Striatal Dopamine D2 Receptor Density Research Articles

Lack of dopamine supersensitivity in rats after chronic administration of blonanserin: Comparison with haloperidol

Long-term treatment with antipsychotic drugs in patients with schizophrenia can lead to dopamine supersensitivity psychosis. It is reported that repeated administration of haloperidol caused dopamine supersensitivity in rats. Blonanserin is an atypical antipsychotic drug with high affinity for dopamine D2, D3 and serotonin2A receptors. In this study, we investigated whether chronic administration of blonanserin leads to dopamine supersensitivity. Following oral treatment with blonanserin (0.78 mg/kg) or haloperidol (1.1 mg/kg) twice daily for 28 days, the dopamine D2 agonist quinpirole-induced hyperlocomotion test and a dopamine D2 receptor binding assay were conducted. We found that haloperidol significantly enhanced both quinpirole-induced hyperlocomotion and striatal dopamine D2 receptor density in rats. On the other hand, repeated administration of blonanserin had no effect on either locomotor activity or striatal dopamine D2 receptor density. Further, our results show that mRNA levels of dopamine D2 and D3 receptors in several brain regions were unaffected by repeated administration of both agents. In addition, we examined the effect of the dopamine D3 receptor antagonist PG-01037 on development of dopamine supersensitivity induced by chronic haloperidol treatment and showed that PG-01037 prevents the development of supersensitivity to quinpirole in chronic haloperidol-treated rats. Given the higher affinity of blonanserin at dopamine D3 receptors than haloperidol, antagonism of blonanserin at dopamine D3 receptors may play a role in lack of dopamine supersensitivity after chronic administration. The present findings suggest long-term treatment with antipsychotic dose of blonanserin may be unlikely to lead to dopamine supersensitivity.

Adenosine receptors as markers of brain iron deficiency: Implications for Restless Legs Syndrome

Deficits of sensorimotor integration with periodic limb movements during sleep (PLMS) and hyperarousal and sleep disturbances in Restless Legs Syndrome (RLS) constitute two pathophysiologically distinct but interrelated clinical phenomena, which seem to depend mostly on alterations in dopaminergic and glutamatergic neurotransmission, respectively. Brain iron deficiency is considered as a main pathogenetic mechanism in RLS. Rodents with brain iron deficiency represent a valuable pathophysiological model of RLS, although they do not display motor disturbances. Nevertheless, they develop the main neurochemical dopaminergic changes found in RLS, such as decrease in striatal dopamine D2 receptor density. On the other hand, brain iron deficient mice exhibit the characteristic pattern of hyperarousal in RLS, providing a tool to find the link between brain iron deficiency and sleep disturbances in RLS. The present study provides evidence for a role of the endogenous sleep-promoting factor adenosine. Three different experimental preparations, long-term (22 weeks) severe or moderate iron-deficient (ID) diets (3- or 7-ppm iron diet) in mice and short-term (3 weeks) severe ID diet (3-ppm iron diet) in rats, demonstrated a significant downregulation (Western blotting in mouse and radioligand binding saturation experiments in rat brain tissue) of adenosine A1 receptors (A1R) in the cortex and striatum, concomitant to striatal D2R downregulation. On the other hand, the previously reported upregulation of adenosine A2A receptors (A2AR) was only observed with severe ID in both mice and rats. The results suggest a key role for A1R downregulation in the PLMS and hyperarousal in RLS.

Dopamine, depressive symptoms, and decision-making: the relationship between spontaneous eye blink rate and depressive symptoms predicts Iowa Gambling Task performance

Depressive symptomatology has been associated with alterations in decision-making, although conclusions have been mixed, with depressed individuals showing impairments in some contexts but advantages in others. The dopaminergic system may link depressive symptoms with decision-making performance. We assessed the role of striatal dopamine D2 receptor density, using spontaneous eye blink rates, in moderating the relationship between depressive symptoms and decision-making performance in a large undergraduate sample that had not been screened for mental illness (N = 104). The regression results revealed that eye blink rate moderated the relationship between depressive symptoms and advantageous decisions on the Iowa Gambling Task, in which individuals with more depressive symptomatology and high blink rates (higher striatal dopamine D2 receptor density) performed better on the task. Our computational modeling results demonstrated that depressive symptoms alone were associated with enhanced loss-aversive behavior, whereas individuals with high blink rates and elevated depressive symptoms tended to persevere in selecting options that led to net gains (avoiding options with net losses). These findings suggest that variation in striatal dopamine D2 receptor availability in individuals with depressive symptoms may contribute to differences in decision-making behavior.

Dopaminergic gene–stress interactions on young adults’ driving performance: A pilot study

Driving requires the integration of executive functions involving brain dopaminergic pathways. The A1 allele of the DRD2/ANKK1 gene (rs1800497) is associated with decreased striatal D2 dopamine receptor density and with executive function deficits. Stress affects brain dopamine activity and moderates effects of dopaminergic genes on executive function. This pilot study experimentally manipulated acute psychosocial stress between groups to investigate the interaction between A1 allelic status and induced stress on driving simulator performance in 71 young drivers. ANOVAs showed significant interactions between A1 status and stress condition on highway driving speeds and speed variability, with A1+ drivers driving at lower speeds and with less variability under stress than under rest. In contrast, A1− drivers showed no differences between stress conditions. Results of cortisol analysis further suggest that the A1 allele confers greater sensitivity to acute psychosocial stress, which may affect driving performance via effects on dopaminergic circuits.

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.

On the molecular genetics of flexibility: The case of task-switching, inhibitory control and genetic variants

The adjustment of behavior to changing goals and environmental constraints requires the flexible switching between different task sets. Cognitive flexibility is an endophenotype of executive functioning and is highly heritable, as indicated by twin studies. Individual differences in global flexibility as assessed by reaction-time measurement in a task-switching paradigm were recently related to a single nucleotide polymorphism in the vicinity of the dopamine d2 receptor gene DRD2. In the present study, we assessed whether the DRD2 gene is related to backward inhibition, a control mechanism that contributes to cognitive flexibility by reducing proactive interference by no longer relevant task sets. We found that carriers of the DRD2 A1+ variant who have a lower striatal dopamine d2 receptor density than A1- carriers show a larger backward inhibition effect. This is in line with previous results demonstrating increased behavioral flexibility in carriers of this genetic variant. The discussion relates the present finding to those of previous studies assessing the neurogenetic foundations of inhibitory control.

Striatal dopamine function in a family with multiple SCA-3 phenotypes

We present single photon emission computed tomography (SPECT) studies using 123IFP-CIT (DAT scan) and 123I-IBZM imaging, performed on four members of a family with genetically proven spinocerebellar ataxia type 3 (SCA-3). DAT scan showed significant asymmetric decreased binding in the striatum in the two members with predominant parkinsonian phenotype, with mild and symmetric decreased binding in the member with the cerebellar phenotype, and normal in the asymptomatic member. The IBZM SPECT studies showed mild and asymmetrical reduction of the striatal dopamine D2 receptor density (parkinsonian members). SCA-3 can present with a levodopa responsive parkinsonism phenotype, and an abnormal DAT scan showing predominant impairment of presynaptic dopamine function.

The orphan GPCR, GPR88, modulates function of the striatal dopamine system: A possible therapeutic target for psychiatric disorders?

In rodents, the orphan G protein-coupled receptor, Gpr88, is highly expressed in brain regions implicated in the pathophysiology of and is modulated by treatments for schizophrenia. We compared striatal function of Gpr88 knockout mice (Gpr88KOs) to wild-type mice using molecular, neurochemical and behavioral tests. Gpr88KOs lacked expression of Gpr88 in striatum, nucleus accumbens and layer IV of cortex. Gpr88KOs had normal striatal dopamine D2 receptor density and affinity and DARPP-32 expression but Gpr88KOs had higher basal striatal phosphorylated DARPP-32 Thr-34. In vivo microdialysis detected lower basal dopamine in Gpr88KOs while amphetamine-induced dopamine release was normal. Behaviorally, Gpr88KOs demonstrated disrupted prepulse inhibition of startle (PPI) and increased sensitivity to apomorphine-induced climbing and stereotypy (AICS) and amphetamine-stimulated locomotor activity. Antipsychotic administration to Gpr88KOs normalized the PPI deficit and blocked AICS. The modulatory role of Gpr88 in striatal dopamine function suggests it may be a new target for treatments for psychiatric disorders.

Relation of obesity to consummatory and anticipatory food reward

This report reviews findings from studies that have investigated whether abnormalities in reward from food intake and anticipated food intake increase risk for obesity. Self-report and behavioral data suggest that obese relative to lean individuals show elevated anticipatory and consummatory food reward. Brain imaging studies suggest that obese relative to lean individuals show greater activation of the gustatory cortex (insula/frontal operculum) and oral somatosensory regions (parietal operculum and Rolandic operculum) in response to anticipated intake and consumption of palatable foods. Yet, data also suggest that obese relative to lean individuals show less activation in the dorsal striatum in response to consumption of palatable foods and reduced striatal D2 dopamine receptor density. Emerging prospective data also suggest that abnormal activation in these brain regions increases risk for future weight gain and that genotypes associated with lowered dopamine signaling amplify these predictive effects. Results imply that individuals who show greater activation in the gustatory cortex and somatosensory regions in response to anticipation and consumption of food, but who show weaker activation in the striatum during food intake, may be at risk for overeating, particularly those at genetic risk for lowered dopamine receptor signaling.

Transcription factor AP-2beta genotype, striatal dopamine D2 receptor density and cerebrospinal fluid monoamine metabolite concentrations in humans.

Transcription factor AP-2beta has been suggested to influence brain monoaminergic systems by regulating target genes. In order to explore a possible functional role, AP-2beta genotype was analysed in relation to striatal dopamine D2 receptor density determined in vivo by positron emission tomography in human subjects (n = 52). The AP-2beta genotype was also analysed in relation to cerebrospinal fluid (CSF) concentrations of homovanillic acid (HVA), 3-methoxy-4-hydroxy-phenylglycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA) in healthy human subjects (n = 90). There was no association between the AP-2beta genotype and measures of dopamine receptor density, or CSF 5-HIAA concentrations. However, AP-2beta genotype was associated with CSF-levels of HVA (in women) and MHPG. These data may suggest a functional involvement of AP-2beta in the dopaminergic system, but should be interpreted with caution until replicated.

Carbamazepine reduces dopamine-mediated behavior in chronic neuroleptic-treated and untreated rats: implications for treatment of tardive dyskinesia and hyperdopaminergic states.

Chronic treatment with neuroleptic drugs such as haloperidol (HAL) can result in a syndrome of abnormal involuntary movements known as tardive dyskinesia (TD). The authors have obtained evidence that TD in humans is reduced in patients also taking anticonvulsant drugs, primarily carbamazepine (CBZ). To test for a causal role of CBZ in this effect, the authors quantified abnormal movements elicited by dopamine (DA) receptor stimulation in rats (Rattus norvegius) withdrawn from chronic treatment with HAL or CBZ alone or in combination. The expected increased behavioral responsiveness to combined D1/D2 stimulation in rats treated with HAL for 8 weeks was significantly attenuated by chronic CBZ, which also attenuated behavioral responsiveness in otherwise untreated rats. Striatal D2 DA receptor density was elevated in rats treated chronically with HAL but unaffected by CBZ. Striatal D1 DA receptor density was elevated by chronic CBZ but unaffected by HAL. These findings suggest that by reducing DA supersensitivity, CBZ may be useful in treating TD and other hyperdopaminergic states.

Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers.

The density of striatal dopamine D2 receptors has been shown to vary considerably among healthy subjects. This variability might be due to genetic or environmental factors. In the present analysis we searched for relationships between dopamine D2 receptor gene (DRD2) polymorphisms and striatal dopamine D2 receptor density in vivo, as measured by positron emission tomography and [11C]raclopride in 56 healthy subjects. There was a significant association between presence of a putative functional DRD2 promoter allele (-141C Del) and high striatal dopamine receptor density (t= 2.32, P= 0.02). In agreement with some previous studies the presence of the DRD2 TaqIA1 allele was associated with measures of low dopamine receptor density (t=2.58, P=0.01). Also the DRD2 TaqIB1 allele was associated with low dopamine receptor density (t= 2.58, P= 0.01) wheras there was no significant relationship between another common silent intronic DRD2 short tandem repeat polymorphism (STRP) and striatal dopamine D2 receptor density. The results suggest that DRD2 genotypes may participate differentially in the regulation of striatal dopamine D2 receptor density in healthy human subjects. The results should be interpreted with caution because of the limited sample size.

Anhedonia in Schizophrenic, Depressed, or Alcohol-Dependent Patients - Neurobiological Correlates

Anhedonia, dysphoria, and avolition are common symptoms of schizophrenic, depressive, and alcohol-dependent patients during withdrawal. These symptoms may be caused by a functional deficit of dopaminergic transmission in the dopaminergic reward system, ascending from the mesencephalon to the ventral striatum (nucleus accumbens). The dopaminergic reward system is functionally and anatomically closely connected with the ascending extrapyramidal pathways from the substantia nigra to the dorsal striatum. A dysfunction of both ascending dopaminergic pathways is therefore expected to cause both psychomotor slowing and dysphoria and anhedonia. This hypothesis is supported by PET and SPECT findings, which show that a reduced striatal density of unoccupied dopamine D2-receptors is correlated with extrapyramidal side-effects in neuroleptic-treated schizophrenics and with craving and dysphoria in drug-dependent patients. In order to further investigate the correlation of anhedonia, psychomotor slowing, and the status of the dopaminergic reward system, the density of striatal dopamine D2-receptors can be measured by IBZM-SPECT and related to psychomotor slowing and anhedonia in different states of schizophrenic, depressive, and alcohol-dependent patients.

11C]raclopride and positron emission tomography in previously untreated patients with Parkinson's disease: Influence of L-dopa and lisuride therapy on striatal dopamine D2-receptors.

We studied cerebral dopamine D2-receptor binding using [11C]raclopride and PET in 18 previously untreated patients with Parkinson's disease (PD) and 14 healthy volunteer subjects. Sixteen patients were scanned before and after 3 to 4 months of stable oral therapy with either L-dopa (300 mg/d) (n = 7) or lisuride (0.8 to 1.2 mg/d) (n = 9). Two additional patients were investigated before and after a continuous IV infusion of L-dopa. In addition, we studied the effect of acute IV L-dopa and lisuride administration on [11C]raclopride binding in a healthy rhesus monkey. At baseline, PD patients showed higher uptake values in the putamen than did healthy subjects (p < 0.0001). Oral lisuride treatment lowered [11C]raclopride uptake in the putamen (-19%) and in the caudate nucleus (-15%) compared with baseline, but the difference did not reach significance upon Bonferroni correction for multiple comparisons. However, putamen tracer uptake returned to baseline in two patients when we repeated [11C]raclopride scans 4 days after lisuride withdrawal. Oral L-dopa treatment did not induce changes in the putamen or caudate nucleus indices. Acute lisuride (25 micrograms) administration in a healthy monkey reduced striatal uptake values, but acute injection of L-dopa (300 mg) did not. The results suggest that lisuride blocks [11C]raclopride binding at dopamine D2-receptor sites and demonstrate that 3 to 4 months' oral therapy with L-dopa or lisuride does not change striatal dopamine D2-receptor density in PD patients.

Striatal D2 Dopamine Receptor Characteristics in Neuroleptic-Naive Schizophrenic Patients Studied With Positron Emission Tomography

According to the D2 dopamine receptor hypothesis of schizophrenia, there is an increased number of D2 receptors in the brains of schizophrenic patients than in those of healthy controls. We tested this hypothesis in 13 newly admitted neuroleptic-naive schizophrenic patients and 10 healthy volunteers using positron emission tomography. The quantification of striatal D2 dopamine receptor density (Bmax) and affinity (Kd) was done using an equilibrium model described for raclopride labeled with carbon 11. No statistically significant alterations were found in D2 receptor densities or affinities between the patient and control groups. However, a subgroup of four patients with a relatively high striatal D2 dopamine density was identified. Two patients, especially, had D2 dopamine densities almost twice as high as the mean control Bmax value. The Kd values also tended to be higher in this subset of patients than in the controls. No consistent striatal D2 dopamine receptor laterality was observed in schizophrenic patients or controls. However, an association of high D2 dopamine density in the left striatum and the mass of raclopride injected in the scan with low-specific radioactivity was observed in patients but not in controls. There are no general changes in D2 dopamine receptor Bmax or Kd values in neuroleptic-naive schizophrenics, but there may be a subgroup of patients with aberrant striatal D2 dopamine receptor characteristics in vivo.

Differentialdiagnose der Parkinson-Erkrankungen -123I-IBZM-SPECT vs. Apomorphin-Test

The aim of our study was to compare the striatal dopamine D2-receptor density as measured by 123I-IBZM-SPECT with the results of the apomorphine-test. 30 patients were studied; 21 with idiopathic Parkinson's disease (IPD), 9 with Parkinson plus syndromes (PPS). Patients with IPD showed a significantly higher striatal IBZM binding as compared to patients with PPS (p = 0.006). A good correlation between IBZM binding and outcome of the apomorphine-test was found (p = 0.006). Low striatal IBZM binding indicates reduced dopamine D2-receptor density. This compromises successful dopaminergic medical therapy and is indicative of non-IPD disease. 123I-IBZM-SPECT could be diagnostic aid in the work-up of patients with extrapyramidal movement disorders. The response to dopaminergic drug treatment might be precluded by IBZM-SPECT in patients with Parkinsonian syndromes.

SPECT imaging of D2 receptors in depression

The basal ganglia have received increasing attention with regard to their role in time pacing, motor function and other components of cognition. The aim of this study was to test whether the finer the motor activity and/or time perception performance were, the higher the striatal dopamine D2 binding would be. Single photon emission computed tomography (SPECT) with [123I]iodobenzamide (IBZM) was performed to measure striatal D2 receptor densities. A battery of neuropsychological tests, including the Wisconsin Card Sorting Test (WCST), the finger tapping test (FTT), and an attention test, was performed by patients with schizophrenia. Results indicated a strong correlation between the FTT score and striatal D2 receptor binding. Neuroleptic dosage plays an important role in the relationship between cognitive tasks and striatal dopamine receptor densities. In addition, the striatal D2 receptor density is more significantly correlated with attentional tests that consider the time effect than those that do not. Among the three tests performed, the WCST was least significantly correlated with striatal D2 receptor densities. A decrease in striatal dopamine D2 receptor density seems to be associated with impaired performance on optimal timing tasks and motor processing in patients with schizophrenia.

Bidirectional changes in striatal D2-dopamine receptor density during chronic ethanol intake

Results of previous studies on the effects of ethanol consumption for a single fixed period on the properties of D2 dopamine receptors appear contradictory and inconclusive. In this study, we have examined the time course of the effects of dietary ethanol on the properties of striatal D2 dopamine receptor. Ethanol intake led to a significant decrease in the maximum number (B max) after 1 (35% of control) and 2 weeks (48% of control), but not after 3 (93% of control) or 4 weeks (97% of control) of treatment. However, there was a significant increase in B max after 6 (118% of control) and 10 weeks (123% of control) of ethanol consumption. The affinity (K d) of the receptor, however, remained unaltered in all cases. In conclusion, these data show that the duration of ethanol exposure may be an important determinant regulating D2-dopamine receptor density.

Neurochemical Basis for the Absence of Overt “Stereotyped” Behaviors in Rats With Up-Regulated Striatal D2 Dopamine Receptors

Because of substantial evidence for the hyperdopaminergic hypothesis of tardive dyskinesia (TD), animal models, especially rats, treated chronically with neuroleptics continue to be used to study this disorder. The rat model has been criticized because, unlike TD, in rats there is an apparent lack of spontaneous abnormal movements even when striatal D2 dopamine receptor (DAr) density is substantially increased. Our data suggest a mechanism by which rats suppress these abnormal movements normally associated with elevated DAr levels. We correlated neurochemical with behavioral changes using several animal models, including nonneuroleptic ones, which elicit varied levels of DAr upregulation. There was (as expected) a robust, significant, positive correlation between striatal DAr density and apomorphine-induced stereotypic behaviors. In contrast, there was a significant negative correlation between increased DAr density and synthesis capacity for striatal DA (Vmax for tyrosine hydroxylase). We conclude that this decrease in Vmax is a compensatory adjustment of the nigrostriatal DA tract for the increased DAr density induced in our animal models. Our data further suggest the generalization that an observed increase in receptor density doesn't necessarily predict a functional change (spontaneous behavior, neuropathology) because compensatory neural mechanisms exist. In TD these compensatory neural mechanisms may fail, leading to spontaneous behaviors.

Striatal D2 dopaminergic receptors assessed with positron emission tomography and [76Br]bromospiperone in untreated schizophrenic patients

Striatal D2 dopaminergic receptors of 12 drug-free schizophrenic patients and 12 normal subjects were investigated with positron emission tomography and [76Br]bromospiperone. Patients were classified according to DSM-III criteria, and their clinical symptoms were rated according to Andreasen's negative and positive symptom scales. The ratio of striatal to cerebellar radioactivity was taken as an index of striatal D2 dopamine receptor density. There was no significant difference between the control subjects and the overall schizophrenic group and no significant relationship between this index and the symptom ratings. However, state-dependent variables could partly account for the striatal D2 receptor density variability.