Extrastriatal Dopamine D2 Receptors Research Articles

Dopamine Dynamics and Neurobiology of Non-Response to Antipsychotics, Relevance for Treatment Resistant Schizophrenia: A Systematic Review and Critical Appraisal

Treatment resistant schizophrenia (TRS) is characterized by a lack of, or suboptimal response to, antipsychotic agents. The biological underpinnings of this clinical condition are still scarcely understood. Since all antipsychotics block dopamine D2 receptors (D2R), dopamine-related mechanisms should be considered the main candidates in the neurobiology of antipsychotic non-response, although other neurotransmitter systems play a role. The aims of this review are: (i) to recapitulate and critically appraise the relevant literature on dopamine-related mechanisms of TRS; (ii) to discuss the methodological limitations of the studies so far conducted and delineate a theoretical framework on dopamine mechanisms of TRS; and (iii) to highlight future perspectives of research and unmet needs. Dopamine-related neurobiological mechanisms of TRS may be multiple and putatively subdivided into three biological points: (1) D2R-related, including increased D2R levels; increased density of D2Rs in the high-affinity state; aberrant D2R dimer or heteromer formation; imbalance between D2R short and long variants; extrastriatal D2Rs; (2) presynaptic dopamine, including low or normal dopamine synthesis and/or release compared to responder patients; and (3) exaggerated postsynaptic D2R-mediated neurotransmission. Future points to be addressed are: (i) a more neurobiologically-oriented phenotypic categorization of TRS; (ii) implementation of neurobiological studies by directly comparing treatment resistant vs. treatment responder patients; (iii) development of a reliable animal model of non-response to antipsychotics.

Imaging extra-striatal dopamine D2 receptors in a maternal immune activation rat model

Maternal immune activation (MIA) is a risk factor for schizophrenia in the offspring. MIA in pregnant rodents can be induced by injection of synthetic polyriboinosinic-polyribocytidilic acid (Poly I:C), which causes decreased striatal dopamine D2 receptor (D2R) expression and behavioral dysfunction mediated by the dopaminergic system in the offspring. However, previous studies did not determine whether Poly I:C induced cortical dopamine D2R abnormality in an MIA rat model. In this study, we performed micro-positron emission tomography (micro-PET) in vivo imaging and ex vivo neurochemical analyses of cortical D2Rs in MIA. In the micro-PET analyses, the anterior cingulate cortex (ACC) region in the offspring showed significantly reduced binding potential for [11C]FLB457, a high affinity radio-ligand toward D2Rs. Neurochemical analysis showed reduction of D2Rs and augmentation of dopamine turnover in the ACC of the rat offspring. Thus, MIA induces dopaminergic dysfunction in the ACC of offspring, similar to the neuronal pathology reported in patients with schizophrenia.

Graph theory analysis of the dopamine D2 receptor network in Parkinson's disease patients with cognitive decline.

Cognitive decline in Parkinson's disease (PD) is a common sequela of the disorder that has a large impact on patient well-being. Its physiological etiology, however, remains elusive. Our study used graph theory analysis to investigate the large-scale topological patterns of the extrastriatal dopamine D2 receptor network. We used positron emission tomography with [11 C]FLB-457 to measure the binding potential of cortical dopamine D2 receptors in two networks: the meso-cortical dopamine network and the meso-limbic dopamine network. We also investigated the application of partial volume effect correction (PVEC) in conjunction with graph theory analysis. Three groups were investigated in this study divided according to their cognitive status as measured by the Montreal Cognitive Assessment score, with a score ≤25 considered cognitively impaired: (a) healthy controls (n=13, 11 female), (b) cognitively unimpaired PD patients (PD-CU, n=13, 5 female), and (c) PD patients with mild cognitive impairment (PD-MCI, n=17, 4 female). In the meso-cortical network, we observed increased small-worldness, normalized clustering, and local efficiency in the PD-CU group compared to the PD-MCI group, as well as a hub shift in the PD-MCI group. Compensatory reorganization of the meso-cortical dopamine D2 receptor network may be responsible for some of the cognitive preservation observed in PD-CU. These results were found without PVEC applied and PVEC proved detrimental to the graph theory analysis. Overall, our findings demonstrate how graph theory analysis can be used to detect subtle changes in the brain that would otherwise be missed by regional comparisons of receptor density.

Low convergent validity of [11C]raclopride binding in extrastriatal brain regions: A PET study of within-subject correlations with [11C]FLB 457

Dopamine D2 receptors (D2-R) in extrastriatal brain regions are of high interest for research in a wide range of psychiatric and neurologic disorders. Pharmacological competition studies and test–retest experiments have shown high validity and reliability of the positron emission tomography (PET) radioligand [11C]FLB 457 for D2-R quantification in extrastriatal brain regions. However, this radioligand is not available at most research centers. Instead, the medium affinity radioligand [11C]raclopride, which has been extensively validated for quantification of D2-R in the high-density region striatum, has been applied also in studies on extrastriatal D2-R. Recently, the validity of this approach has been questioned by observations of low occupancy of [11C]raclopride in extrastriatal regions in a pharmacological competition study with quetiapine. Here, we utilise a data set of 16 healthy control subjects examined with both [11C]raclopride and [11C]FLB 457 to assess the correlation in binding potential (BPND) in extrastriatal brain regions. BPND was quantified using the simplified reference tissue model with cerebellum as reference region. The rank order of mean regional BPND values were similar for both radioligands, and corresponded to previously reported data, both post-mortem and using PET. Nevertheless, weak to moderate within-subject correlations were observed between [11C]raclopride and [11C]FLB 457 BPND extrastriatally (Pearson's R: 0.30–0.56), in contrast to very strong correlations between repeated [11C]FLB 457 measurements (Pearson's R: 0.82–0.98). In comparison, correlations between repeated [11C]raclopride measurements were low to moderate (Pearson's R: 0.28–0.75). These results are likely related to low signal to noise ratio of [11C]raclopride in extrastriatal brain regions, and further strengthen the recommendation that extrastriatal D2-R measures obtained with [11C]raclopride should be interpreted with caution.

Extrastriatal dopamine D2-receptor availability in social anxiety disorder

Alterations in the dopamine system are hypothesized to influence the expression of social anxiety disorder (SAD) symptoms. However, molecular imaging studies comparing dopamine function between patients and control subjects have yielded conflicting results. Importantly, while all previous investigations focused on the striatum, findings from activation and blood flow studies indicate that prefrontal and limbic brain regions have a central role in the pathophysiology. The objective of this study was to investigate extrastriatal dopamine D2-receptor (D2-R) availability in SAD. We examined 12 SAD patients and 16 healthy controls using positron emission tomography and the high-affinity D2-R radioligand [11C]FLB457. Parametric images of D2-R binding potential were derived using the Logan graphical method with cerebellum as reference region. Two-tailed one-way independent ANCOVAs, with age as covariate, were used to examine differences in D2-R availability between groups using both region-based and voxel-wise analyses. The region-based analysis showed a medium effect size of higher D2-R levels in the orbitofrontal cortex (OFC) in patients, although this result did not remain significant after correction for multiple comparisons. The voxel-wise comparison revealed elevated D2-R availability in patients within OFC and right dorsolateral prefrontal cortex after correction for multiple comparisons. These preliminary results suggest that an aberrant extrastriatal dopamine system may be part of the disease mechanism in SAD.

LP23: Association among extrastriatal dopamine D2 receptor binding, idea fluency and depersonalization: A positron emission tomography study

LP23: Association among extrastriatal dopamine D2 receptor binding, idea fluency and depersonalization: A positron emission tomography study

Changes in dopamine D2-receptor binding are associated to symptom reduction after psychotherapy in social anxiety disorder

The dopamine system has been suggested to play a role in social anxiety disorder (SAD), partly based on molecular imaging studies showing reduced levels of striatal dopaminergic markers in patients compared with control subjects. However, the dopamine system has not been examined in frontal and limbic brain regions proposed to be central in the pathophysiology of SAD. In the present study, we hypothesized that extrastriatal dopamine D2-receptor (D2-R) levels measured using positron emission tomography (PET) would predict symptom reduction after cognitive behavior therapy (CBT). Nine SAD patients were examined using high-resolution PET and the high-affinity D2-R antagonist radioligand [11C]FLB 457, before and after 15 weeks of CBT. Symptom levels were assessed using the anxiety subscale of Liebowitz Social Anxiety Scale (LSASanx). At posttreatment, there was a statistically significant reduction of social anxiety symptoms (P<0.005). Using a repeated measures analysis of covariance, significant effects for time and time × LSASanx change on D2-R-binding potential (BPND) were shown (P<0.05). In a subsequent region-by-region analysis, negative correlations between change in D2-R BPND and LSASanx change were found for medial prefrontal cortex and hippocampus (P<0.05). This is the first study to report a direct relationship between symptom change after psychological treatment and a marker of brain neurotransmission. Using an intra-individual comparison design, the study supports a role for the dopamine system in cortical and limbic brain regions in the pathophysiology of SAD.

Striatal and extrastriatal dopamine D2 receptor occupancy by the partial agonist antipsychotic drug aripiprazole in the human brain: a positron emission tomography study with [11C]raclopride and [11C]FLB457

Second-generation antipsychotics demonstrate clinical efficacy with fewer extrapyramidal side effects compared with first-generation antipsychotics. One of the proposed explanations is the hypothesis of preferential extrastriatal dopamine D₂ receptor occupancy (limbic selectivity) by antipsychotics. In the present study, we focused on aripiprazole, which has a unique pharmacological profile with partial agonism at dopamine D₂ receptors and the minimal risk of extrapyramidal side effects. Previous positron emission tomography (PET) studies using high-affinity radioligands for dopamine D₂ receptors have reported inconsistent results regarding regional differences of dopamine D₂ receptor occupancy by aripiprazole. To test the hypothesis of preferential binding to extrastriatal dopamine D₂ receptors by aripiprazole, we investigated its regional dopamine D₂ receptor occupancies in healthy young subjects. Using PET and two radioligands with different affinities for dopamine D₂ receptors, [¹¹C]raclopride and [¹¹C]FLB457, striatal and extrastriatal dopamine D₂ receptor bindings at baseline and after oral administration of 6 mg aripiprazole were measured in 11 male healthy subjects. Our data showed that dopamine D₂ receptor occupancies in the striatum measured with [¹¹C]raclopride were 70.1% and 74.1%, with the corresponding values for the extrastriatal regions measured with [¹¹C]FLB457 ranging from 46.6% to 58.4%. In the present study, preferential extrastriatal dopamine D₂ receptor occupancy by aripiprazole was not observed. Our data suggest partial agonism at dopamine D₂ receptors is the most likely explanation for the minimal risk of extrapyramidal side effects in the treatment by aripiprazole.

Striatal and extrastriatal dopamine D2 receptor availability as assessed by [18F]fallypride and PET in patients with alcohol use disorder

Dopaminergic pathways are implicated in substance use disorders. Molecular imaging revealed reductions in dopamine D2 receptor availability in the striatum of withdrawn abusers of cocaine; corresponding results in alcoholics have been inconsistent so far. Here, we used [18F]fallypride to investigate D2 receptor availability in patients with alcohol use disorder (AUD) before and after undergoing a detoxification protocol. 17 patients (44 ± 5y) with AUD were scanned with 180 MBq [18F]fallypride upon hospital admission and after detoxification. Four patients with long term abstinence were rescanned at one year. The control group consisted of age-matched controls. Dynamic PET recordings were used for VOI-based and voxel-wise analyses of striatal and extrastriatal [18F]fallypride binding potential (BPND). In patients mean striatal BPND at baseline was 15.7 ± 3.6, similar to healthy controls (16.8 ± 3.0). BPND was lower in thalamus, hippocampus, insular and temporal cortex (p < 0.05). There were inverse correlations of BPND with age (r-0.45) and daily alcohol consumption (r-0.2). Age-dependence of BPND was pronounced in the patients. BPND was unaltered at short term follow-up, but increased by 30% at one year follow up. VOI-based PET revealed extrastriatal group differences in D2 receptor availability. BPND increased in patients with long term follow up, suggesting reversibility of receptor changes. Regressions with age suggest an accelerated loss of D2 receptors in patients with AUD.

Improvement of Oral Dyskinesia After Switching From Aripiprazole to Paliperidone: A Case Report

Back to table of contents Previous article Next article LettersFull AccessImprovement of Oral Dyskinesia After Switching From Aripiprazole to Paliperidone: A Case ReportChien-Han Lai, M.D., M.Sc.Chien-Han LaiSearch for more papers by this author, M.D., M.Sc.Published Online:1 Jul 2011AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Paliperidone is associated with fewer extrapyramidal side effects (EPS) than typical antipsychotics. Here, we reported a case of schizophrenia with oral and tongue dyskinesia after aripiprazole treatment. The patient had improvement of dyskinesia after switching to paliperidone.Case Report“Miss B” had her first episode of schizophrenia 1 year ago. The symptoms included delusion of persecution toward her colleagues, delusion of reference toward her boss, auditory hallucinations, and visual hallucinations. Her psychotic symptoms improved after the first 3 months of therapy with aripiprazole 15 mg/day. However, she had irregular, involuntary, persistent, and repetitive movements of mouth and tongue after aripiprazole treatment for 1 month. These movements were very irregular, either in intensity or direction. The intensity of movements varied over time and ranged from mild to moderate. The direction of tongue movements was random, in any possible direction, either within the oral cavity or outside the mouth. Her oral dyskinesia was not relieved after the aripiprazole was tapered to 10 mg/day in the 6th month and 5 mg/day in the 9th month. After 3 months of 5 mg/day aripiprazole therapy, her oral dyskinesia had still not responded to biperidin 2 mg/day. Because of the possibility of aripiprazole-related oral dyskinesia, the antipsychotic was switched to paliperidone. The irregular movements improved, with gradual decline in intensity, frequency, and duration within 1 month. No significant cholinergic rebound symptoms or side effects were noted after the abrupt switch. Her psychotic symptoms still remained stable. The remission of dyskinesia remained after therapy of paliperidone for the next 3 months.DiscussionThis patient had improvement of dyskinesia after switching to paliperidone. The dose (3 mg/day) is relatively low for schizophrenia but equal to her previous aripiprazole dose of 5 mg/day. This patient had dramatic relief of dyskinesia side effects, which might be related to different binding patterns for neurotransmitter receptors of these two kinds of atypical antipsychotics. In a positron emission tomography study, 6–9 mg/day of paliperidone showed equal dopamine-binding at D2 receptors (around 70%–80%) over striatum and temporal cortex.1 This patient just received 3 mg/day of paliperidone and had complete remission of dyskinesia. Lower binding of D2 receptors over striatum at the dose of 3 mg/day might be the reason. Aripiprazole has a well-known low risk of EPS, with incidence comparable to placebo, and it could modulate dopamine release over prefrontal cortex through the action on serotonin 5-HT1A receptors.2 The dopamine release is not observed over sriatum areas, and, with D2 occupancy over 90%, still did not produce EPS.3 Its tardive dyskinesia incidence is also comparable to placebo group without significant risk. However, this patient had dyskinesia side effects even using aripiprazole at a lower dose. The relatively higher antagonism over 5-HT2A receptor of paliperidone than aripiprazole4 might provide another reason why this patient had remission of dyskinesia after the antipsychotic switch. 5-HT2A antagonism also suppressed the abnormal involuntary movements and dyskinesia of dopamine-depleted rats after receiving dopamine agonists.5 These findings might help explain clinical phenomenon in this patient.Dept. of Psychiatry, Buddhist Tzu-Chi General Hospital, Taipei Branch, Taipei, Taiwan;Institute of Brain Science, National Yang Ming University, Taipei City, Taiwan e-mail: [email protected]com.tw1. Arakawa R , Ito H , Takano A , et al.: Dose-finding study of paliperidone ER based on striatal and extrastriatal dopamine D2 receptor occupancy in patients with schizophrenia. Psychopharmacology (Berl) 2008; 197:229–235Crossref, Medline, Google Scholar2. Bortolozzi A , Diaz-Mataix L , Toth M , et al.: In-vivo actions of aripiprazole on serotonergic and dopaminergic systems in rodent brain. Psychopharmacology (Berl) 2007; 191:745–758Crossref, Medline, Google Scholar3. Yokoi F , Grunder G , Biziere K , et al.: Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C]raclopride. Neuropsychopharmacology 2002; 27:248–259Crossref, Medline, Google Scholar4. Pae CU , Serretti A , Patkar AA , et al.: Aripiprazole in the treatment of depressive and anxiety disorders: a review of current evidence. CNS Drugs 2008; 22:367–388Crossref, Medline, Google Scholar5. Taylor JL , Bishop C , Ullrich T , et al.: Serotonin 2A receptor antagonist treatment reduces dopamine D1 receptor-mediated rotational behavior but not L-dopa-induced abnormal involuntary movements in the unilateral dopamine-depleted rat. Neuropharmacology 2006; 50:761–768Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited ByNone Volume 23Issue 3 Summer 2011Pages E18-E18 Metrics PDF download History Published online 1 July 2011 Published in print 1 July 2011

Association between striatal and extrastriatal dopamine D2-receptor binding and social desirability

Research on the biological underpinnings of personality can provide leads to the pathophysiology of psychiatric disorders. In particular, interpersonal aspects of behavior are a common problem during the course of psychiatric illness. Animal research has demonstrated a role for the dopamine system in social behaviour, and recent molecular imaging studies have shown a negative correlation between dopamine D2-receptor binding in the striatum and social desirability. The emotional and cognitive aspects of social behavior suggest involvement of brain regions outside of the striatum, such as limbic structures. The aim of the present study was to explore associations between the personality trait social desirability and dopamine D2-receptor binding in both striatal and extrastriatal brain regions. We examined 16 control subjects with Positron Emission Tomography and the radioligands [11C]raclopride and [11C]FLB 457, in relation to social desirability in the inventory Swedish universities Scales of Personality. [11C]raclopride D2-receptor binding in the striatum showed negative correlations to social desirability scores, corroborating previous findings. Furthermore, a correlation of a higher statistical significance was demonstrated for [11C]FLB 457 binding in the hippocampal–amygdala complex. A separate analysis of social desirability items in relation to a model of interpersonal behaviour revealed that the associations were driven by items reflecting high submissiveness and high affiliation. Taken together with previous evidence on D2-receptor binding and social behaviour, a role for dopaminergic neurotransmission in regulating displays of dominance vs. submissive behaviour is proposed.

Extrastriatal dopamine D2 receptor occupancy in olanzapine-treated patients with schizophrenia

Olanzapine is described as a multi-acting receptor-targeted antipsychotic agent. Although regional differences of dopamine D(2) receptor occupancy, i.e., limbic selectivity, were reported for olanzapine, contradictory results were also reported. We measured dopamine D(2) receptor occupancy of olanzapine in extrastriatal regions in patients with schizophrenia using positron-emission tomography with [(11)C]FLB457 and the plasma concentrations of olanzapine. Ten patients with schizophrenia taking 5-20 mg/day of olanzapine participated. Dopamine D(2) receptor occupancy in the temporal cortex ranged from 61.1 to 85.8%, and plasma concentration was from 12.7 to 115.4 ng/ml. The ED(50) value was 3.4 mg/day for dose and 10.5 ng/ml for plasma concentration. The ED(50) values obtained in this study were quite similar to those previously reported in the striatum. In conclusion, although the subjects and methods were different from previous striatal occupancy studies, these results suggest that limbic occupancy by olanzapine may not be so different from that in the striatum.

Extrastriatal dopamine D2 receptor binding modulates intraindividual variability in episodic recognition and executive functioning

Intraindividual variability (IIV) reflects lawful but transient within-person changes in performance. Increased IIV in cognition shares systematic associations with numerous conditions characterized by alterations in dopamine (DA) neuromodulation (e.g., old age, ADHD, schizophrenia, and Parkinson's disease). In a group of normal middle-aged adults, we examined links between PET-derived measures of D2 receptor binding in striatum, orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and hippocampus (HC) and IIV for tasks assessing recognition memory and executive functioning. An index of IIV, the intraindividual standard deviation (ISD), was computed across successful response latency trials for each cognitive outcome. Lower D2 binding in OC, ACC, and HC, but not striatum, was associated with increasing ISDs for the memory and executive measures. Consistent with neurocomputational models, the present findings suggest a role for extrastriatal DA neurotransmission in modulating variability in cognitive functioning.

No regional difference in dopamine D2 receptor occupancy by the second-generation antipsychotic drug risperidone in humans: a positron emission tomography study

The effects of antipsychotic drugs have generally been considered to be mediated by blockade of dopamine D2 receptors. The concept of limbic and cortical selectivity of second-generation antipsychotics, i.e. higher dopamine D2 receptor occupancy in the cerebral cortices than in the striatum, has been suggested to explain their clinical efficacy with lower incidence of extrapyramidal side-effects. In this study, regional distribution of dopamine D2 receptor occupancy by risperidone was determined in order to elucidate the limbic and cortical selectivity of second-generation antipsychotics. Striatal and extrastriatal dopamine D2 receptor binding at baseline and after oral administration of 2 mg risperidone were measured in ten healthy men by positron emission tomography (PET) using different tracers with different affinity for the receptors, [11C]raclopride and [11C]FLB 457, respectively. Striatal and extrastriatal occupancies of dopamine D2 receptors were calculated for each brain region. Occupancies of dopamine D2 receptors were about 70% and 60% in the striatum and extrastriatum, respectively. A simulation study showed that non-negligible specific binding in the reference region (cerebellum), could cause systemic underestimation of occupancy in [11C]FLB 457 PET studies, indicating that occupancies in both the striatum and extrastriatum may not have differed. Among the extrastriatal regions including limbic and neocortical regions, no significant regional differences in dopamine D2 receptor occupancy were observed. Thus, limbic and cortical selectivity was not observed by one of the second-generation antipsychotics, risperidone.

EARLY NON-RESPONSE TO ANTIPSYCHOTIC MEDICATIONS IS AN IMPORTANT CLINICAL MARKER OF SUBSEQUENT NON-RESPONSE IN THE TREATMENT OF SCHIZOPHRENIA

Epidepride, (S)-N[1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2,3-dimethoxy-benzamide, the iodine analogue of isoremoxipride (FLB 457), was found to be a very potent dopamine D2 receptor antagonist. Optimal in vitro binding required incubation at 25°C for 4 h at pH 7.4 in a buffer containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2 and 1 mM MgCl2. Scatchard analysis of in vitro binding to striatal, medial frontal cortical, hippocampal and cerebellar membranes revealed a KD of 24 pM in all regions, with Bmax's of 36.7, 1.04, 0.85, and 0.37 pmol/g tissue, respectively. The Hill coefficients ranged from 0.91–1.00 in all four regions. The IC50's for inhibition of [125I]epidepride binding to striatal, medial frontal cortical, and hippocampal membranes for SCH 23390, SKF 83566, serotonin, ketanserin, mianserin, naloxone, QNB, prasozin, clonidine, alprenolol, and norepinephrine ranged from 1 μM to > 10 μM. Partial displacement of [125I]epidepride by nanomolar concentrations of clonidine was noted in the frontal cortex and hippocampus, but not in the striatum. Scatchard analysis of epidepride binding to α2 noradrenergic receptors in the frontal cortex and hippocampus revealed an apparent KD of 9 nM. At an epidepride concentration equal to the KD for the D2 receptor, i.e. 25 pM, no striatal α2 binding was seen and only 7% of the specific epidepride binding in the cortex or hippocampus was due to binding at the α2 site. Correlation of inhibition of [3H]spiperone and [125I]epidepride binding to striatal membranes by a variety of D2 ligands revealed a correlation coefficient of 0.99, indicating that epidepride labels a D2 site. In vitro autoradiography revealed high densities of receptor binding in layers V and VI of prefrontal and cingulate cortices as well as in striatum. In vivo rat brain uptake revealed a hippocampal:cerebellar and frontal cortical:cerebellar ratio of 2.2:1 which fell to 1.1:1 following haloperidol pretreatment. These properties suggest that [125I]epidepride is a superior radioligand for the in vitro and in vivo study of striatal and extrastriatal dopamine D2 receptors.

Dose–Occupancy Study of Striatal and Extrastriatal Dopamine D2 Receptors by Aripiprazole in Schizophrenia with PET and [18F]Fallypride

Positron emission tomography (PET) and the high affinity D(2/3) radiotracer [(18)F]fallypride allow the assessment of D(2/3) receptor occupancy of antipsychotic drugs in striatal and extrastriatal brain regions. We measured regional occupancy attained across a range of clinical dosing by the partial D(2) agonist aripiprazole using these methods. Twenty-eight PET scans were acquired on the ECAT EXACT HR+ camera in 19 patients with schizophrenia or schizoaffective disorder. Daily aripiprazole doses ranged from 2 to 40 mg, with a minimum of 10 days on steady dose. Mean regional occupancies, a model-independent estimate of aripiprazole effect on pituitary binding, and PANSS ratings changes were evaluated. Occupancy levels were high across regions of interest, ranging from 71.6+/-5.5% at 2 mg/day to 96.8+/-5.3% at 40 mg/day. Occupancy levels were higher in extrastriatal than striatal regions. Pituitary measures of aripiprazole effect correlated with doses and were unrelated to prolactin levels, which remained within the normal range under medication. PANSS positive (but not negative) symptom improvement correlated with striatal but not extrastriatal occupancies. These data show, for the first time, D(2) occupancy by aripiprazole in treated patients with schizophrenia in extrastriatal as well as striatal regions, with high occupancy for all doses. We discuss possible explanations for higher extrastriatal than striatal occupancy. Correlations of ratings of clinical improvement with regional occupancy suggest that aripiprazole, as do other antipsychotics, benefits positive symptoms of schizophrenia most directly through its modulation of striatal rather than cortical or other extrastriatal dopamine activity.

Dose-finding study of paliperidone ER based on striatal and extrastriatal dopamine D2 receptor occupancy in patients with schizophrenia

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. 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. 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. 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. 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.

Normal database of dopaminergic neurotransmission system in human brain measured by positron emission tomography

The central dopaminergic system is of interest in the pathophysiology of schizophrenia and other neuropsychiatric disorders. Both pre- and postsynaptic dopaminergic functions can be estimated by positron emission tomography (PET) with different radiotracers. However, an integrated database of both pre- and postsynaptic dopaminergic neurotransmission components including receptors, transporter, and endogenous neurotransmitter synthesis has not yet been reported. In the present study, we constructed a normal database for the pre- and postsynaptic dopaminergic functions in the living human brain using PET. To measure striatal and extrastriatal dopamine D(1) and D(2) receptor bindings, dopamine transporter binding, and endogenous dopamine synthesis rate, PET scans were performed on healthy men after intravenous injection of [(11)C]SCH23390, [(11)C]raclopride, [(11)C]FLB457, [(11)C]PE2I, or L-[beta-(11)C]DOPA. All PET images were anatomically standardized using SPM2, and a database was built for each radiotracer. Gray matter images were segmented and extracted from all anatomically standardized magnetic resonance images using SPM2, and they were used for partial volume correction. These databases allow the comparison of regional distributions of striatal and extrastriatal dopamine D(1) and D(2) receptors, dopamine transporter, and endogenous dopamine synthesis capability. These distributions were in good agreement with those from human postmortem studies. This database can be used in various researches to understand the physiology of dopaminergic functions in the living human brain. This database could also be used to investigate regional abnormalities of dopaminergic neurotransmission in neuropsychiatric disorders.

The role of dopamine for the pathophysiology of schizophrenia

Since decades, experimental approaches and clinical experience have suggested a dopaminergic system's dysregulation playing an important role within the pathophysiology of schizophrenia. This paper summarizes the actual standard of knowledge of the physiological fundamentals and hypothesized dysbalances of the dopamine (DA) system with respect to schizophrenia including interaction with other neurotransmitter systems (glutamate, GABA). The assumed functional role of DA with respect to physiological and illness-associated cognitive performance, especially working memory, reward, and motivation, as it was assessed by fMRI studies, is presented. A third focus concentrates on giving a short survey of SPECT and PET studies measuring the amount of the striatal and extrastriatal DA, the striatal and extrastriatal dopamine D2 receptor, and the dopamine transporter (DAT) comparing first-episode, drug-naïve, treated, and relapsing schizophrenic patients and healthy control persons.

Memory and frontal lobe functions; possible relations with dopamine D2 receptors in the hippocampus

Cerebral cortical regions are thought to be important for cognitive functions such as memory and executive function. Although the functional associations between dopamine D2 receptors and motor and cognitive functions have been extensively examined in the striatum using positron emission tomography (PET), the role of dopamine D2 receptors in extrastriatal regions has been unexplored. We aimed to investigate the relationship between dopamine D2 receptors in extrastriatal regions and the performance of a broad spectrum of cognitive functions including memory, language, attention, and executive function in healthy subjects. Extrastriatal dopamine D2 receptors were measured in 25 male subjects using PET with [(11)C]FLB457. After the PET scans, a battery of neuropsychological tests was administered to all subjects. We found that the binding potential (BP) of [(11)C]FLB457 in the hippocampus was positively correlated with memory function. Furthermore, BP of [(11)C]FLB457 in the hippocampus, but not in the prefrontal cortex, was associated with frontal lobe functions such as executive function and verbal fluency. Our findings suggest that dopamine D2 receptors in the hippocampus might affect the local hippocampal function, but also brain functions outside the hippocampus such as the prefrontal cortex.