.J Cereb Blood Flow Metab10740747
- 37. Loc'h C, Halldin C, Bottlaender M, Swahn CG, Moresco RM, et al. (1996) Preparation of [76Br]FLB 457 and [76Br]FLB 463 for examination of striatal and extrastriatal dopamine D-2 receptors with PET. Nucl Med Biol 23: 813–819.C. Loc'hC. HalldinM. BottlaenderCG SwahnRM Moresco1996Preparation of [76Br]FLB 457 and [76Br]FLB 463 for examination of striatal and extrastriatal dopamine D-2 receptors with PET.Nucl Med Biol23813819
- 38. Nestler EJ, Carlezon WA Jr (2006) The mesolimbic dopamine reward circuit in depression. Biol Psychiatry 59: 1151–1159.EJ NestlerWA Carlezon Jr2006The mesolimbic dopamine reward circuit in depression.Biol Psychiatry5911511159
- 39. Di Chiara G, Loddo P, Tanda G (1999) Reciprocal changes in prefrontal and limbic dopamine responsiveness to aversive and rewarding stimuli after chronic mild stress: implications for the psychobiology of depression. Biol Psychiatry 46: 1624–1633.G. Di ChiaraP. LoddoG. Tanda1999Reciprocal changes in prefrontal and limbic dopamine responsiveness to aversive and rewarding stimuli after chronic mild stress: implications for the psychobiology of depression.Biol Psychiatry4616241633
- 40. Nikolaus S, Antke C, Muller HW (2009) In vivo imaging of synaptic function in the central nervous system: II. Mental and affective disorders. Behav Brain Res 204: 32–66.S. NikolausC. AntkeHW Muller2009In vivo imaging of synaptic function in the central nervous system: II. Mental and affective disorders.Behav Brain Res2043266
- 41. Cabib S, Puglisi-Allegra S (1996) Stress, depression and the mesolimbic dopamine system. Psychopharmacology (Berl) 128: 331–342.S. CabibS. Puglisi-Allegra1996Stress, depression and the mesolimbic dopamine system.Psychopharmacology (Berl)128331342
- 42. LeDoux JE (2000) Emotion circuits in the brain. Annu Rev Neurosci 23: 155–184.JE LeDoux2000Emotion circuits in the brain.Annu Rev Neurosci23155184
- 43. Drevets WC (1998) Functional neuroimaging studies of depression: the anatomy of melancholia. Annu Rev Med 49: 341–361.WC Drevets1998Functional neuroimaging studies of depression: the anatomy of melancholia.Annu Rev Med49341361
- 44. Remy P, Doder M, Lees A, Turjanski N, Brooks D (2005) Depression in Parkinson's disease: loss of dopamine and noradrenaline innervation in the limbic system. Brain 128: 1314–1322.P. RemyM. DoderA. LeesN. TurjanskiD. Brooks2005Depression in Parkinson's disease: loss of dopamine and noradrenaline innervation in the limbic system.Brain12813141322
- 45. Espejo EF, Minano FJ (1999) Prefrontocortical dopamine depletion induces antidepressant-like effects in rats and alters the profile of desipramine during Porsolt's test. Neuroscience 88: 609–615.EF EspejoFJ Minano1999Prefrontocortical dopamine depletion induces antidepressant-like effects in rats and alters the profile of desipramine during Porsolt's test.Neuroscience88609615
- 46. Ohmori T, Arora RC, Meltzer HY (1992) Serotonergic measures in suicide brain: the concentration of 5-HIAA, HVA, and tryptophan in frontal cortex of suicide victims. Biol Psychiatry 32: 57–71.T. OhmoriRC AroraHY Meltzer1992Serotonergic measures in suicide brain: the concentration of 5-HIAA, HVA, and tryptophan in frontal cortex of suicide victims.Biol Psychiatry325771
- 47. Agren H, Reibring L, Hartvig P, Tedroff J, Bjurling P, et al. (1992) PET studies with L-[11C]5-HTP and L-[11C]dopa in brains of healthy volunteers and patients with major depression. Clin Neuropharmacol 15: Suppl 1 Pt A235A–236A.H. AgrenL. ReibringP. HartvigJ. TedroffP. Bjurling1992PET studies with L-[11C]5-HTP and L-[11C]dopa in brains of healthy volunteers and patients with major depression.Clin Neuropharmacol15Suppl 1 Pt A235A236A
- 48. Garcia-Cabezas MA, Rico B, Sanchez-Gonzalez MA, Cavada C (2007) Distribution of the dopamine innervation in the macaque and human thalamus. Neuroimage 34: 965–984.MA Garcia-CabezasB. RicoMA Sanchez-GonzalezC. Cavada2007Distribution of the dopamine innervation in the macaque and human thalamus.Neuroimage34965984
- 49. Sanchez-Gonzalez MA, Garcia-Cabezas MA, Rico B, Cavada C (2005) The primate thalamus is a key target for brain dopamine. J Neurosci 25: 6076–6083.MA Sanchez-GonzalezMA Garcia-CabezasB. RicoC. Cavada2005The primate thalamus is a key target for brain dopamine.J Neurosci2560766083
- 50. Garcia-Cabezas MA, Martinez-Sanchez P, Sanchez-Gonzalez MA, Garzon M, Cavada C (2009) Dopamine innervation in the thalamus: monkey versus rat. Cereb Cortex 19: 424–434.MA Garcia-CabezasP. Martinez-SanchezMA Sanchez-GonzalezM. GarzonC. Cavada2009Dopamine innervation in the thalamus: monkey versus rat.Cereb Cortex19424434
- 51. Vilkman H, Kajander J, Nagren K, Oikonen V, Syvalahti E, et al. (2000) Measurement of extrastriatal D2-like receptor binding with [11C]FLB 457–a test-retest analysis. Eur J Nucl Med 27: 1666–1673.H. VilkmanJ. KajanderK. NagrenV. OikonenE. Syvalahti2000Measurement of extrastriatal D2-like receptor binding with [11C]FLB 457–a test-retest analysis.Eur J Nucl Med2716661673
- 52. Olsson H, Halldin C, Swahn CG, Farde L (1999) Quantification of [11C]FLB 457 binding to extrastriatal dopamine receptors in the human brain. J Cereb Blood Flow Metab 19: 1164–1173.H. OlssonC. HalldinCG SwahnL. Farde1999Quantification of [11C]FLB 457 binding to extrastriatal dopamine receptors in the human brain.J Cereb Blood Flow Metab1911641173
- 53. Sudo Y, Suhara T, Inoue M, Ito H, Suzuki K, et al. (2001) Reproducibility of [11 C]FLB 457 binding in extrastriatal regions. Nucl Med Commun 22: 1215–1221.Y. SudoT. SuharaM. InoueH. ItoK. Suzuki2001Reproducibility of [11 C]FLB 457 binding in extrastriatal regions.Nucl Med Commun2212151221
- 54. Kaasinen V, Vilkman H, Hietala J, Nagren K, Helenius H, et al. (2000) Age-related dopamine D2/D3 receptor loss in extrastriatal regions of the human brain. Neurobiol Aging 21: 683–688.V. KaasinenH. VilkmanJ. HietalaK. NagrenH. Helenius2000Age-related dopamine D2/D3 receptor loss in extrastriatal regions of the human brain.Neurobiol Aging21683688
- 55. Inoue M, Suhara T, Sudo Y, Okubo Y, Yasuno F, et al. (2001) Age-related reduction of extrastriatal dopamine D2 receptor measured by PET. Life Sci 69: 1079–1084.M. InoueT. SuharaY. SudoY. OkuboF. Yasuno2001Age-related reduction of extrastriatal dopamine D2 receptor measured by PET.Life Sci6910791084
- 56. De Lean A, Kilpatrick BF, Caron MG (1982) Dopamine receptor of the porcine anterior pituitary gland. Evidence for two affinity states discriminated by both agonists and antagonists. Mol Pharmacol 22: 290–297.A. De LeanBF KilpatrickMG Caron1982Dopamine receptor of the porcine anterior pituitary gland. Evidence for two affinity states discriminated by both agonists and antagonists.Mol Pharmacol22290297
- 57. Sibley DR, De Lean A, Creese I (1982) Anterior pituitary dopamine receptors. Demonstration of interconvertible high and low affinity states of the D-2 dopamine receptor. J Biol Chem 257: 6351–6361.DR SibleyA. De LeanI. Creese1982Anterior pituitary dopamine receptors. Demonstration of interconvertible high and low affinity states of the D-2 dopamine receptor.J Biol Chem25763516361
- 58. George SR, Watanabe M, Di Paolo T, Falardeau P, Labrie F, et al. (1985) The functional state of the dopamine receptor in the anterior pituitary is in the high affinity form. Endocrinology 117: 690–697.SR GeorgeM. WatanabeT. Di PaoloP. FalardeauF. Labrie1985The functional state of the dopamine receptor in the anterior pituitary is in the high affinity form.Endocrinology117690697
- 59. Seneca N, Finnema SJ, Farde L, Gulyas B, Wikstrom HV, et al. (2006) Effect of amphetamine on dopamine D2 receptor binding in nonhuman primate brain: a comparison of the agonist radioligand [11C]MNPA and antagonist [11C]raclopride. Synapse 59: 260–269.N. SenecaSJ FinnemaL. FardeB. GulyasHV Wikstrom2006Effect of amphetamine on dopamine D2 receptor binding in nonhuman primate brain: a comparison of the agonist radioligand [11C]MNPA and antagonist [11C]raclopride.Synapse59260269
- 60. Narendran R, Hwang DR, Slifstein M, Talbot PS, Erritzoe D, et al. (2004) 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. Synapse 52: 188–208.R. NarendranDR HwangM. SlifsteinPS TalbotD. Erritzoe2004In 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.Synapse52188208
- 61. Finnema SJ, Halldin C, Bang-Andersen B, Gulyas B, Bundgaard C, et al. (2009) Dopamine D(2/3) receptor occupancy of apomorphine in the nonhuman primate brain–a comparative PET study with [11C]raclopride and [11C]MNPA. Synapse 63: 378–389.SJ FinnemaC. HalldinB. Bang-AndersenB. GulyasC. Bundgaard2009Dopamine D(2/3) receptor occupancy of apomorphine in the nonhuman primate brain–a comparative PET study with [11C]raclopride and [11C]MNPA.Synapse63378389
- 62. Peng T, Zysk J, Dorff P, Elmore CS, Strom P, et al. (2010) D2 receptor occupancy in conscious rat brain is not significantly distinguished with [(3)H]-MNPA, [(3)H]-(+)-PHNO, and [(3)H]-raclopride. Synapse 64: 624–633.T. PengJ. ZyskP. DorffCS ElmoreP. Strom2010D2 receptor occupancy in conscious rat brain is not significantly distinguished with [(3)H]-MNPA, [(3)H]-(+)-PHNO, and [(3)H]-raclopride.Synapse64624633
- 63. Asselin MC, Montgomery AJ, Grasby PM, Hume SP (2007) Quantification of PET studies with the very high-affinity dopamine D2/D3 receptor ligand [11C]FLB 457: re-evaluation of the validity of using a cerebellar reference region. J Cereb Blood Flow Metab 27: 378–392.MC AsselinAJ MontgomeryPM GrasbySP Hume2007Quantification of PET studies with the very high-affinity dopamine D2/D3 receptor ligand [11C]FLB 457: re-evaluation of the validity of using a cerebellar reference region.J Cereb Blood Flow Metab27378392