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

Dopamine (DA) integrity is suggested as a potential cause of individual differences in working memory (WM) performance among older adults. Still, the principal dopaminergic mechanisms giving rise to WM differences remain unspecified. Here, 61 single-nucleotide polymorphisms, located in or adjacent to various dopamine-related genes, were assessed for their links to WM performance in a sample of 1313 adults aged 61–80 years from the Berlin Aging Study II. Least Absolute Shrinkage and Selection Operator (LASSO) regression was conducted to estimate associations between polymorphisms and WM. Rs40184 in the DA transporter gene, SLC6A3, showed allelic group differences in WM, with T-carriers performing better than C homozygotes (p<0.01). This finding was replicated in an independent sample from the Cognition, Brain, and Aging study (COBRA; baseline: n = 181, ages: 64–68 years; 5-year follow up: n = 129). In COBRA, in vivo DA integrity was measured with 11C-raclopride and positron emission tomography. Notably, WM as well as in vivo DA integrity was higher for rs40184 T-carriers at baseline (p<0.05 for WM and caudate and hippocampal D2-receptor availability) and at the 5-year follow-up (p<0.05 for WM and hippocampal D2 availability). Our findings indicate that individual differences in DA transporter function contribute to differences in WM performance in old age, presumably by regulating DA availability.

•We developed a large-scale atlas of human type 2 dopamine receptor (D2R).•D2R availability decreases similarly among males and females and overall females have a higher availability than males through age.•Potential sex-dependencies in D2R expression may predispose males and females to different neuropsychiatric conditions.•Striatal [11C]raclopride binding potential can be calculated reliably from positron emission tomography (PET) scan without magnetic resonance image (MRI). The dopamine system contributes to a multitude of functions ranging from reward and motivation to learning and movement control, making it a key component in goal-directed behavior. Altered dopaminergic function is observed in neurological and psychiatric conditions. Numerous factors have been proposed to influence dopamine function, but due to small sample sizes and heterogeneous data analysis methods in previous studies their specific and joint contributions remain unresolved. In this cross-sectional register-based study we investigated how age, sex, body mass index (BMI), as well as cerebral hemisphere and regional volume influence striatal type 2 dopamine receptor (D2R) availability in the human brain. We analyzed a large historical dataset (n=156, 120 males and 36 females) of [11C]raclopride PET scans performed between 2004 and 2018. Striatal D2R availability decreased through age for both sexes (2-5 % in striatal ROIs per 10 years) and was higher in females versus males throughout age (7-8% in putamen). BMI and striatal D2R availability were weakly associated. There was no consistent lateralization of striatal D2R. The observed effects were independent of regional volumes. These results were validated using two different spatial normalization methods, and the age and sex effects also replicated in an independent sample (n=135). D2R availability is dependent on age and sex, which may contribute to the vulnerability of neurological and psychiatric conditions involving altering D2R expression.

Transcranial direct-current stimulation (tDCS) to the dorsolateral prefrontal cortex (DLPFC) has been established as an effective and noninvasive method to modulate cognitive function. Nevertheless, the mechanisms causing those cognitive changes under the tDCS remain largely unknown. We strove to elucidate the cognito-biological relation under the tDCS condition by examining whether the dopamine system activated by tDCS is involved in cognitive changes in human participants, or not. To evaluate the dopamine system, we used [11C]-raclopride positron emission tomography (PET) scanning: 20 healthy men underwent two [11C]-raclopride PET scans and subsequent neuropsychological tests. One scan was conducted after tDCS to the DLPFC. One was conducted after sham stimulation (control). Results of [11C]-raclopride PET measurements demonstrate that tDCS to the DLPFC caused dopamine release in the right ventral striatum. Neuropsychological tests for attentiveness revealed that tDCS to the DLPFC-enhanced participants’ accuracy. Moreover, this effect was correlated significantly with dopamine release. This finding provides clinico-biological evidence, demonstrating that enhancement of dopamine signaling by tDCS in the ventral striatum is associated with attention enhancement.

Moves to legalize marijuana highlight the urgency to investigate effects of chronic marijuana in the human brain. Here, we challenged 48 participants (24 controls and 24 marijuana abusers) with methylphenidate (MP), a drug that elevates extracellular dopamine (DA) as a surrogate for probing the reactivity of the brain to DA stimulation. We compared the subjective, cardiovascular, and brain DA responses (measured with PET and [ ¹¹C]raclopride) to MP between controls and marijuana abusers. Although baseline (placebo) measures of striatal DA D2 receptor availability did not differ between groups, the marijuana abusers showed markedly blunted responses when challenged with MP. Specifically, compared with controls, marijuana abusers had significantly attenuated behavioral (“self-reports” for high, drug effects, anxiety, and restlessness), cardiovascular (pulse rate and diastolic blood pressure), and brain DA [reduced decreases in distribution volumes (DVs) of [ ¹¹C]raclopride, although normal reductions in striatal nondisplaceable binding potential (BP ND)] responses to MP. In ventral striatum (key brain reward region), MP-induced reductions in DVs and BP ND (reflecting DA increases) were inversely correlated with scores of negative emotionality, which were significantly higher for marijuana abusers than controls. In marijuana abusers, DA responses in ventral striatum were also inversely correlated with addiction severity and craving. The attenuated responses to MP, including reduced decreases in striatal DVs, are consistent with decreased brain reactivity to the DA stimulation in marijuana abusers that might contribute to their negative emotionality (increased stress reactivity and irritability) and addictive behaviors.

•PET was employed in β-arrestin-2 knock-out mice to study receptor internalization.•[11C]Raclopride was used to study D2/D3 receptor occupancy and binding potential.•Knock-out mice exhibited preserved occupancy to repeated amphetamine challenge.•Wild-type mice showed severely blunted occupancy on repeated amphetamine challenge.•PET binding was depressed longer in wild-type than knock-out mice after drug. While all reversible receptor-targeting radioligands for positron emission tomography (PET) can be displaced by competition with an antagonist at the receptor, many radiotracers show limited occupancies using agonists even at high doses. [11C]Raclopride, a D2/D3 receptor radiotracer with rapid kinetics, can identify the direction of changes in the neurotransmitter dopamine, but quantitative interpretation of the relationship between dopamine levels and radiotracer binding has proven elusive. Agonist-induced receptor desensitization and internalization, a homeostatic mechanism to downregulate neurotransmitter-mediated function, can shift radioligand-receptor binding affinity and confound PET interpretations of receptor occupancy. In this study, we compared occupancies induced by amphetamine (AMP) in drug-naive wild-type (WT) and internalization-compromised β-arrestin-2 knockout (KO) mice using a within-scan drug infusion to modulate the kinetics of [11C]raclopride. We additionally performed studies at 3 h following AMP pretreatment, with the hypothesis that receptor internalization should markedly attenuate occupancy on the second challenge, because dopamine cannot access internalized receptors. Without prior AMP treatment, WT mice exhibited somewhat larger binding potential than KO mice but similar AMP-induced occupancy. At 3 h after AMP treatment, WT mice exhibited binding potentials that were 15 % lower than KO mice. At this time point, occupancy was preserved in KO mice but suppressed by 60 % in WT animals, consistent with a model in which most receptors contributing to binding potential in WT animals were not functional. These results demonstrate that arrestin-mediated receptor desensitization and internalization produce large effects in PET [11C]raclopride occupancy studies using agonist challenges.

A cognitive training program that improves working memory is associated with increased dopamine release during task performance. Updating of working memory has been associated with striato-frontal brain regions and phasic dopaminergic neurotransmission. We assessed raclopride binding to striatal dopamine (DA) D2 receptors during a letter-updating task and a control condition before and after 5 weeks of updating training. Results showed that updating affected DA activity before training and that training further increased striatal DA release during updating. These findings highlight the pivotal role of transient neural processes associated with D2 receptor activity in working memory.

The rewarding effects of stimulant drugs such as methylphenidate (MP) depend crucially on how fast they raise dopamine in the brain. Yet how the rate of drug-induced dopamine increases impacts brain network communication remains unresolved. We manipulated route of MP administration to generate fast versus slow dopamine increases. We hypothesized that fast versus slow dopamine increases would result in a differential pattern of global brain connectivity (GBC) in association with regional levels of dopamine D1 receptors, which are critical for drug reward. Twenty healthy adults received MP intravenously (0.5 mg/kg; fast dopamine increases) and orally (60 mg; slow dopamine increases) during simultaneous [ 11 C]raclopride PET-fMRI scans (double-blind, placebo-controlled). We tested how GBC was temporally associated with slow and fast dopamine increases on a minute-to-minute basis. Connectivity patterns were strikingly different for slow versus fast dopamine increases, and whole-brain spatial patterns were negatively correlated with one another (rho = −0.54, p spin  < 0.001). GBC showed “fast>slow” associations in dorsal prefrontal cortex, insula, posterior thalamus and brainstem, caudate and precuneus; and “slow>fast” associations in ventral striatum, orbitofrontal cortex, and frontopolar cortex ( p FDR  < 0.05). “Fast>slow” GBC patterns showed significant spatial correspondence with D1 receptor availability (estimated via normative maps of [ 11 C]SCH23390 binding; rho = 0.22, p spin  < 0.05). Further, hippocampal GBC to fast dopamine increases was significantly negatively correlated with self-reported ‘high’ ratings to intravenous MP across individuals ( r ( 19)  = −0.68, p bonferroni  = 0.015). Different routes of MP administration produce divergent patterns of brain connectivity. Fast dopamine increases are uniquely associated with connectivity patterns that have relevance for the subjective experience of drug reward.

Research in humans and nonhuman animals indicates that social affiliation, and particularly maternal bonding, depends on reward circuitry. Although numerous mechanistic studies in rodents demonstrated that maternal bonding depends on striatal dopamine transmission, the neurochemistry supporting maternal behavior in humans has not been described so far. In this study, we tested the role of central dopamine in human bonding. We applied a combined functional MRI-PET scanner to simultaneously probe mothers’ dopamine responses to their infants and the connectivity between the nucleus accumbens (NAcc), the amygdala, and the medial prefrontal cortex (mPFC), which form an intrinsic network (referred to as the “medial amygdala network”) that supports social functioning. We also measured the mothers’ behavioral synchrony with their infants and plasma oxytocin. The results of this study suggest that synchronous maternal behavior is associated with increased dopamine responses to the mother’s infant and stronger intrinsic connectivity within the medial amygdala network. Moreover, stronger network connectivity is associated with increased dopamine responses within the network and decreased plasma oxytocin. Together, these data indicate that dopamine is involved in human bonding. Compared with other mammals, humans have an unusually complex social life. The complexity of human bonding cannot be fully captured in nonhuman animal models, particularly in pathological bonding, such as that in autistic spectrum disorder or postpartum depression. Thus, investigations of the neurochemistry of social bonding in humans, for which this study provides initial evidence, are warranted.