Validation of [(11) C]ORM-13070 as a PET tracer for alpha2c -adrenoceptors in the human brain.

This study explored the use of the α2C -adrenoceptor PET tracer [(11) C]ORM-13070 to monitor α2C -AR occupancy in the human brain. The subtype-nonselective α2 -AR antagonist atipamezole was administered to eight healthy volunteer subjects to determine its efficacy and potency (Emax and EC50 ) at inhibiting tracer uptake. We also explored whether the tracer could reveal changes in the synaptic concentrations of endogenous noradrenaline in the brain, in response to several pharmacological and sensory challenge conditions. We assessed occupancy from the bound-to-free ratio measured during 5-30 min post injection. Based on extrapolation of one-site binding, the maximal extent of inhibition of striatal [(11) C]ORM-13070 uptake (Emax ) achievable by atipamezole was 78% (95% CI 69-87%) in the caudate nucleus and 65% (53-77%) in the putamen. The EC50 estimates of atipamezole (1.6 and 2.5 ng/ml, respectively) were in agreement with the drug's affinity to α2C -ARs. These findings represent clear support for the use of [(11) C]ORM-13070 for monitoring drug occupancy of α2C -ARs in the living human brain. Three of the employed noradrenaline challenges were associated with small, approximately 10-16% average reductions in tracer uptake in the dorsal striatum (atomoxetine, ketamine, and the cold pressor test; P < 0.05 for all), but insulin-induced hypoglycemia did not affect tracer uptake. The tracer is suitable for studying central nervous system receptor occupancy by α2C -AR ligands in human subjects. [(11) C]ORM-13070 also holds potential as a tool for in vivo monitoring of synaptic concentrations of noradrenaline, but this remains to be further evaluated in future studies.

Mesolimbic dopamine release is linked to symptom severity in pathological gambling.

BACKGROUND: Brain dopamine neurons code rewarding environmental stimuli by releasing endogenous dopamine, a transmission signal that is important for reinforcement learning. Human reward-seeking gambling behavior, and especially pathological gambling, has been presumed to be modulated by brain dopamine. METHODS: Striatal dopamine release was studied with [(11)C]raclopride positron emission tomography (PET) during gambling with an ecologically valid slot machine gambling task. Twenty-four males with and without pathological gambling (DSM-IV) were scanned three times, and the effects of different gambling outcomes (high-reward and low-reward vs. control task) on dopamine release were evaluated. RESULTS: Striatal dopamine was released in both groups during high-reward but also low-reward tasks. The dopamine release during the low-reward task was located in the associative part of the caudate nucleus. During the high-reward task, the effect was also seen in the ventral striatum and the magnitude of dopamine release was associated with parallel gambling "high". Furthermore, there was a positive correlation between dopamine release during the low-reward and the high-reward task. There was no general difference in the magnitude of dopamine release between pathological gamblers and controls. However, in pathological gamblers, dopamine release correlated positively with gambling symptom severity. CONCLUSIONS: Striatal dopamine is released during gambling irrespective of gambling outcome suggesting that the mere expectation/prediction of reward is sufficient to induce dopaminergic changes. Although dopamine release during slot machine gambling is comparable between healthy controls and pathological gamblers, greater gambling symptom severity is associated with greater dopaminergic responses. Thus, as the dopamine reward deficiency theory predicts blunted mesolimbic dopamine responses to gambling in addicted individuals, our results question the validity of the reward deficiency hypothesis in pathological gambling.

Cortical dopamine D2/D3 receptors and verbal memory in man.

INTRODUCTION: It has been previously reported that hippocampal dopamine D2/D3 receptors are involved in the regulation of verbal memory and learning in healthy volunteers. We tested this hypothesis further and studied whether cortical dopamine D2/D3 receptor availability in vivo is associated with verbal memory as assessed with the revised Wechsler Memory Scale (WMS-R). METHODS: Forty healthy Finnish subjects were evaluated according to the WMS-R and scanned with positron emission tomography (PET) and dopamine D2/D3 receptor radioligand [(11)C]FLB457 for the measurement of cortical D2/D3 receptor binding. RESULTS: WMS-R verbal memory and learning parameters did not significantly correlate with D2/D3 receptor binding potential (BP(ND)) in the studied cortical regions. CONCLUSIONS: Our findings do not support a major role for cortical D2/D3 receptors in the regulation of verbal memory in healthy individuals.

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 [(11)C]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.

COMT Val158Met genotype does not alter cortical or striatal dopamine D2 receptor availability in vivo.

PURPOSE: Catechol-O-methyl transferase (COMT) is a pivotal regulator of brain dopamine function with a region-specific role. COMT is important in dopamine elimination in the prefrontal cortex, whereas dopamine reuptake is the main mechanism for synaptic removal of dopamine in the striatum. We studied whether the functional COMT gene polymorphism (Val158Met) associates with altered dopamine D2 receptor binding characteristics in vivo hypothesizing an effect in the cortex but not in the striatum. PROCEDURES: Samples of 38 and 45 Finnish healthy subjects scanned previously with PET and the D2/D3 receptor radioligands [(11)C]FLB457 or [(11)C]raclopride, respectively, were genotyped for the Val158Met polymorphism. RESULTS: No significant associations were found between the Val158Met genotype and D2 receptor binding characteristics in the cortex or the striatum as measured with [(11)C]FLB457 and [(11)C]raclopride, respectively. CONCLUSIONS: COMT genotype is not related with alterations in baseline D2 receptor availability in vivo in the cortex or the striatum. This information is useful for the interpretation of genetic studies on COMT in neuropsychiatry.

C957T polymorphism of the human dopamine D2 receptor gene predicts extrastriatal dopamine receptor availability in vivo.

The C957T (rs6277) single nucleotide polymorphism (SNP) of the human dopamine D2 receptor (DRD2) gene (DRD2) affects DRD2 mRNA stability and has been shown to predict striatal DRD2 availability (B(max)/K(D)) in vivo in man. Specifically, the C/C genotype is associated with low striatal DRD2 availability (C/CC/T>T/T). Also the TaqIA A1 allele carriers (p=0.101) tended to have higher extrastriatal DRD2 BP(ND) compared to non-carriers whereas the -141C Ins/Del genotype did not influence extrastriatal DRD2 BP(ND). Our findings indicate that the DRD2 SNPs regulate DRD2 availability in the human cortex and in the thalamus in vivo. However, the regulation pattern is different from that observed previously for striatal DRD2 availability in vivo, which may reflect distinct functional roles of dopamine and DRD2 in the cortex versus the striatum. The results provide useful information for the interpretation of genetic studies exploring the role of the DRD2 in normal physiology as well as in psychiatric and neurological diseases.