Human Striatal Dopamine Research Articles

Maturation of the human striatal dopamine system revealed by PET and quantitative MRI

The development of the striatum dopamine (DA) system through human adolescence, a time of increased sensation seeking and vulnerability to the emergence of psychopathology, has been difficult to study due to pediatric restrictions on direct in vivo assessments of DA. Here, we applied neuroimaging in a longitudinal sample of n = 146 participants aged 12–30. R2′, an MR measure of tissue iron which co-localizes with DA vesicles and is necessary for DA synthesis, was assessed across the sample. In the 18–30 year-olds (n = 79) we also performed PET using [11C]dihydrotetrabenazine (DTBZ), a measure of presynaptic vesicular DA storage, and [11C]raclopride (RAC), an indicator of D2/D3 receptor availability. We observed decreases in D2/D3 receptor availability with age, while presynaptic vesicular DA storage (as measured by DTBZ), which was significantly associated with R2′ (standardized coefficient = 0.29, 95% CI = [0.11, 0.48]), was developmentally stable by age 18. Our results provide new evidence for maturational specialization of the striatal DA system through adolescence.

Brain Imaging Studies on the Cognitive, Pharmacological and Neurobiological Effects of Cannabis in Humans: Evidence from Studies of Adult Users.

Cannabis is the most widely used illicit drug worldwide. Regular cannabis use has been associated with a range of acute and chronic mental health problems, such as anxiety, depression, psychotic symptoms and neurocognitive impairments and their neural mechanisms need to be examined. This review summarizes and critically evaluates brain-imaging studies of cannabis in recreational and regular cannabis users between January 2000 and January 2016. The search has yielded eligible 103 structural and functional studies. Regular use of cannabis results in volumetric, gray matter and white matter structural changes in the brain, in particular in the hippocampus and the amygdala. Regular use of cannabis affects cognitive processes such as attention, memory, inhibitory control, decision-making, emotional processing, social cognition and their associated brain areas. There is evidence that regular cannabis use leads to altered neural function during attention and working memory and that recruitment of activity in additional brain regions can compensate for it. Similar to other drugs of abuse, cannabis cues activated areas in the reward pathway. Pharmacological studies showed a modest increase in human striatal dopamine transmission after administration of THC in healthy volunteers. Regular cannabis use resulted in reduced dopamine transporter occupancy and reduced dopamine synthesis but not in reduced striatal D2/D3 receptor occupancy compared with healthy control participants. Studies also showed different effects of Δ-9 tetrahydrocannabinol (THC) and cannabidiol (CBD) on emotion, cognition and associated brain regions in healthy volunteers, whereby CBD protects against the psychoactive effects of THC. Brain imaging studies using selective high-affinity radioligands for the imaging of cannabinoid CB1 receptor availability in Positron Emission Tomography (PET) showed downregulation of CB1 in regular users of cannabis. In conclusion, regular use of the cannabinoids exerts structural and functional changes in the human brain. These changes have profound implications for our understanding of the neuropharmacology of cannabis and its effects on cognition, mental health and the brain.

Further human evidence for striatal dopamine release induced by administration of ∆9-tetrahydrocannabinol (THC): selectivity to limbic striatum.

Elevated dopamine function is thought to play a key role in both the rewarding effects of addictive drugs and the pathophysiology of schizophrenia. Accumulating epidemiological evidence indicates that cannabis use is a risk factor for the development of schizophrenia. However, human neurochemical imaging studies that examined the impact of ∆9-tetrahydrocannabinol (THC), the main psychoactive component in cannabis, on striatal dopamine release have provided inconsistent results. The objective of this study is to assess the effect of a THC challenge on human striatal dopamine release in a large sample of healthy participants. We combined human neurochemical imaging data from two previous studies that used [(11)C]raclopride positron emission tomography (PET) (n = 7 and n = 13, respectively) to examine the effect of THC on striatal dopamine neurotransmission in humans. PET images were re-analysed to overcome differences in PET data analysis. THC administration induced a significant reduction in [(11)C]raclopride binding in the limbic striatum (-3.65 %, from 2.39 ± 0.26 to 2.30 ± 0.23, p = 0.023). This is consistent with increased dopamine levels in this region. No significant differences between THC and placebo were found in other striatal subdivisions. In the largest data set of healthy participants so far, we provide evidence for a modest increase in human striatal dopamine transmission after administration of THC compared to other drugs of abuse. This finding suggests limited involvement of the endocannabinoid system in regulating human striatal dopamine release and thereby challenges the hypothesis that an increase in striatal dopamine levels after cannabis use is the primary biological mechanism underlying the associated higher risk of schizophrenia.

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

BackgroundIn 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. MethodsSixty-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. ResultsStriatal 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. LimitationsDifferent subjects were examined at different time points in our study. In addition, the sex and tobacco use distributions differed between groups. ConclusionThe central dopaminergic system may play a role in the neurobiological characteristics of sunshine-exposure variation.

Striatal Dopamine Mediates the Interface between Motivational and Cognitive Control in Humans: Evidence from Genetic Imaging

Dopamine has been hypothesized to provide the basis for the interaction between motivational and cognitive control. However, there is no evidence for this hypothesis in humans. We fill this gap by using fMRI, a novel behavioral paradigm and a common polymorphism in the DAT1 gene (SLC6A3). Carriers of the 9-repeat (9R) allele of a 40 base pair repeat polymorphism in the 3' untranslated region of DAT1, associated with high striatal dopamine, showed greater activity in the ventromedial striatum during reward anticipation than homozygotes for the 10-repeat allele, replicating previous genetic imaging studies. The crucial novel finding is that 9R carriers also exhibited a greater influence of anticipated reward on switch costs, as well as greater activity in the dorsomedial striatum during task switching in anticipation of high reward relative to low reward. These data establish a crucial role for human striatal dopamine in the modulation of cognitive flexibility by reward anticipation, thus, elucidating the neurochemical mechanism of the interaction between motivation and cognitive control.

Long-Term Methamphetamine Administration in the Vervet Monkey Models Aspects of a Human Exposure: Brain Neurotoxicity and Behavioral Profiles

Methamphetamine (METH)-associated alterations in the human striatal dopamine (DA) system have been identified with positron emission tomography (PET) imaging and post-mortem studies but have not been well correlated with behavioral changes or cumulative METH intake. Animal studies that model some aspects of human long-term METH abuse can establish dose-dependency profiles of both behavioral changes and potential brain neurotoxicities for identifying consequences of particular cumulative exposures. Based on parameters from human and our monkey pharmacokinetic studies, we modeled a prevalent human METH exposure of daily multiple doses in socially housed vervet monkeys. METH doses were escalated over 33 weeks, with final dosages resulting in estimated peak plasma METH concentrations of 1-3 microM, a range measured in human abusers. With larger METH doses, progressive increases in abnormal behavior and decreases in social behavior were observed on 'injection' days. Anxiety increased on 'no injection' days while aggression decreased throughout the study. Thereafter, during 3 weeks abstinence, differences in baseline vs post-METH behaviors were not observed. Post-mortem analysis of METH brains showed 20% lower striatal DA content while autoradiography studies of precommissural striatum showed 35% lower [3H]WIN35428 binding to the DA transporter. No statistically significant changes were detected for [3H]dihydrotetrabenazine binding to the vesicular monoamine transporter (METH-lower by 10%) or for [3H]SCH 23390 and [3H]raclopride binding to DA D1 and D2 receptors, respectively. Collectively, this long-term, escalating dose METH exposure modeling a human abuse pattern, not associated with high-dose binges, resulted in dose-dependent behavioral effects and caused persistent changes in presynaptic striatal DA system integrity.

Striatal dopamine transporter availability with [123I]β-CIT SPECT is unrelated to gender or menstrual cycle

The effect of gender and female menstrual cycle on human striatal dopamine transporters (DATs) was investigated with single-photon emission computed tomography (SPECT) using the ligand 2beta-carbomethoxy-3beta-(4-[(123)I]iodophenyl)tropane. Ten female subjects aged 18-40 years (25.3+/-7.3 years) were scanned twice during the early follicular and the mid-luteal phases to detect any hormone-mediated changes in DAT availability in the striatum or serotonin transporter (SERT) availability in brainstem-diencephalon. Plasma estradiol and progesterone levels were obtained at the time of SPECT and confirmed the expected increases from the follicular to the luteal phases. Finally, in a post hoc analysis of a previously published healthy-subject sample, striatal DAT availability was compared between 70 male and 52 female subjects who ranged in age from 18 to 88 years. In the ten menstrual cycle subjects, DAT availability (V(3)'') in striatum and SERT availability in brainstem-diencephalon did not differ between follicular and luteal phases. Moreover, change in V(3)'' for striatum or brainstem-diencephalon was uncorrelated with change in plasma estradiol or progesterone from the follicular to the luteal phase. In the larger healthy-subject sample, there was no significant effect of gender or the interaction of age and gender on striatal V(3)''. These findings suggest that in using DAT or SERT ligands in the study of neuropsychiatric disorders, matching of female subjects according to a menstrual cycle phase is unnecessary. Although the present investigation did not confirm previous reports of gender differences in striatal DAT availability, controlling for gender in such studies still seems advisable.

Abnormal structure of human striatal dopamine re-uptake sites in habitually violent alcoholic offenders: a fractal analysis

Both animal and human studies imply that aggressive behaviour is associated with increased dopaminergic transmission. Our hypothesis was that impulsive violent offenders have also higher heterogeneity of the striatal dopamine transporter (DAT) density than controls. We performed a fractal analysis in 21 impulsive violent offenders, 10 non-violent alcoholics and 21 controls to measure the heterogeneity and laterality of the striatal DAT density characterised by [ 123I] β-CIT single-photon emission tomography (SPET). The [ 123I] β-CIT distribution was significantly more heterogeneous in the right striatum of violent offenders than in healthy controls. In addition, in young violent offenders there was no normal left-to-right asymmetry observed in control subjects of the same age. The normalisation of the left-to-right asymmetry may reflect late neurobiological maturation.

Nitrogen-based drugs are not essential for blockade of monoamine transporters.

In brain, monoamine transporters are principal targets of widely used therapeutic drugs including antidepressants, methylphenidate (Ritalin), and the addictive drug cocaine. Without exception, these transport blocking agents contain an amine nitrogen. A prevalent view and untested premise is that an amine nitrogen is needed to bind to the same counterion on the transporter as does the amine nitrogen of the monoamine neurotransmitter. We report that several compounds without nitrogen (8-oxa-bicyclo-3-aryl-[3.2.1] octanes, or aryloxatropanes) are active at monoamine transporters. One of these, tropoxane (0-914), bound with high affinity to the dopamine (IC50: 3.35 +/- 0.39 nM), serotonin (IC50: 6.52 +/- 2.05 nM), and norepinephrine (IC50: 20.0 +/- 0.3 nM) transporters in monkey brain, the human striatal dopamine transporter (IC50: 5.01 +/- 1.74 nM), and blocked dopamine transport (IC50: 7.2 +/- 3.0 nM) in COS-7 cells transfected with the human dopamine transporter. These unique compounds require a revision of current concepts of the drug binding domains on monoamine transporters, open avenues for discovery of a new generation of drugs and raise the issue of whether mammalian transporters and receptors may respond to, as yet, undiscovered non-amine bearing neurotransmitters or drugs.

Decrease in human striatal dopamine D2 receptor density with age: a PET study with [11C]raclopride.

The effect of age on human striatal dopamine D2 receptors was investigated with positron emission tomography (PET) using [11C]raclopride as a radioligand. Twenty-one healthy volunteers aged from 20 to 81 years were studied. An equilibrium method was applied and two separate PET scans with different specific activities of [11C]raclopride were performed. The maximal number of receptors (Bmax) and their dissociation constant (Kd) were calculated using Scatchard analysis. There was an age-dependent decline in the Bmax (r = -0.49; p = 0.02) of striatal D2 receptors while the Kd remained unchanged. The results show that there is an age-related loss of striatal D2 receptors, which, together with other changes in the brain nigrostriatal dopaminergic system, may contribute to extrapyramidal symptoms associated with aging.

Human striatal dopamine receptors are organized in compartments.

Dopamine (D2) receptors visualized in postmortem human striatum by quantitative autoradiography of [3H]spiroperidol binding are organized into circumscribed zones of low receptor density separated from other such zones by regions of higher D2 density. The D2-rich zones of the caudate nucleus and putamen contain twice the binding of D2-poor zones. The Hill coefficient, obtained from saturation analysis of [3H]spiroperidol binding to thin sections of human striatum, gave a value near unity, indicating the binding was occurring to a single type of site. The patchiness of [3H]spiroperidol binding was unaltered by postincubation removal of lipid from the tissue sections, indicating that a differential absorption of tritium in white and grey matter does not account for the heterogeneous distribution. The D2-rich and D2-poor regions appear to form labyrinths oriented in the anterior-posterior axis and are typically aligned with, respectively, acetylcholinesterase-rich and -poor compartments as visualized on stained adjacent sections. Thus, the distribution of dopamine D2 receptors conforms to the "striosomal" organization of the human caudate-putamen, a finding that suggests that this receptor subtype may mediate the influence of dopamine on distinct neurochemical compartments within the structure.

Decreased density of human striatal dopamine uptake sites with age

Decreased density of human striatal dopamine uptake sites with age