Striatal Dopamine D2 Receptor Research Articles

Treadmill exercise elevates striatal dopamine D2 receptor binding potential in patients with early Parkinson’s disease

We have previously demonstrated changes in dopaminergic neurotransmission after intensive exercise in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of Parkinson's disease (PD), including an increase in the dopamine D2 receptor (DA-D2R), using noninvasive PET imaging with the radioligand [18F]fallypride. The purpose of this feasibility and translational study was to examine whether intensive exercise leads to similar alterations in DA-D2R expression using PET imaging with [18F]fallypride in individuals with early-stage PD. In this pilot study, four patients with early-stage PD were randomized to receive intensive exercise (treadmill training sessions three times/week for 8 weeks) or no exercise. Two healthy age-matched individuals participated in treadmill training. Alterations in the DA-D2R binding potential (BP) as a marker for receptor expression were determined using PET imaging with [18F]fallypride. Turning performance in the patients with PD as a measure of postural control and the Unified Parkinson's Disease Rating Scale scores pre-exercise and postexercise were determined. Our data showed an exercise-induced increase in [18F]fallypride BP as well as improved postural control in patients with PD who exercised. Changes in DA-D2R BP were not observed in patients with PD who did not exercise. These results suggest that exercise can lead to neuroplasticity in dopaminergic signaling and contribute to improved function that may be task specific (postural control) in early-stage PD.

Engineering animal models of dystonia

Dystonia is a neurological disorder characterized by abnormal involuntary movements that are prolonged and often cause twisting and turning. Several genetically modified worms, fruit flies, and rodents have been generated as models of genetic dystonias, in particular DYT1, DYT11, and DYT12 dystonias. Although these models do not show overt dystonic symptoms, the rodent models exhibit motor deficits in specialized behavioral tasks, such as the rotarod and beam-walking tests. For example, in a rodent model of DYT12 dystonia, which is generally stress triggered, motor deficits are observed only after the animal is stressed. Moreover, in a rodent model of DYT1 dystonia, the motor and electrophysiological deficits can be rescued by trihexyphenidyl, a common anticholinergic medication used to treat dystonic symptoms in human patients. Biochemically, the DYT1 and DYT11 animal models also share some similarities to patients, such as a reduction in striatal D2 dopamine receptor and binding activities. In addition, conditional knockout mouse models for DYT1 and DYT11 dystonia demonstrate that loss of the causal dystonia-related proteins in the striatum leads to motor deficits. Interestingly, loss of the DYT1 dystonia causal protein in Purkinje cells shows an improvement in motor performance, suggesting that gene therapy targeting of the cerebellum or intervention in its downstream pathways may be useful. Finally, recent studies using DYT1 dystonia worm and mouse models led to a potential novel therapeutic agent, which is currently undergoing clinical trials. These results indicate that genetic animal models are powerful tools to elucidate the pathophysiology and to further develop new therapeutics for dystonia.

Combination of prenatal immune challenge and restraint stress affects prepulse inhibition and dopaminergic/GABAergic markers

Gestational immune challenge with the viral-like antigen poly I:C is a well-established neurodevelopmental model of schizophrenia. However, exposure to inflammation during early life may sensitize the developing brain to secondary insults and enhance the central nervous system vulnerability. To gain a better understanding of the pathophysiology of schizophrenia, we thus developed a two-hit animal model based on prenatal poly I:C immune challenge followed by restraint stress in juvenile mice. C57BL/6 gestational mice were intraperitoneally injected with poly I:C or saline at gestational day 12. Pups were then submitted or not, to restraint stress for 2h, for three consecutive days, from postnatal days 33 to 35. Prepulse inhibition (PPI) of acoustic startle response is commonly used to assess sensorimotor gating, a neural process severely disrupted in patients with schizophrenia. Our results revealed that the combination of prenatal immune challenge with poly I:C followed by a restraint stress period was able to induce a PPI disruption in 36-day-old pups, as opposed to each insult applied separately. PPI deficits were accompanied by dopaminergic and GABAergic abnormalities in the prefrontal cortex and striatum. Indeed, measurements of cortical and striatal dopamine D2 receptor (D2R) mRNA and protein levels revealed that the combination of gestational exposure to poly I:C and postnatal restraint stress induced an increase in D2R protein and mRNA levels. Likewise, the combination of both insults reduced the mRNA and protein expression levels of the 67 kDa form of glutamic acid decarboxylase (GAD67), in those two brain regions. To our knowledge, this two-hit animal model is the first in vivo model reporting PPI deficits at pubertal age. This two-hit animal model may also help in studying innovative therapies dedicated to the treatment of schizophrenia, especially in its early phase.

Aripiprazole in an Animal Model of Chronic Alcohol Consumption and Dopamine D2 Receptor Occupancy in Rats

Background: Epidemiologic studies and clinical assessment of schizophrenic population have revealed a high incidence of overlap between schizophrenia and addictive disorders. Objective: The aim of the present investigation was to study the effect of aripiprazole in a preclinical animal model of chronic alcohol self-administration (CASA) and also to evaluate the influence of CASA on plasma pharmacokinetics and dopamine D2 receptor (D2R) occupancy in rats. Methods: The effect of oral administration of aripiprazole (1, 3, and 10 mg/kg) on 4% alcohol intake in CASA was studied for a period of 45 min after a post-dosing interval of 60 min. Brain penetration, pharmacokinetics, and D2R occupancy of aripiprazole were evaluated in normal and CASA rats. Results: Aripiprazole reduced alcohol consumption in CASA rats by 13, 28, and 86% at 1, 3, and 10 mg/kg, respectively, and the effect reached statistical significance at 10 mg/kg (p < .01). At this behavioral effective dose, a decrease (75%) in total plasma apparent clearance and an increase in oral area under the concentration–time curve (3.98-fold) and bioavailability (3.50-fold) of aripiprazole was observed in CASA rats. Striatal D2R occupancy and brain exposure of aripiprazole were significantly higher (∼twofold) in CASA rats when compared to normal rats (p < .01). Conclusion: Chronic alcohol intake results in a significant increase in exposure of aripiprazole in plasma and brain and striatal D2R occupancy. Scientific significance: Chronic alcohol intake would increase aripiprazole exposure, thus aripiprazole dose might have to be decreased (assuming this same phenomenon occurs in humans).

Dopamine D2/3 occupancy of ziprasidone across a day: a within-subject PET study

Ziprasidone is an atypical antipsychotic recommended to be administered twice daily. The purpose of this study was to investigate whether occupancy of the dopamine D2/3 receptors by ziprasidone is maintained across a day employing a within subject design. Positron emission tomography (PET) scans with [(11)C]-raclopride were performed in 12 patients with schizophrenia while treated with ziprasidone 60 mg twice daily. Each patient completed [(11)C]-raclopride PET scans at 5, 13 and 23 h after the last dose of ziprasidone. Dopamine D2/3 receptor occupancy was estimated with reference to binding potential data of 44 age- and sex-matched control subjects in the caudate, putamen and ventral striatum. Eleven scans were available at each time point, and the mean occupancies at 5-, 13- and 23-h scans were 66, 39 and 2 % in the putamen; 62, 35 and -6 % in the caudate; and 68, 47 and 11 % in the ventral striatum, respectively. The time-course of receptor occupancy across the regions indicated an occupancy half-life of 8.3 h. The serum level of ziprasidone associated with 50 % D2/3 receptors occupancy was estimated to be 204 nmol/L (84 ng/ml). Prolactin levels were highest at 5-h post-dose and none showed hyperprolactinemia at 23-h scans. The absence of ziprasidone striatal D2/3 receptor binding 23 h after taking 60 mg under steady-state conditions is consistent with its peripheral half-life. The results support our earlier report that ziprasidone 60 mg administered twice daily appears to be the minimal dose expected to achieve therapeutic central dopamine D2/3 receptor occupancy (i.e. 60 %). 24-Hour Time Course of Striatal Dopamine D2 Receptor Occupancy of Ziprasidone: A PET Study, www.clinicaltrials.gov/ct2/show/NCT00818298 , NCT00818298.

Striatal CB1 and D2 receptors regulate expression of each other, CRIP1A and delta opioid systems

Although biochemical and physiological evidence suggests a strong interaction between striatal CB1 cannabinoid (CB1 R) and D2 dopamine (D2 R) receptors, the mechanisms are poorly understood. We targeted medium spiny neurons of the indirect pathway using shRNA to knockdown either CB1 R or D2 R. Chronic reduction in either receptor resulted in deficits in gene and protein expression for the alternative receptor and concomitantly increased expression of the cannabinoid receptor interacting protein 1a (CRIP1a), suggesting a novel role for CRIP1a in dopaminergic systems. Both CB1 R and D2 R knockdown reduced striatal dopaminergic-stimulated [(35) S]GTPγS binding, and D2 R knockdown reduced pallidal WIN55212-2-stimulated [(35) S]GTPγS binding. Decreased D2 R and CB1 R activity was associated with decreased striatal phosphoERK. A decrease in mRNA for opioid peptide precursors pDYN and pENK accompanied knockdown of CB1 Rs or D2 Rs, and over-expression of CRIP1a. Down-regulation in opioid peptide mRNAs was followed in time by increased DOR1 but not MOR1 expression, leading to increased [D-Pen2, D-Pen5]-enkephalin-stimulated [(35) S]GTPγS binding in the striatum. We conclude that mechanisms intrinsic to striatal medium spiny neurons or extrinsic via the indirect pathway adjust for changes in CB1 R or D2 R levels by modifying the expression and signaling capabilities of the alternative receptor as well as CRIP1a and the DELTA opioid system.

Estrogen receptors and lesion-induced response of striatal dopamine receptors

Neuroprotection by 17β-estradiol and an estrogen receptor (ER) agonist against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion were shown to implicate protein kinase B (Akt) signaling in mice. In order to evaluate the associated mechanisms, this study compared estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) intact or knockout (KO) and wild-type (WT) C57Bl/6 male mice following MPTP treatment of 7, 9, 11mg/kg and/or 17β-estradiol. Striatal D1 and D2 dopamine (DA) receptors were measured by autoradiography with the specific ligands [3H]-SCH 23390 and [3H]-raclopride, respectively and signaling by Western blot for Akt, glycogen synthase kinase 3β (GSK3β) and extracellular-regulated signal kinases (ERK1 and ERK2). Control ERKOβ mice had lower striatal [3H]-SCH 23390 specific binding than WT and ERKOα mice; both KO mice had lower [3H]-raclopride specific binding. Striatal D1 receptors decreased with increasing doses of MPTP in correlation with striatal DA concentrations in ERKOα mice and remained unchanged in WT and ERKOβ mice. Striatal D2 receptors decreased with increasing doses of MPTP in correlation with striatal DA concentrations in WT and ERKOα mice and increased in ERKOβ mice. In MPTP-lesioned mice, 17β-estradiol treatment increased D1 receptors in ERKOα and ERKOβ mice and D2 receptors in WT and ERKOβ mice. MPTP did not affect striatal pAkt/Akt and pGSK3β/GSK3β levels in WT and ERKOα mice, while in vehicle-treated ERKOβ mice these levels were higher and increased with MPTP lesioning. Striatal pERK1/ERK1 and pERK2/ERK2 levels showed to a lesser extent a similar pattern. In conclusion, ERs affected the response of striatal DA receptors to a MPTP lesion and post receptor signaling.

Cirrhosis-related Parkinsonism: Prevalence, mechanisms and response to treatments

Extrapyramidal and cerebellar symptoms belong to the most prominent features of episodic hepatic encephalopathy, and usually decrease upon ammonia-lowering therapy. Rapidly progressing parkinsonian symptoms, which are unresponsive to treatment of hepatic encephalopathy, indicate cirrhosis-related Parkinsonism. This study aims at analyzing the prevalence of cirrhosis-related Parkinsonism in patients with liver cirrhosis, and to study the functional status of the striatal dopaminergic system in these patients. 214 patients with liver cirrhosis who were consecutively seen at the out-patient clinic for liver transplant candidates and/or at the transplantation wards at Hannover Medical School, between August 1, 2008 and March 31, 2011, underwent a standardized neurological examination while on the waiting list or immediately after liver transplantation. Single photon emission computer tomography (SPECT) using (123)I-beta-CIT, for the evaluation of the striatal dopamine transporter function, and (123)I-IBZM for the evaluation of the striatal dopamine D2 receptor availability, was performed in 6 patients with cirrhosis-related Parkinsonism. Cirrhosis-related Parkinsonism was diagnosed in 9 of 214 patients (4.2%). SPECT revealed significantly decreased dopamine receptor availability in 5 of 6 patients studied, and significantly decreased dopamine transporter availability in 3. Levodopa improved motor dysfunction in two of four patients treated, although only temporarily. Incomplete recovery was observed in two patients after liver transplantation. Cirrhosis-related Parkinsonism is more frequent than presumed. The presented data suggest pre- and postsynaptic alteration of striatal dopaminergic neurotransmission as a possible cause of cirrhosis-related Parkinsonism and reveal the limited effects of dopaminergic therapy.

Striatal dopamine D1 receptors are involved in the dissociation of learning based on reward-magnitude

Here we investigate the contribution of striatal dopamine receptors (D1) to the influence of reward-magnitude on learning. Pigeons (Columba livia) were trained on a discrimination-task with two pairs of stimuli; correct discrimination resulted in a large reward in one pair of stimuli and in a small reward in the other pair. Acquisition of the discrimination-task was accompanied by intracranial injections to the medial striatum, either of a dopamine-antagonist (Sch23390) or of vehicle. In the control-condition the rate of learning was modulated by the magnitude of the reward; discrimination was learned faster if contingent rewards were large and learning was slower if contingent rewards were small. Following injections of D1 antagonist this effect vanished even though the ability to discriminate between the rewards was unaffected. Interestingly, the mean rate of learning was indistinguishable between the control and antagonist conditions. Consequently, it appears that not learning per se but the effect of reward-magnitude on learning is mediated through D1 receptors in the striatum.We argue that the injections of dopamine-antagonist cause a shift in strategy underlying learning. In the control-condition animals rely on positive feedback and thus learning is affected by the magnitude of the contingent reward; in the antagonist-condition, however, learning might rely on negative feedback and is thus insensitive to reward-magnitude.

Dopamine D2 receptor SPECT in corticobasal syndrome and autopsy-confirmed corticobasal degeneration

BackgroundCorticobasal degeneration (CBD) is a rare neurodegenerative disorder characterized by tau-positive neuronal and glial lesions in the cortex and striatum with neuronal loss in cortical regions and in the substantia nigra. Striatal dopamine D2 receptor binding in autopsy-confirmed CBD has not been studied before. MethodsWe performed D2 receptor single photon emission computerized tomography using 123I-IBZM in nine patients with a clinically diagnosed corticobasal syndrome (CBS) and on ten healthy controls. Two of the patients subsequently came to autopsy and were diagnosed with CBD. ResultsOverall striatal D2 receptor binding was preserved in 8/9 patients, but more asymmetric than in controls. Overall striatal binding in pathologically confirmed CBD was reduced in one case and normal in the other, and was lower contralateral to the clinically more affected side in both. ConclusionThis first study on D2 receptor imaging in autopsy-confirmed CBD demonstrates that loss of postsynaptic striatal neurons in CBD is a variable finding. Given the heterogeneity of our findings in pathology-confirmed cases, D2 receptor imaging seems to be of little practical value in the diagnostic workup of patients with CBS.

Schizophrenia in translation: dissecting motivation in schizophrenia and rodents.

The negative symptoms of schizophrenia include deficits in motivation, for which there is currently no treatment available. Animal models provide a powerful tool for identifying the potential pathophysiological mechanisms underlying the motivation deficits of schizophrenia with the aim of discovering novel treatment targets. The success of such an approach critically depends on meticulously detailed analysis of motivational phenotypes in patients and in animal models. Here, we review the results of recent human behavioral and imaging studies of motivation, and we relate those findings to the results from animal studies, including a mouse model of striatal dopamine D2 receptor hyperfunction. The motivational deficit in patients with schizophrenia is not due to an inability to experience pleasure in the moment as hedonic reaction appears intact in patients. Instead, the motivation deficit represents a reduced capacity for anticipating future pleasure resulting from goal-directed action. The diminished anticipation appears to be a consequence of an inability to accurately represent the expected reward values of actions. A strikingly similar phenotype in incentive motivation has also been described in mice with striatal dopamine D2 receptor hyperfunction. These convergent findings identify potential pathophysiological mechanisms that underlie the deficit in anticipatory motivation, and importantly, the mouse model provides a tool for investigating novel treatment strategies, which we discuss here.

Amelioration of the haloperidol-induced memory impairment and brain oxidative stress by cinnarizine.

Haloperidol is a classic antipsychotic drug known for its propensity to cause extrapyramidal symptoms and impaired memory, owing to blockade of striatal dopamine D2 receptors. Cinnarizine is a calcium channel blocker with D2 receptor blocking properties which is widely used in treatment of vertiginous disorders. The present study aimed to see whether cinnarizine would worsen the effect of haloperidol on memory function and on oxidative stress in mice brain. Cinnarizine (5, 10 or 20 mg/kg), haloperidol, or haloperidol combined with cinnarizine was administered daily via the subcutaneous route and mice were examined on weekly basis for their ability to locate a submerged plate in the water maze test. Mice were euthanized 30 days after starting drug injection. Malondialdehyde (MDA), reduced glutathione (GSH) and nitric oxide (nitrite/nitrate) were determined in brain. Haloperidol substantially impaired water maze performance. The mean time taken to find the escape platform (latency) was significantly delayed by haloperidol (2 mg/kg, i.p.) on weeks 1-8 of the test, compared with saline control group. In contrast, those treated with haloperidol and cinnarizine showed significantly shorter latencies, which indicated that learning had occurred immediately. Haloperidol resulted in increased MDA in cortex, striatum, cerebellum and midbrain. GSH decreased in cortex, striatum and cerebellum and nitric oxide increased in cortex. Meanwhile, treatment with cinnarizine (20 mg/kg) and haloperidol resulted in significant decrease in MDA cortex, striatum, cerebellum and midbrain and an increase in GSH in cortex and striatum, compared with haloperidol group. These data suggest that cinnarizine improves the haloperidol induced brain oxidative stress and impairment of learning and memory in the water maze test in mice.

Reinforcing properties of Pramipexole in normal and parkinsonian rats

Striatal D2 and D3 dopamine receptors are involved in mediating the reinforcing properties of natural rewards and drugs. In Parkinson's disease, while D2/3 dopamine agonists alleviate motor symptoms, behavioral addictions and withdrawal syndrome are reported in up to 15% of patients. The origin of such adverse effects is poorly understood but suggests that D2/3 agonists could possess reinforcing properties. We evaluated the reinforcing properties of the widely used D2/3 agonist, Pramipexole (PPX), in normal and parkinsonian rats. Intracerebroventricular injections of 6-OHDA induced a bilateral loss of tyrosine hydroxylase-positive cells in the substantia nigra (−51%) and ventral tegmental area (−31%). The animals were then allowed to self-administer intravenous PPX under fixed ratio and progressive ratio (PR) reinforcement schedules before being tested for extinction of PPX seeking. While parkinsonian were slower than sham rats in acquiring self-administration behavior, they later reached the same level of intake. The reinforcing value of PPX, as assessed during PR and extinction, was moderate in both groups. PPX heightened ∆FosB expression in dorsal striatum of lesioned rats and similar PR results involved different striatal subregions between groups. Altogether, our results show that drug-naïve rats self-administer PPX and that the dopaminergic lesion does not affect its reinforcing effects. While PPX reinforcing value was moderate in most rats, a subset of animals displayed a high number of responses and appeared to be particularly sensitive to this drug. These data suggest that PPX may not be responsible for the reported side-effects but rather call for further investigating the differential vulnerability among individuals.

Aggression is suppressed by acute stress but induced by chronic stress: Immobilization effects on aggression, hormones, and cortical 5-HT1B/ striatal dopamine D2 receptor density

Although it has been established by a number of investigators that a variety of stressors are associated with the induction of aggressive behavior, two specific issues remain unanswered. First, it is unclear whether the contexts surrounding stressors (e.g., stressor length and chance of winning over opponents) change outcomes regarding aggressive behavior. Second, if a relationship exists between stress and aggressive behavior, altered levels of stress-related hormone (e.g., corticosterone [CORT]), as well as aggression-related biomarkers (e.g., testosterone [T], density of prefronto-cortical 5-HT(1B) receptor and striatal dopamine D(2) receptor [D2r]) may contribute to changes in aggressive behavior. Thus, we examined how immobilization (with a 1-, 5-, or 10-day exposure) would impact (1) a longitudinal course of aggression toward different-sized opponents, (2) levels of CORT and T, and (3) densities of 5-HT(1B) receptor (5-HT1Br) in the prefrontal cortex (PFC) and D2r in the striatum. It was found that, regardless of small or large opponents, a single 2-h exposure to immobilization reduced aggressive behavior (stress-suppressed aggression) over time, whereas repeated (10-day) exposure to immobilization escalated aggressive behavior (stress-induced aggression). These stress effects persisted up to 1 week of recovery from immobilization stress. Moreover, immobilized rats demonstrated elevated levels of T, but not CORT, as compared with controls. Finally, acute immobilization altered D2r densities in the shell of the nucleus accumbens, and chronic immobilization changed 5-HT1Br in the PFC, including the downregulation of 5-HT1Br densities in the right prelimbic and orbitolateral cortices. The potential relationships among stress, aggression, and 5-HT1Br/D2r roles are discussed.

No involvement of the adenosine A2A receptor in tardive dyskinesia in Russian psychiatric inpatients from Siberia

The adenosine A2A receptor forms a heteromeric complex with the striatal dopamine D2 receptor. We examined whether a specific polymorphism in adenosine A2A receptor (2592 C/Tins) is associated with tardive dyskinesia. Tardive dyskinesia was assessed cross-sectionally in 146 Caucasian psychiatric inpatients from Siberia. Between-group comparisons of genotypic or allelic frequencies showed no statistically significant difference. Logistic regression analysis with the occurrence of tardive dyskinesia as dependent variable showed no significant association with age, duration of illness, gender, and genotype. The interaction between the A2A and D2 receptors seems not involved in the development of tardive dyskinesia.

Psychopathology: genetics and the stress-vulnerability hypothesis

Since the findings of dopamine blockade by antipsychotics, a dysfunction of the dopamine system has been proposed to underly psychopathological symptoms in schizophrenia. In SPECT and PET imaging studies, radioligand binding to the dopamine receptor or transporter reflects the occupancy by dopamine itself or antipsychotics. Using dual-isotope imaging for the evaluation of pre- and postsynaptic site, Schmitt et al. [1] examined striatal dopamine transporter and dopamine D2 receptor availability in first-episode schizophrenia patients and patients with haloperidol treatment compared to healthy controls. In drug-naive patients with positive symptoms, dopamine transporter availability correlated negatively with psychopathology as did D2 receptor binding with disorganization and hallucinatory behavior, thus strengthening the dopamine hypothesis for positive symptoms. D2 receptor and dopamine transporter availability was lower in the haloperidol group which confirms previous dopamine blockade studies. However, response to antipsychotics is individual, and genetic factors may contribute to a different outcome. Mossner et al. [2] reported that patients homozygous for the risk allele ZNF804A show poorer improvement of positive symptoms compared to patients with a protective allele. Thus, identification of risk genes may help identifying patients with a different course of the disorder. A pharmacogenetic study of Crisafulli et al. [3] investigated 10 SNPs of genes related to pathophysiological pathways in Korean patients. They found a SNP within 5HTR1A associated with clinical improvement in both positive and negative symptoms. In schizophrenia patients, improvement of quality of life as treatment outcome among others is dependent on support in case of problems and assistance in coping with daily life demands. Landolt et al. [4] revealed that unmet needs changing to fulfilled ones enhanced quality of life. In this context, psychosocial functioning and psychotic symptoms may be influenced by alterations of theory of mind and empathy as underlying social-cognitive deficits and possibly are heritable. In first-degree relatives of schizophrenia patients, Montag et al. [5] showed impairment in cognitive skills, suggesting that social-cognitive abilities may serve as an intermediate phenotype for schizophrenia. In a re-analysis of AMDP data by nonmetric multidimensional scaling, Lage et al. [6] replicated clusters of psychopathological symptoms in two independent samples dating from 1980 and 2003. In individual’s health, the psychological well-being dimension and depressive symptoms are important variables and Morelatto de Souza and Paz Loayza Hidalgo [7] validated the WHO well-being index in a Brazilian population and showed this scale to be a useful tool for screening of depressive symptoms. Hagihara and Abe [8] highlight the influence of media reports on suicide and counteracting effects of stopping the sale of suicide-related products in Japan. Beside genetics, stressful experience and trauma are risk factors for the development of psychiatric diseases. Linden et al. [9] analyzed 100 case files of German servicemen during World War I and classified them in agreement with modern diagnoses. Most ancient diagnoses were “psychopathic constitution” or “hysteria.” Using contemporary diagnostics, some of these soldiers had symptoms of post-traumatic stress disorder. There was a high incidence of pseudoseizures that highlights different human responses to traumatic experience and stress in a historical context. Stressful experiences are known to increase vulnerability to schizophrenia. Rossi et al. [10] evaluated the Community Assessment of Psychic Experiences (CAPE) in students who survived an earthquake 2009 in Italy. Unexpectedly, earth quake survivors showed lower CAPE scores than nonexposed subjects. This is in line with the hypothesis that stressful events preceding psychosis are not derived from external traumatic experiences. In a previous study, Puustinen et al. [11] reported C-reactive protein, marker of cardiovascular disease, to be associated with psychological distress. However, in a cross-sectional and 3-year follow-up study in Japanese male workers, Kawada [12] failed to show this relationship, which is probably due to ethnicity. Life experience, stressful events and other environmental factors are known to influence the risk of developing mental diseases. The missing link between environment and neurobiology may be explained by epigenetic mechanisms, such as DNA methylation and acetylation in disease-related brain regions. Wiers [13] refers to an fMRI study of the COMT gene with the Val allele being associated with DNA methylation [14]. She proposes the use of genetic imaging in combination with investigations of epigenetic markers in blood cells to unravel gene-environmental interactions in severe psychiatric disorders.

Alteration of Striatal Dopaminergic Neurotransmission in a Mouse Model of DYT11 Myoclonus-Dystonia

BackgroundDYT11 myoclonus-dystonia (M-D) syndrome is a neurological movement disorder characterized by myoclonic jerks and dystonic postures or movement that can be alleviated by alcohol. It is caused by mutations in SGCE encoding ε-sarcoglycan (ε-SG); the mouse homolog of this gene is Sgce. Paternally-inherited Sgce heterozygous knockout (Sgce KO) mice exhibit myoclonus, motor impairment and anxiety- and depression-like behaviors, modeling several clinical symptoms observed in DYT11 M-D patients. The behavioral deficits are accompanied by abnormally high levels of dopamine and its metabolites in the striatum of Sgce KO mice. Neuroimaging studies of DYT11 M-D patients show reduced dopamine D2 receptor (D2R) availability, although the possibility of increased endogenous dopamine, and consequently, competitive D2R occupancy cannot be ruled out.Methodology/Principal FindingsThe protein levels of striatal D2R, dopamine transporter (DAT), and dopamine D1 receptor (D1R) in Sgce KO mice were analyzed by Western blot. The striatal dopamine release after amphetamine injection in Sgce KO mice were analyzed by microdialysis in vivo. The striatal D2R was significantly decreased in Sgce KO mice without altering DAT and D1R. Sgce KO mice also exhibited a significant increase of dopamine release after amphetamine injection in comparison to wild-type (WT) littermates.Conclusion/SignificanceThe results suggest ε-SG may have a role in the regulation of D2R expression. The loss of ε-SG results in decreased striatal D2R, and subsequently leads to increased discharge of dopamine which could contribute to the behavioral impairment observed in DYT11 dystonia patients and in Sgce KO mice. The results suggest that reduction of striatal D2R and enhanced striatal dopamine release may contribute to the pathophysiology of DYT11 M-D patients.

Schizotypy trait and striatal dopamine receptors in healthy volunteers

Individuals with schizotypal features exhibit cognitive, perceptual and social deficits that are similar to but less prominent than those seen in patients with schizophrenia. Dopaminergic hyperactivity in the striatum has been related to the positive symptoms of schizophrenia, and brain-imaging studies of dopamine uptake in the striatum are thought to be linked to the pathophysiological mechanisms underlying schizophrenia. The aim of this study was to investigate whether the increased availability of striatal dopamine (DA) D2/3 receptors is related to elevated levels of schizotypal features in healthy individuals. The Schizotypal Personality Questionnaire (SPQ) was administered to 55 healthy volunteers. The availability of their striatal DA D2/3 receptors was analysed using [123I] iodobenzamide single photon emission computed tomography (SPECT). Although the SPQ total scores showed no correlation with the availability of total (left and right) striatal DA D2 receptors, the SPQ disorganised subscale scores were positively correlated with the availability of right striatal DA D2/3 receptors. Our findings demonstrated that the availability of striatal DA D2/3 receptors may be associated with schizotypal features in healthy volunteers.

Repeat variation in the human PER2 gene as a new genetic marker associated with cocaine addiction and brain dopamine D2 receptor availability.

Low dopamine D2 receptor (D2R) levels in the striatum are consistently reported in cocaine abusers; inter-individual variations in the degree of the decrease suggest a modulating effect of genetic makeup on vulnerability to addiction. The PER2 (Period 2) gene belongs to the clock genes family of circadian regulators; circadian oscillations of PER2 expression in the striatum was modulated by dopamine through D2Rs. Aberrant periodicity of PER2 contributes to the incidence and severity of various brain disorders, including drug addiction. Here we report a newly identified variable number tandem repeat (VNTR) polymorphism in the human PER2 gene (VNTR in the third intron). We found significant differences in the VNTR alleles prevalence across ethnic groups so that the major allele (4 repeats (4R)) is over-represented in non-African population (4R homozygosity is 88%), but not in African Americans (homozygosity 51%). We also detected a biased PER2 genotype distribution among healthy controls and cocaine-addicted individuals. In African Americans, the proportion of 4R/three repeat (3R) carriers in healthy controls is much lower than that in cocaine abusers (23% vs 39%, P=0.004), whereas among non-Africans most 3R/4R heterozygotes are healthy controls (10.5% vs 2.5%, P=0.04). Analysis of striatal D2R availability measured with positron emission tomography and [11C]raclopride revealed higher levels of D2R in carriers of 4R/4R genotype (P<0.01). Taken together, these results provide preliminary evidence for the role of the PER2 gene in regulating striatal D2R availability in the human brain and in vulnerability for cocaine addiction.

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.