Dopamine D2 Receptor Density Research Articles

Regulation of dopamine D3 receptor in the striatal regions and substantia nigra in diffuse Lewy body disease

The regulation of D3 receptor has not been well documented in diffuse Lewy body disease (DLBD). In this study, a novel D3-preferring radioligand [3H]WC-10 and a D2-preferring radioligand [3H]raclopride were used and the absolute densities of the dopamine D3 and D2 receptors were determined in the striatal regions and substantia nigra (SN) from postmortem brains from five cases of DLBD, which included dementia with Lewy bodies (DLB, n=4) and Parkinson disease dementia (PDD, n=1). The densities of the dopamine D1 receptor, vesicular monoamine transporter 2 (VMAT2), and dopamine transporter (DAT) were also measured by quantitative autoradiography using [3H]SCH23390, [3H]dihydrotetrabenazine, and [3H]WIN35428, respectively. The densities of these dopaminergic markers were also measured in the same brain regions in 10 age-matched control cases. Dopamine D3 receptor density was significantly increased in the striatal regions including caudate, putamen and nucleus accumbens (NAc). There were no significant changes in the dopamine D1 and D2 receptor densities in any brain regions measured. VMAT2 and DAT densities were reduced in all the brain regions measured in DLB/PDD, however, the significant reduction was found in the putamen for DAT and in the NAc and SN for VMAT2. The decrease of dopamine pre-synaptic markers implies neuronal loss in the substantia nigra pars compacta (SNpc) in these DLB/PDD cases, while the increase of D3 receptors in striatal regions could be attributed to dopaminergic medication history and psychiatric states such as hallucinations. Whether it also reflects compensatory regulation upon dopaminergic denervation warrants further confirmations on larger populations.

Prenatal Stress Induces Increased Striatal Dopamine Transporter Binding in Adult Nonhuman Primates

To determine the effects in adult offspring of maternal exposure to stress and alcohol during pregnancy, we imaged striatal and midbrain dopamine transporter (DAT) binding by positron emission tomography in rhesus monkeys (Macaca mulatta). We also evaluated the relationship between DAT binding and behavioral responses previously found to relate to dopamine D2 receptor density (responsivity to tactile stimuli, performance on a learning task, and behavior during a learning task). Subjects were adult offspring derived from a 2 × 2 experiment in which pregnant monkeys were randomly assigned to control, daily mild stress exposure (acoustic startle), voluntary consumption of moderate-level alcohol, or both daily stress and alcohol. Adult offspring (n = 38) were imaged by positron emission tomography with the DAT ligand [(18)F]2β-carbomethoxy-3β-(4-chlorophenyl)-8-(2-fluoroethyl)-nortropane ([(18)F]FECNT). Results showed that prenatal stress yielded an overall increase of 15% in [(18)F]FECNT binding in the striatum (p = .016), 17% greater binding in the putamen (p = .012), and 13% greater binding in the head of the caudate (p = .028) relative to animals not exposed to prenatal stress. Striatal [(18)F]FECNT binding correlated negatively with habituation to repeated tactile stimulation and positively with tactile responsivity. There were no significant effects of prenatal alcohol exposure on [(18)F]FECNT binding. Maternal exposure to mild daily stress during pregnancy yielded increases in striatal DAT availability that were apparent in adult offspring and were associated with behavioral characteristics reflecting tactile hyperresponsivity, a condition associated with problem behaviors in children.

Mesolimbic dopamine D2 receptor plasticity contributes to stress resilience in rats subjected to chronic mild stress

RationaleFew studies have investigated neurobiological and biochemical differences between stress-resilient and stress-vulnerable experimental animals.ObjectivesWe investigated alterations in mesolimbic dopamine D2 receptor density and mRNA expression level in stressed rats at two time points, i.e. after 2 and 5 weeks of chronic mild stress (CMS).MethodsWe used the chronic mild stress paradigm because it is a well-established animal model of depression. Two groups of stressed rats were distinguished during CMS experiments: (1) stress reactive (70 %), which displayed a decrease in the drinking of a palatable sucrose solution during the stress regimen, and (2) stress resilient (30 %), which exhibited an unaltered drinking profile when compared with the unchallenged control group. [3H]Domperidone was used as a ligand to label dopamine D2 receptors, and a mixture of three specific oligonucleotides was used to evaluate dopamine D2 receptor mRNA changes in various regions of the rat brain.ResultsCMS strongly affected the mesolimbic dopamine circuit in stress-resilient group after 2 weeks and stress-reactive group of rats after 5 weeks which exhibited a decrease in the level of dopamine D2 receptor protein without alterations in D2 mRNA expression. Stress-resilient animals, but not stress-reactive animals, effectively adapted to the extended stress and coped with it. The increase in D2 mRNA expression returned the dopamine D2 receptor density to control levels in stress-resilient rats after 5 weeks of CMS, but not in stress-reactive animals.ConclusionsThese results clearly demonstrate that, despite earlier blunting, the activation of dopamine receptor biosynthesis in the dopamine mesoaccumbens system in stress-resilient rats is involved in active coping with stressful experiences, and it exhibits a delay in time.

Long-term exposure to oral methylphenidate or dl-amphetamine mixture in peri-adolescent rhesus monkeys: effects on physiology, behavior, and dopamine system development.

The stimulants methylphenidate and amphetamine are used to treat children with attention deficit/hyperactivity disorder over important developmental periods, prompting concerns regarding possible long-term health impact. This study assessed the effects of such a regimen in male, peri-adolescent rhesus monkeys on a variety of cognitive/behavioral, physiological, and in vivo neurochemical imaging parameters. Twice daily (0900 and 1200 hours), for a total of 18 months, juvenile male monkeys (8 per group) consumed either an unadulterated orange-flavored solution, a methylphenidate solution, or a dl-amphetamine mixture. Doses were titrated to reach blood/plasma levels comparable to therapeutic levels in children. [¹¹C]MPH and [¹¹C]raclopride dynamic PET scans were performed to image dopamine transporter and D₂-like receptors, respectively. Binding potential (BP(ND)), an index of tracer-specific binding, and amphetamine-induced changes in BP(ND) of [¹¹C]raclopride were estimated by kinetic modeling. There were no consistent differences among groups on the vast majority of measures, including cognitive (psychomotor speed, timing, inhibitory control, cognitive flexibility), general activity, physiological (body weight, head circumference, crown-to-rump length), and neurochemical (ie, developmental changes in dopamine transporter, dopamine D₂ receptor density, and amphetamine-stimulated dopamine release were as expected). Cytogenetic studies indicated that neither drug was a clastogen in rhesus monkeys. Thus, methylphenidate and amphetamine at therapeutic blood/plasma levels during peri-adolescence in non-human primates have little effect on physiological or behavioral/cognitive development.

Chronic Δ9-Tetrahydrocannabinol Exposure Induces a Sensitization of Dopamine D2/3 Receptors in the Mesoaccumbens and Nigrostriatal Systems

Δ⁹-tetrahydrocannabinol (THC), through its action on cannabinoid type-1 receptor (CB₁R), is known to activate dopamine (DA) neurotransmission. Functional evidence of a direct antagonistic interaction between CB₁R and DA D₂-receptors (D₂R) suggests that D₂R may be an important target for the modulation of DA neurotransmission by THC. The current study evaluated, in rodents, the effects of chronic exposure to THC (1 mg/kg/day; 21 days) on D₂R and D₃R availabilities using the D₂R-prefering antagonist and the D₃R-preferring agonist radiotracers [¹⁸F]fallypride and [³H]-(+)-PHNO, respectively. At 24 h after the last THC dose, D₂R and D₃R densities were significantly increased in midbrain. In caudate/putamen (CPu), THC exposure was associated with increased densities of D₂R with no change in D₂R mRNA expression, whereas in nucleus accumbens (NAcc) both D₃R binding and mRNA levels were upregulated. These receptor changes, which were completely reversed in CPu but only partially reversed in NAcc and midbrain at 1 week after THC cessation, correlated with an increased functionality of D₂/₃R in vivo, based on findings of increased locomotor suppressive effect of a presynaptic dose and enhanced locomotor activation produced by a postsynaptic dose of quinpirole. Concomitantly, the observations of a decreased gene expression of tyrosine hydroxylase in midbrain together with a blunted psychomotor response to amphetamine concurred to indicate a diminished presynaptic DA function following THC. These findings indicate that the early period following THC treatment cessation is associated with altered presynaptic D₂/₃R controlling DA synthesis and release in midbrain, with the concurrent development of postsynaptic D₂/₃R supersensitivity in NAcc and CPu. Such D₂/₃R neuroadaptations may contribute to the reinforcing and habit-forming properties of THC.

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.

Interaction of environment and chronic methylphenidate on anxiety‐like behavior and dopamine receptors in adolescent rodents

Environmental rearing conditions are reported to alter behavior and dopamine (DA) transmission in rodents. Administration of DA‐ergic drugs, such as methylphenidate (MPH), may have varying effects depending on environmental exposure. This study explored the interactive effects of environment and chronic MPH on DA receptors and anxiety‐like behavior in adolescent rats. Sprague‐ Dawley rats (PND 21; n=8/group) were housed in isolated/impoverished (II), pair‐housed (PH), or socially/environmentally enriched (EE) conditions for 4 weeks. At 1 week, rats were implanted with ALZET minipumps that delivered saline or MPH (2 or 8 mg/kg/day) for 3 weeks. Post treatment, rats were tested for locomotor behavior and anxiety‐like behavior in an elevated plus maze (EPM). Rats were sacrificed at PND 50; brains processed for in vitro autoradiography to quantify DA D1 and D2 receptors in striatal regions. II rats had greater locomotor activity and spent less time in the open arms of the EPM than EE and PH rats. Environment did not affect the density of D1 or D2 receptors in striatal regions. MPH did not impact any measure of behavior. However, there was a dose‐dependent decrease in DA D2 receptor density in caudate putamen and a similar trend in accumbens across housing groups. While D1 receptor density was not affected by MPH across housing groups, preliminary results suggest that D1 receptors were increased by 8 mg/kg/day MPH in II rats, but decreased in PH and EE animals. Differences in locomotor and anxiety‐like behavior between II, PH, and EE animals highlight the importance of considering housing conditions in rodent studies. MPH did not impact behavior, but did decrease D2 receptor density across housing conditions. Despite no main effect of MPH on D1 receptors, there was a trend towards an interaction between MPH and housing. Thus, chronic MPH causes alterations in DA systems, which may appear more pronounced in animals with a history of isolation.

Increased striatal dopamine transporter density in moderately severe old restless legs syndrome patients

Dopamine dysregulation in restless legs syndrome (RLS) may be varied by the severity of RLS, which could contribute to the conflicting results from previous functional neuroimaging studies on the central dopaminergic neurotransmission of RLS. The aim of this study was to observe whether reduced striatal dopaminergic neurotransmission is associated with moderate to moderately severe RLS. Thirteen elderly patients with RLS and 12 normal elderly controls were enrolled in the study. All the subjects were dopaminergic-drug naïve and twelve patients with RLS had the severity of moderate to moderately severe degree based on the International Restless Legs Syndrome Study Group (IRLSSG) Severity Scale. We compared dopamine transporter density (DAT) availability and D2 receptor density in the striatum between patients with RLS and controls using [(123)I]2β-carbomethoxy-3β-(4-iodophenyl)tropane single-photon emission computed tomography (SPECT) and [(123)I]iodobenzamide SPECT. Dopamine transporter density of patients with RLS was increased in the caudate (P = 0.037), posterior putamen (P = 0.041), and entire striatum (P = 0.046) compared with that of normal controls. DAT density was higher in the anterior putamen of patients with RLS than controls, although statistically not significant (P = 0.079). There was no difference in the D2 receptor density between patients with RLS and normal controls in the whole striatum or any of subregions. Dysregulation rather than simple upregulation or downregulation of central dopaminergic neurotransmission may underlie the pathogenesis of RLS, and decreased dopaminergic neurotransmission may cause moderate to moderately severe RLS in the elderly.

Gender-dependent behavioral and biochemical effects of adolescent delta-9-tetrahydrocannabinol in adult maternally deprived rats

Preclinical data support the long-term adverse effects on cognition, emotionality, and psychotic-like behaviors of adolescent exposure to natural and synthetic cannabinoids. To investigate whether the long-lasting adverse effects induced by cannabinoids in adolescence are influenced by early-life stress, female and male rats were subjected to 24-h maternal deprivation at postnatal day (PND) 9 and treated with tetrahydrocannabinol (THC) during adolescence (PND 35–45) according to our previously reported protocol. At adulthood, rats were tested in the novel object recognition, social interaction, and forced swim tests, to evaluate possible alterations in recognition memory, social behavior, and coping strategy. Moreover, cannabinoid CB1 receptor density and functionality, as well as NMDA and dopamine D1 and D2 receptor densities were measured through autoradiographic binding studies. In female maternally deprived rats, THC failed to impair recognition memory, counteracted aggressiveness induced by maternal deprivation, whereas no interaction was observed in the passive coping behavior. In males, the association of the two events increased passive coping response without affecting other behaviors. This behavioral picture was accompanied by gender-dependent and region-specific alterations in NMDA, D1 and D2 receptors. In conclusion, this study demonstrates that adolescent THC exposure might have different behavioral outcomes in animals previously exposed to early-life stress compared with non-stressed controls. The interaction between the two events is not univocal, and different combinations may arise depending on the sex of the animals and the behavior considered. Alterations in NMDA, D1 and D2 receptors might be involved in the behavioral responses induced by maternal deprivation and in their modulation by THC.This article is part of a Special Issue entitled: Stress, Emotional Behavior and the Endocannabinoid System.

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.

Caudate Dopamine D1 Receptor Density Is Associated with Individual Differences in Frontoparietal Connectivity during Working Memory

We assess the relationship of age-related losses in striatal D1 receptor densities to age-related reductions in functional connectivity between spatially distinct cortical regions in healthy human participants. Previous neuroimaging studies have reported age-related differences in functional connectivity of the frontoparietal working memory network and the default mode network during task performance. We used functional magnetic resonance imaging and seed-based connectivity (right dorsolateral and medial prefrontal cortex) to extend these findings: Anterior-posterior connectivity of both these functional networks was reduced in older (65-75 years, n = 18) compared with younger (20-30 years, n = 19) adults, whereas bilateral connectivity in prefrontal cortex was increased in older adults. Positron emission tomography with the D1 receptor ligand [(11)C]SCH23390 was used to assess caudate D1 receptor density in the same sample. Older adults showed significantly reduced caudate D1 receptor density compared to the younger adults. Of key interest, partial correlations showed that individual differences in caudate D1 receptor density were positively associated with individual differences in dorsolateral prefrontal connectivity to right parietal cortex (BA40) and negatively with medial prefrontal connectivity to right parietal cortex (BA40 and postcentral gyrus), after controlling for age. We found no correlation of caudate D1 receptor density with anterior-posterior coupling within the default mode network or with bilateral frontal connectivity. These results are consistent with animal work that has identified a role for caudate D1 receptors in mediating information transfer between prefrontal areas and parietal cortex.

The effects of scopolamine and the nootropic drug phenotropil on rat brain neurotransmitter receptors during testing of the conditioned passive avoidance task

We studied the effects of administration of the new nootropic drug phenotropil (N-carbamoylmethyl-4-phenyl-2-pyrrolidone) at a dose of 100 mg/kg on the quantitative characteristics of dopamine (DA), serotonin (5-HT), glutamate (NMDA), GABA-A (BDZ), and acetylcholine (nACh) receptors in rats using the conditioned passive avoidance task (PAT) under normal conditions and during scopolamine-induced amnesia ex vivo. We found that the cholinolytic drug scopolamine induced a substantial increase in the density (Bmax) of n-choline receptors in the cortex (by 99% as compared to the control) and NMDA receptors in the hippocampus (by 93%). A single administration of phenotropil (100mg/kg, intraperitoneally) abolished the effect of scopolamine and decreased the number of nACh and NMDA receptors by 46% and 14%, respectively. Phenotropil also abolished the effect of scopolamine on the benzodiazepine receptors and dopamine D1 receptors. Scopolamine decreased the density of D1 receptors by 20% and BDZ receptors by 17%, whereas phenotropil increased the density of receptors by 16% and 25%, respectively. Phenotropil considerably increased the density of dopamine D2 and D3 receptors by 29% and 62%, respectively. Scopolamine also increased the density of D3 receptors by 44% as compared to the control. We did not find any changes in the binding characteristics of 5-HT2 receptors during scopolamine-induced amnesia or during phenotropil treatment. These results demonstrate the role of these receptors in the development of scopolamine-induced amnesia and in neurochemical mechanisms of the anti-amnestic effects of phenotropil.

Pharmacologic Rescue of Motivational Deficit in an Animal Model of the Negative Symptoms of Schizophrenia

Deficits in incentive motivation, the energizing of behavior in pursuit of a goal, occur in many psychiatric disorders including schizophrenia. We previously reported deficits in both cognition and incentive motivation in a transgenic mouse model of increased striatal-specific dopamine D2 receptor (D2R) density (D2R-OE mice). This molecular alteration is observed in patients with schizophrenia, making D2R-OE mice a suitable system to study the cellular and molecular mechanisms of motivation and avolition, as well as a tool for testing potential therapies against motivational deficits. Behavioral studies using operant conditioning methods were performed both to further characterize the incentive motivation deficit in D2R-OE mice and test a novel pharmacological treatment target that arose from an unbiased expression study performed using gene chips and was validated by quantitative reverse transcription polymerase chain reaction, in situ hybridization, and immunohistochemistry. The reluctance of D2R-OE mice to work is due neither to intolerance for low rates of reward, decreased reactivity to reward, nor increased sensitivity to satiety or fatigue but to a difference in willingness to work for reward. As in patients with schizophrenia, this deficit was not ameliorated by D2R blockade, suggesting that reversal of the motivational deficit by switching off the transgene results from molecular changes downstream of D2R overexpression. We observed a reversible increase in serotonin subtype 2C (5-HT2C) receptor expression in D2R-OE mice. Systemic injection of a 5-HT2C receptor antagonist increased incentive motivation in D2R-OE and control mice. We propose that targeting 5-HT2C receptors may be a useful approach to modulate incentive motivation in psychiatric illness.

Mutant DISC1 affects methamphetamine-induced sensitization and conditioned place preference: a comorbidity model

Genetic factors involved in neuroplasticity have been implicated in major psychiatric illnesses such as schizophrenia, depression, and substance abuse. Given its extended interactome, variants in the Disrupted-In-Schizophrenia-1 (DISC1) gene could contribute to drug addiction and psychiatric diseases. Thus, we evaluated how dominant-negative mutant DISC1 influenced the neurobehavioral and molecular effects of methamphetamine (METH). Control and mutant DISC1 mice were studied before or after treatment with non-toxic escalating dose (ED) of METH. In naïve mice, we assessed METH-induced conditioned place preference (CPP), dopamine (DA) D2 receptor density and the basal and METH-induced activity of DISC1 partners, AKT and GSK-3β in the ventral striatum. In ED-treated mice, 4 weeks after METH treatment, we evaluated fear conditioning, depression-like responses in forced swim test, and the basal and METH-induced activity of AKT and GSK-3β in the ventral striatum. We found impairment in METH-induced CPP, decreased DA D2 receptor density and altered METH-induced phosphorylation of AKT and GSK-3β in naïve DISC1 female mice. The ED regimen was not neurotoxic as evidenced by unaltered brain regional monoamine tissue content. Mutant DISC1 significantly delayed METH ED-produced sensitization and affected drug-induced phosphorylation of AKT and GSK-3β in female mice. Our results suggest that perturbations in DISC1 functions in the ventral striatum may impact the molecular mechanisms of reward and sensitization, contributing to comorbidity between drug abuse and major mental diseases.This article is part of a Special Issue entitled ‘Schizophrenia’.

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.

Differential treatment regimen-related effects of cannabinoids on D1 and D2 receptors in adolescent and adult rat brain

Animal studies suggest differential effects of cannabinoids on dopamine-related behaviours in adolescence and adulthood however few studies have investigated the underlying neurochemical effects of cannabinoids during adolescence. The aim of the present study was to compare the effects of treatment with the synthetic cannabinoid, HU210, on dopamine receptor density in adolescent and adult rats. Adolescent (postnatal day (PND) 35) and adult (PND 70) rats received a single dose of 100 μg/kg HU210 or 25, 50 or 100 μg/kg HU210 for 4 or 14 days. Dopamine D1 receptor (D1R) or D2 receptor (D2R) density was measured in the medial and lateral (CPUL) caudate putamen, nucleus accumbens, olfactory tubercle (TU) and substantia nigra (D1R only) using in vitro autoradiography. D1R and D2R densities were 1.6–1.7- and 1.1–1.4-fold higher respectively in adolescent control rats compared to adults. In adult rats, D1R density was increased by 1.2- and 1.3-fold ( p < 0.05) in CPUL and TU respectively compared to controls, after 14 days of HU210 treatment. A significant overall effect of treatment ( p < 0.05) on D2R density was also observed in adults after the single dose and 4 and 14 days administration of HU210. In adolescents, an overall effect of treatment on D1R density after a single exposure to HU210 was seen ( p = 0.0026) but no changes in D1R or D2R densities were observed in other treatment groups. These results suggest that the adolescent rat brain does not display the same compensatory mechanisms activated in the adult brain following cannabinoid treatment.

Thinking Outside a Less Intact Box: Thalamic Dopamine D2 Receptor Densities Are Negatively Related to Psychometric Creativity in Healthy Individuals

Several lines of evidence support that dopaminergic neurotransmission plays a role in creative thought and behavior. Here, we investigated the relationship between creative ability and dopamine D2 receptor expression in healthy individuals, with a focus on regions where aberrations in dopaminergic function have previously been associated with psychotic symptoms and a genetic liability to schizophrenia. Scores on divergent thinking tests (Inventiveness battery, Berliner Intelligenz Struktur Test) were correlated with regional D2 receptor densities, as measured by Positron Emission Tomography, and the radioligands [11C]raclopride and [11C]FLB 457. The results show a negative correlation between divergent thinking scores and D2 density in the thalamus, also when controlling for age and general cognitive ability. Hence, the results demonstrate that the D2 receptor system, and specifically thalamic function, is important for creative performance, and may be one crucial link between creativity and psychopathology. We suggest that decreased D2 receptor densities in the thalamus lower thalamic gating thresholds, thus increasing thalamocortical information flow. In healthy individuals, who do not suffer from the detrimental effects of psychiatric disease, this may increase performance on divergent thinking tests. In combination with the cognitive functions of higher order cortical networks, this could constitute a basis for the generative and selective processes that underlie real life creativity.

Dopamine D2 receptor density in the limbic striatum is related to implicit but not explicit movement sequence learning

A large body of literature suggests that motor sequence learning involves dopamine-modulated plastic processes in the basal ganglia. Sequence learning can occur both implicitly, without conscious awareness and intention to learn, and explicitly, i.e., under conscious control. Here, we investigated whether individual differences in implicit and explicit sequence learning of movement sequences in a group of 15 healthy participants are related to dopamine D2 receptor densities in functional subregions of the striatum. Sequence learning was assessed using the serial reaction time task, and measures of implicit and explicit knowledge were estimated using a process dissociation procedure. Correlation analyses were performed between these measures and D2 receptor densities, which had been measured previously with positron emission tomography. Striatal D2 densities were negatively related to measures of sequence learning. In the limbic subregion, D2 densities were specifically related to implicit but not explicit learning. These findings suggest that individual differences in striatal DA function underlie differences in sequence learning ability and support that implicit and explicit sequence learning depend on partly distinct neural circuitry. The findings are also in line with the general view that implicit learning systems are evolutionarily primitive and tend to rely more on phylogenetically old neural circuitry than does explicit learning and cognition.

3H]4‐(dimethylamino)‐N‐(4‐(4‐(2‐methoxyphenyl)piperazin‐1‐yl) butyl)benzamide: A selective radioligand for dopamine D3 receptors. II. Quantitative analysis of dopamine D3 and D2 receptor density ratio in the caudate‐putamen

4-(Dimethylamino)-N-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)benzamide (WC-10), a N-phenyl piperazine analog, displays high affinity and moderate selectivity for dopamine D(3) receptors versus dopamine D(2) receptors (Chu et al. [2005] Bioorg Med Chem 13:77-87). In this study, WC-10 was radiolabeled with tritium (specific activity = 80 Ci/mmol), and quantitative autoradiography studies were conducted using rhesus monkey and Sprague-Dawley rat brain sections. K(d) values for the binding of [3H]WC-10 to D(3) receptors obtained from quantitative autoradiography with rhesus monkey and rat brain sections are in agreement with K(d) values obtained from cloned human and rat receptors (Xu et al. [2009] Synapse 63:717-728). The D(2) selective antagonist [3H]raclopride binds with 11-fold higher affinity to human HEK D(2L) (K(d) = 1.6 nM) than HEK D(3) (K(d) = 18 nM) receptors; [3H]raclopride binds to rat Sf9 rD(2L) receptors with a K(d) of 6.79 nM, a value that is 4-fold lower than binding to human HEK D(2L) receptors and 2.5-fold higher than binding to rat Sf9 rD(3) receptors. In vitro quantitative autoradiography studies with [3H]WC-10 and [3H]raclopride were conducted on adult rat and rhesus monkey brain sections. A mathematical model for calculating the absolute densities of dopamine D(2) and D(3) receptors based on the in vitro receptor binding data of [3H]WC-10 and [3H]raclopride was developed.

Genetically Determined Differences in Brain Response to a Primary Food Reward: Figure 1.

Combining genetic and neuroimaging techniques may elucidate the biological underpinnings of individual differences in neurophysiology and potential vulnerabilities to disease. The TaqIA A1 variant is associated with diminished dopamine D(2) receptor density, higher body mass, and food reinforcement. It also moderates the relationship between brain response to food and future weight gain. This suggests that the polymorphism is associated with a fundamental difference in the neurophysiology of food that may predispose toward overeating. An alternative possibility is that factors, such as impulsivity, eating style, reward drive, and perception, which may covary with the polymorphism, influence reward coding and eating behavior. To distinguish between these alternatives, we used functional magnetic resonance imaging to measure neural response to the ingestion of palatable and caloric milkshakes in healthy subjects with (A1+; n = 13) and without (A1-; n = 13) the TaqIA A1 allele. The groups were selected from a larger group to be matched for linked individual factors such as age, gender, education, body mass index, impulsivity, eating style, and perceptual responses to the milkshake. We demonstrate an interaction between genotype (A1+ vs A1-) and stimulus (milkshake vs a tasteless/odorless baseline) in the midbrain, thalamus, and orbital frontal cortex; whereas A1- shows increased responses to milkshake, A1+ shows decreased responses to milkshake relative to baseline. This interaction occurs despite similar ratings of milkshake pleasantness, intensity, and familiarity. We therefore conclude that there is a specific association between the TaqIA A1 polymorphism and brain response during ingestion of a palatable food.