Correlation between striatal dopamine D2 receptor density and neuroticism in community volunteers

The central dopaminergic system, as well as the central serotonergic system, has been reported to be correlated with higher neuroticism. The present study examined the relationship between striatal dopamine D(2) receptor density and neuroticism. Neuroticism was assessed with the Maudsley Personality Inventory, and psychiatric morbidity was evaluated with both the Mini International Neuropsychiatric Interview and the Hamilton Depression Rating Scale (HAM-D). Single photon emission computed tomography with [(123)I]iodo-benzamide was used to measure striatal dopamine D(2) receptor density. HAM-D scores and psychiatric morbidity in high-neuroticism individuals were higher than in low-neuroticism individuals. Moreover, striatal dopamine D(2) receptor densities were significantly correlated with the neuroticism score of the 41 subjects. The central dopaminergic system may play an important role in the neurobiological characteristics of neuroticism.     

Correlation between fine motor activity and striatal dopamine D2 receptor density in patients with schizophrenia and healthy controls

Striatal dopamine D2 receptor density is an important indicator of many neuropsychiatric disorders and also of motor activity. This study examined the relationship between a fine motor task (finger tapping test, FTT) and striatal D2 dopamine receptor density by examining 20 healthy volunteers and 20 schizophrenic patients. Striatal D2 receptor density was determined with single photon emission computed tomography using [123I]IBZM (iodo-benzamide). The correlation between the FTT score and striatal D2 receptor density was statistically significant not only in the patient group but also in healthy controls. The FTT scores and striatal D2 receptor density were lower in medicated patients than that in healthy controls. Compared with the Simpson-Angus Scale scores, the FTT scores were more strongly associated with striatal D2 receptor density. The use of neuroleptic medication seemed to influence the associations between FTT scores and striatal D2 receptor density in the patient group. The FTT scores and striatal D2 receptor density were age-sensitive in healthy controls. FTT may be a more sensitive tool for detecting neuroleptic-induced motor impairment in patients with schizophrenia. The sensitivity of the FTT to age and neuroleptic effects may be explained in part by a decline in dopamine D2 density.     

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) D(2/3) 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 D(2/3) receptors was analysed using [(123)I] 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 D(2) receptors, the SPQ disorganised subscale scores were positively correlated with the availability of right striatal DA D(2/3) receptors. Our findings demonstrated that the availability of striatal DA D(2/3) receptors may be associated with schizotypal features in healthy volunteers.     

Polymorphisms in the dopamine D4 receptor gene and attention-deficit hyperactivity disorder

There is considerable evidence to support a role of dopamine-related genes in the molecular aetiology of attention-deficit hyperactivity disorder (ADHD). A 48 bp repeat in exon three of the dopamine D4 receptor gene has been widely studied in clinical ADHD samples, and a meta-analysis of published studies suggests it is associated with ADHD. A number of other polymorphisms across this gene have been characterised but not so thoroughly investigated in relation to ADHD. In this study we have genotyped five polymorphisms (a 120 bp promoter-region duplication, the -616 C/G substitution, the -521 C/T substitution, a poly-G repeat in intron 1, and the 48 bp exon 3 repeat) across the gene in a large clinical sample (n = 188) and their families. We found that none of the markers is individually associated with ADHD, although there is evidence to suggest that a haplotype of markers in the 5' promoter region of the gene (allele 2 of the 120 bp duplication, the C allele of the -616 substitution, and the C allele of the -521 substitution) may confer susceptibility.     

Test-retest variability and reliability of 123I-IBZM SPECT measurement of striatal dopamine D2 receptor availability in healthy volunteers and influence of iterative reconstruction algorithms

OBJECTIVE: 123I-IBZM single photon emission computed tomography (SPECT) is a widely used method to measure D(2) receptor availability. However, test-retest variability and reliability have not been reported yet. This study aimed to further characterize 123I-IBZM SPECT in healthy volunteers (HVs), by assessing (1) pseudoequilibrium interval after bolus injection; (2) normal specific uptake ratio (SUR) values using filtered-backprojection (FBP); and the iterative reconstruction algorithm ordered-subsets expectation maximization (OSEM); (3) test-retest variability and reliability (intraclass correlation coefficient); and (4) influence of OSEM on test-retest variability and reliability. METHODS: Ten HVs (Group A) were scanned twice 48 h apart for test-retest variability and reliability measurements, and n = 4 of them were sequentially scanned over time. Eighteen HVs (Group B) were scanned once at pseudoequilibrium. For reconstruction FBP was used. Test-retest scans were reconstructed in addition using OSEM. SPECT-MRI coregistration was used for region of interest drawing. RESULTS: Pseudoequilibrium was achieved at 90 min postinjection (p.i.) and maintained until the end of the SPECT session (n = 4), and mean SUR at this time point was 0.96 +/- 0.14 (Groups A + B, n = 28). Mean SUR at test was 0.96 +/- 0.19 and at retest 0.94 +/- 0.19 (Group A, n = 10). Using FBP, test-retest variability was (12.7 +/- 9.6)% and reliability was 0.74. Using OSEM with 18 equivalent iterations, test-retest variability and reliability were improved to (6.5 +/- 5.2)% and 0.84, respectively. CONCLUSIONS: 123I-IBZM SPECT imaging using the bolus injection and a single scan at 90 min p.i. is a reproducible method showing acceptable test-retest variability and reliability. Test-retest variability and reliability can be substantially improved using OSEM with 12-36 equivalent iterations.     

Decreased striatal D2 dopamine receptor mRNA synthesis during aging

Decreases in striatal dopamine receptors during aging are related to deficits in motor functions, and are highly correlated with the D₂ receptor subtype. Some receptor loss is attributed to cell death, while the remainder is thought to be related to synthetic capacity. We discuss here our findings, for isolated rat striatal nuclei, which indicate a 50% overall decrease in the synthesis of the dopamine D₂ mRNA in aged nuclei.     

Investigation of striatal dopamine D2 receptor acquisition following prenatal neuroleptic exposure.

To test the hypothesis that neuroleptic blockade impairs the development of striatal dopamine D2 receptors, pregnant rats were given haloperidol, thiothixene, or trifluoperazine for gestational days 15-18 (short-term exposure) or days 5-20 (long-term exposure). All of the drugs were demonstrated to cross the placenta and enter the fetal brains equally well. Striatal dopamine D2 receptors of the pups were assayed on postnatal day 14. Neither receptor density nor receptor affinity was altered significantly by the short- or long-term prenatal neuroleptic treatment.     

Dopamine supersensitivity and D1/D2 synergism are unrelated to changes in striatal receptor density.

Experiments were conducted to elucidate the relationships among striatal dopamine receptor density, behavioral manifestations of D1/D2 synergism (i.e., the requirement of concomitant stimulation of D1 and D2 receptors for the expression of stereotyped sniffing, licking and gnawing), and behavioral supersensitivity to dopamine agonists. The state of D1/D2 synergism was found to be independent of striatal D1 or D2 receptor density in rats as: (1) increasing striatal D1 and/or D2 receptor density (as confirmed by quantitative receptor autoradiography) by chronic treatment with SCH 23390 (0.5 mg/kg/day for 21 days) and/or haloperidol (0.5 mg/kg/day for 21 days) did not alter the normal pattern of D1/D2 synergism as determined by behavioral responsiveness to agonist stimulation of D1 or D2 receptors, and (2) 5 days of reserpine treatment (1 mg/kg/day), although not significantly changing striatal D1 or D2 receptor density, induced a breakdown in D1/D2 synergism (i.e., behavior was elicited by independent stimulation of D1 or D2 receptors). In addition, the density of striatal D2 binding sites was not indicative of behavioral sensitivity to D2 agonists. Chronic haloperidol treatment increased behavioral sensitivity to the D2 agonist quinpirole by a factor of 2. When tested 96 h after bilateral 6-hydroxy-dopamine injections or after 5 daily reserpine injections, supersensitivity to quinpirole was at least double that following chronic haloperidol, without accompanying increases in striatal D2 density. This enhanced sensitivity to quinpirole was no greater than that observed in neurologically intact rats treated concomitantly with a maximally stimulating dose of SKF 38393. Furthermore, rats with unilateral 6-hydroxydopamine lesions that were treated chronically with eticlopride continued to rotate contralateral to the lesion in response to quinpirole despite having hemispheric symmetry of striatal D2 receptor binding. By contrast, when rats with unilateral 6-hydroxydopamine lesions were given 5 daily reserpine injections, rotation was abolished, having been replaced by intense stereotyped sniffing, indicative of bilateral supersensitivity. The results support the hypothesis that two distinct types of dopamine supersensitivity exist: a modest one associated with increased D2 density, and a more profound one associated with a breakdown in D1/D2 synergism and independent of D2 density.     

Dopamine D4 receptor gene polymorphism and personality traits in healthy volunteers

An association between long alleles of a variable number tandem repeat (VNTR) polymorphism in the dopamine receptor D4 gene and the extraversion related personality traits Excitement and Novelty Seeking has been reported in healthy subjects. In an attempt to replicate the previous findings, 256 healthy Caucasian volunteers were analysed for a potential relationship between the dopamine receptor D4 exon III VNTR polymorphism and Extraversion as assessed by the Revised Neo Personality Inventory (NEO PI-R). The present study did not yield evidence for an association between Extraversion and the dopamine receptor D4 polymorphism. Received: 8 June 1999 / Accepted: 4 April 2000     

Chronic neuroleptic treatment: D2 dopamine receptor supersensitivity and striatal glutamatergic transmission.

We studied the in vitro electrical activity of rat neostriatal neurons following chronic neuroleptic treatment. In haloperidol-treated rats, unlike naive animals, activation of neostriatal D2 dopamine receptors induced a potent presynaptic inhibition of glutamate-mediated excitatory synaptic potentials. Haloperidol treatment did not affect the intrinsic membrane properties of the neostriatal neurons. Pre- and postsynaptic physiological responses to direct and indirect gamma-aminobutyric acid (GABA)-ergic and cholinergic agonists were not affected by chronic haloperidol treatment. These findings suggest that movement disorders induced by chronic neuroleptic treatment may result, at least in part, from a hypersensitivity of presynaptic D2 dopamine receptors regulating the release of glutamate.     

Changes in striatal dopamine D2 receptor binding in pre-clinical Huntington's disease

Background:  Carriers of the Huntington disease (HD) mutation develop a progressive neurodegenerative disorder after a pre-clinical phase. We examined the value of ¹¹C-raclopride PET (RAC) as a biomarker for pre-clinical HD pathophysiology.
Methods:  In a prospective cohort study with clinical and neuropsychological assessment we collected complete RAC data in 18 pre-clinical mutation carriers (HD-PMC) and 11 controls. Follow-up was 2 years. We calculated striatal RAC binding potential (BP) to measure dopamine D2 receptor availability.
Results:  No HD-PMC had overt neuropsychological dysfunction. RAC-BP in putamen was abnormal in up to 44% of HD-PMC. The rate of RAC-BP decline (2.6% per year) was not significantly higher than in controls. Follow-up putaminal BP correlated weakly with predicted distance to onset of clinical HD ( P =  0.034), but the rate of decline did not. Three HD-PMC developed motor abnormalities suspect for HD but did not show an increased rate of decline of putaminal BP.
Conclusions:  Many HD-PMC have striatal abnormalities but we found no clearly increased rate of D2 receptor changes around the onset of clinical HD. A longer follow-up of the present study cohort is needed to establish the value of RAC-BP in assessing the risk of clinical conversion from striatal D2 binding data.     

C957T polymorphism of dopamine D2 receptor gene affects striatal DRD2 in vivo availability by changing the receptor affinity

The C957T polymorphism of the human dopamine D2 receptor gene (DRD2) regulates DRD2 availability in striatum in vivo. Specifically, the T allele predicts high DRD2 availability in healthy volunteers (T/T>T/C>C/C). However, this finding was unexpected as in vitro the T allele is associated with a decrease in DRD2 mRNA stability and synthesis of the receptor through a putative alteration in the receptor mRNA folding. To elucidate further how changes in DRD2 density (B_max) and affinity (K_D) contribute to the differences in DRD2 availability between the C957T genotypes, we studied these parameters separately in a sample of 45 healthy volunteers. The subjects had two PET scans with [¹¹C]raclopride (high and low specific radioactivity scans) for the estimation of B_max and K_D, and were genotyped for the C957T. Moreover, the role of the related and previously studied functional TaqIA polymorphism of ankyrin repeat and kinase domain containing 1 (ANKK1) gene was reassessed for comparative purposes. The results indicate that the C957T increased binding potential by decreasing DRD2 K_D (C/C>C/T>T/T), while B_max was not significantly altered. These preliminary findings indicate that the C957T genotype‐dependent changes in DRD2 availability are driven by alterations in receptor affinity and putatively in striatal dopamine levels. This mechanism seems to differ from that observed previously for the ANKK1 gene TaqIA polymorphism, where the minor allele (A1) affects DRD2 availability predominantly by changing B_max. The hypothesis that the two SNPs may have independent effects on dopamine neurotransmission needs to be further tested. Synapse 63:907–912, 2009. © 2009 Wiley‐Liss, Inc.     

Caffeine increases striatal dopamine D2/D3 receptor availability in the human brain

Caffeine, the most widely consumed psychoactive substance in the world, is used to promote wakefulness and enhance alertness. Like other wake-promoting drugs (stimulants and modafinil), caffeine enhances dopamine (DA) signaling in the brain, which it does predominantly by antagonizing adenosine A_2A receptors (A_2AR). However, it is unclear if caffeine, at the doses consumed by humans, increases DA release or whether it modulates the functions of postsynaptic DA receptors through its interaction with adenosine receptors, which modulate them. We used positron emission tomography and [¹¹C]raclopride (DA D₂/D₃ receptor radioligand sensitive to endogenous DA) to assess if caffeine increased DA release in striatum in 20 healthy controls. Caffeine (300 mg p.o.) significantly increased the availability of D₂/D₃ receptors in putamen and ventral striatum, but not in caudate, when compared with placebo. In addition, caffeine-induced increases in D₂/D₃ receptor availability in the ventral striatum were associated with caffeine-induced increases in alertness. Our findings indicate that in the human brain, caffeine, at doses typically consumed, increases the availability of DA D₂/D₃ receptors, which indicates that caffeine does not increase DA in the striatum for this would have decreased D₂/D₃ receptor availability. Instead, we interpret our findings to reflect an increase in D₂/D₃ receptor levels in striatum with caffeine (or changes in affinity). The association between increases in D₂/D₃ receptor availability in ventral striatum and alertness suggests that caffeine might enhance arousal, in part, by upregulating D₂/D₃ receptors.     

Repeated D1 dopamine receptor agonist administration prevents the development of both D1 and D2 striatal receptor supersensitivity following denervation.

Following 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopamine (DA) pathway, rat caudate-putamen (CPu) neurons are supersensitive to the inhibitory effects of both D1 and D2 dopamine (DA) receptor selective agonists. In addition, both the necessity of D1 receptor stimulation for D2 agonist-induced inhibition and the synergistic inhibitory effects of D1 and D2 agonists are abolished by denervation. The present study attempted to determine the relative roles of D1 and D2 DA receptors in the development of denervation supersensitivity to DA agonists and the "uncoupling" of functional interactions between the receptors following 6-OHDA lesions of the nigrostriatal DA pathway. Beginning on the day after an intraventricular 6-OHDA (or vehicle) injection, groups of rats received daily injections of either the selective D1 receptor agonist SKF 38393 (8.0 mg/kg, s.c.), the D2 agonist quinpirole (0.5 mg/kg, s.c.), or saline for 7 days. On the day following the last agonist injection, rats were anesthetized and prepared for extracellular single cell recording with iontophoretic drug administration. Daily administration of quinpirole selectively prevented the development of D2 receptor supersensitivity, whereas daily administration of SKF 38393 prevented the development of both D1 and D2 receptor supersensitivity. In addition, D1, but not D2, agonist treatment prevented the loss of synergistic inhibitory responses typically produced by 6-OHDA lesions. Behavioral observations revealed similar effects; daily injections of SKF 38393, but not quinpirole, prevented contralateral rotational responses to the mixed D1/D2 agonist apomorphine (1.0 mg/kg, s.c.) in rats with unilateral 6-OHDA lesions of the nigrostriatal pathway. After a 4-week withdrawal from repeated D1 agonist treatment, both supersensitive inhibitory responses of CPu neurons and contralateral rotations to apomorphine were evident, indicating that the preventative effects on DA receptor supersensitivity were not permanent. These findings indicate that continued agonist occupation of striatal D1 DA receptors following DA denervation not only prevents the development of D1 DA receptor supersensitivity but also exerts a similar regulation of D2 receptor sensitivity.     

Role of ventral striatal dopamine D1 receptor in cigarette craving.

BACKGROUND: Several theories of cigarette craving suggest that dopaminergic function in the ventral striatum plays an important role. The objective of this study was to determine correlations between craving-related brain activation and dopamine D1 receptor (D1R) binding in smokers. METHODS: Twelve smokers and 12 nonsmoking controls underwent [(15)O]H(2)O-positron emission tomography activation study and D1R-binding study using [(11)C]SCH 23390, and the correlations between receptor binding and cue-induced regional cerebral blood flow (rCBF) changes were assessed. Consecutive D1R-binding changes were examined during a period of 6 months of postsmoking abstinence in five smokers. RESULTS: Cue-induced activation was observed in the left ventral striatum including the nucleus accumbens in smokers. D1R binding in the ventral striatum showed a negative relationship with cue-induced craving and rCBF changes. D1R binding was significantly low in smokers, and there was a trend of increase after smoking abstinence. CONCLUSIONS: D1R binding and cue-induced rCBF changes in the ventral striatum suggest the important role of D1R in this region in cigarette craving.     

Sunshine-exposure variation of human striatal dopamine D2/D3 receptor availability in healthy volunteers

Background

In addition to the serotonergic system, the central dopaminergic system has been reported to be correlated with seasonality. The aim of this study was to explore the difference in striatal dopamine D₂/D₃ receptor availability between healthy volunteers who had a high-sunshine exposure and those who had a low exposure.

Methods

Sixty-eight participants were enrolled, and those in the upper and lower quartiles in terms of sunshine exposure were categorized into high- (n = 17) and low-sunshine-exposure (n = 18) subgroups. Single photon emission computed tomography with [¹²³I] iodo-benzamide was used to measure striatal dopamine D₂/D₃ receptor availability.

Results

Striatal dopamine D₂/D₃ receptor availability was significantly greater in the subjects with high-sunshine exposure than in those with low-sunshine exposure (F = 7.97, p = 0.01) after controlling for age, sex, and smoking status.

Limitations

Different subjects were examined at different time points in our study. In addition, the sex and tobacco use distributions differed between groups.

Conclusion

The central dopaminergic system may play a role in the neurobiological characteristics of sunshine-exposure variation.     

Interactions of dopamine D1 and D2 receptor antagonists with D-methamphetamine-induced hyperthermia and striatal dopamine and serotonin reductions

The effects of the dopamine D1 receptor antagonist R(+)-SCH-23390 and D2 receptor antagonist S(-)-eticlopride on d-methamphetamine-induced striatal monoamine reductions 72 h after treatment were investigated in relation to changes in body temperature. Rats were administered four 10-mg/kg doses of d-methamphetamine or saline with a 2-h interval between treatments; 0.5 mg/kg eticlopride or SCH-23390 was administered 15 min before each methamphetamine or saline injection. Two ambient temperature conditions were investigated: 24 and 33 degrees C. Methamphetamine administered at 24 degrees C induced hyperthermia and reduced striatal dopamine content by 73%; 0.5 mg/kg eticlopride or SCH-23390 administered in combination with methamphetamine at 24 degrees C attenuated methamphetamine-induced hyperthermia and prevented significant reductions in dopamine content. At 33 degrees C, eticlopride and SCH-23390 were ineffective in blocking methamphetamine-induced hyperthermia and dopamine content was reduced by 65% in the SCH-23390-methamphetamine group. By contrast, dopamine content was reduced by only 31% in the 33 degrees C eticlopride-methamphetamine group. Thus, although the eticlopride-methamphetamine treatment combination at 33 degrees C exhibited a hyperthermic response comparable to that seen with methamphetamine alone at 24 degrees C, reductions in dopamine content were attenuated in the combination group compared with methamphetamine alone at 24 degrees C. Serotonin changes showed similar attenuated reductions after SCH-23390 or eticlopride pretreatment at 24 degrees C in combination with methamphetamine, but this attenuation was absent at 33 degrees C. The dissociation of methamphetamine-induced striatal dopamine reduction and hyperthermia seen after eticlopride pretreatment suggests a dopamine D2 receptor mechanism in mediating methamphetamine-induced dopamine depletion. However this D2 mechanism does not apply to methamphetamine-induced striatal serotonin reductions.     

Differential regulation of the dopamine D1, D2 and D3 receptor gene expression and changes in the phenotype of the striatal neurons in mice lacking the dopamine transporter

Mice with a genetic disruption of the dopamine transporter (DAT-/-) exhibit locomotor hyperactivity and profound alterations in the homeostasis of the nigrostriatal system, e.g. a dramatic increase in the extracellular dopamine level. Here, we investigated the adaptive changes in dopamine D1, D2 and D3 receptor gene expression in the caudate putamen and nucleus accumbens of DAT-/- mice. We used quantitative in situ hybridization and found that the constitutive hyperdopaminergia results in opposite regulations in the gene expression for the dopamine receptors. In DAT-/- mice, we observed increased mRNA levels encoding the D3 receptor (caudate putamen, +60-85%; nucleus accumbens, +40-107%), and decreased mRNA levels for both D1 (caudate putamen, -34%; nucleus accumbens, -45%) and D2 receptors (caudate putamen, -36%; nucleus accumbens, -33%). Furthermore, we assessed the phenotypical organization of the striatal efferent neurons by using double in situ hybridization. Our results show that in DAT+/+ mice, D1 and D2 receptor mRNAs are segregated in two different main populations corresponding to substance P and preproenkephalin A mRNA-containing neurons, respectively. The phenotype of D1 or D2 mRNA-containing neurons was unchanged in both the caudate putamen and nucleus accumbens of DAT-/- mice. Interestingly, we found an increased density of preproenkephalin A-negative neurons that express the D3 receptor mRNA in the nucleus accumbens (core, +35%; shell, +46%) of DAT-/- mice. Our data further support the critical role for the D3 receptor in the regulation of D1-D2 interactions, an action being restricted to neurons coexpressing D1 and D3 receptors in the nucleus accumbens.