Brain region binding of the D2/3 agonist [11C]-(+)-PHNO and the D2/3 antagonist [11C]raclopride in healthy humans

The D(2) receptors exist in either the high- or low-affinity state with respect to agonists, and while agonists bind preferentially to the high-affinity state, antagonists do not distinguish between the two states. [(11)C]-(+)-PHNO is a PET D(2) agonist radioligand and therefore provides a preferential measure of the D(2) (high) receptors. In contrast, [(11)C]raclopride is an antagonist radioligand and thus binds with equal affinity to the D(2) high- and low-affinity states. The aim was to compare the brain uptake, distribution and binding characteristics between [(11)C]-(+)-PHNO and [(11)C]raclopride in volunteers using a within-subject design. Both radioligands accumulated in brain areas rich in D(2)/D(3)-receptors. However, [(11)C]-(+)-PHNO showed preferential uptake in the ventral striatum and globus pallidus, while [(11)C]raclopride showed preferential uptake in the dorsal striatum. Mean binding potentials were higher in the putamen (4.3 vs. 2.8) and caudate (3.4 vs 2.1) for [(11)C]raclopride, equal in the ventral-striatum (3.4 vs. 3.3), and higher in the globus pallidus for [(11)C]-(+)-PHNO (1.8 vs. 3.3). Moreover [(11)C]-(+)-PHNO kinetics in the globus pallidus showed a slower washout than other regions. One explanation for the preferential binding of [(11)C]-(+)-PHNO in the globus pallidus and ventral-striatum could be the presence of a greater proportion of high- vs. low-affinity receptors in these areas. Alternatively, the observed distribution could also be explained by a preferential binding of D(3)-over-D(2) with [(11)C]-(+)-PHNO. This differential binding of agonist vs. antagonist radioligand, especially in the critically important region of the limbic striatum/pallidum, offers new avenues to investigate the role of the dopamine system in health and disease.     

Dopamine D2 receptors and transporters in type 1 and 2 alcoholics measured with human whole hemisphere autoradiography

Increasing evidence implies the involvement of the dopamine (DA) system in the pathogenesis of alcoholism. We measured striatal DA D(2) receptors in Cloninger type 1 and 2 alcoholics by using [(125)I]epidepride in human postmortem whole hemispheric autoradiography (WHA), which provides high-resolution images corresponding to positron emission tomographic (PET) studies. We also evaluated the correlation between transporter and receptor DA binding site densities and putative correlation of [(125)I]epidepride binding between the dorsal striatum and nucleus accumbens. In the type 1 alcoholics, the DA D(2) receptor density was 21.4-32.6% lower in all dorsal striatal structures (caudate, putamen, globus pallidus) when compared with the controls. Type 2 alcoholics had 19.6-21.4% lower binding in other dorsal striatal structures, except medial globus pallidus, where they were not significantly different from controls. The density of DA D(2) receptors and DAT had a significant positive correlation only in the putamen of type 1 alcoholics. The binding of [(125)I]epidepride showed also consistent and statistically significant positive correlation between nucleus accumbens and all dorsal striatal areas in type 1 alcoholics but not in the controls. In the type 2 alcoholics, the correlation was weaker than that observed in the type 1 alcoholics, and no correlation was observed between nucleus accumbens and globus pallidus. Our results show that these two subgroups of alcoholics have stark differences in their DA D(2) receptor binding characteristics. Type 2 alcoholics may have selective deficiency in the dorsal striatum, whereas in limbic structures they may not differ significantly from controls. Moreover, WHA provides a useful tool for detailed mapping of neuronal receptors in healthy as well as diseased brain, and can also be used in radioligand development for PET.     

High-affinity states of human brain dopamine D2/3 receptors imaged by the agonist [11C]-(+)-PHNO.

BACKGROUND: The high-affinity states of dopamine D2-receptors (D2(high)) are postulated to be functionally responsible for signal transduction. At present, no useful in vivo method exists to selectively measure D2(high) in humans, as current D2 radioligands for positron emission tomography (PET) are either not D2-selective or do not differentiate between D2 high- and low-affinity states. METHODS: The D2-agonist (+)-PHNO [(+)4-propyl-9-hydroxynaphthoxazine] was labeled with carbon-11 and studied with PET. Eight [11C]-(+)-PHNO scans were acquired in four healthy volunteers. RESULTS: We observed greatest [11C]-(+)-PHNO accumulation in caudate, putamen, and globus pallidus [binding potentials (BPs): 3.00 +/- .4, 3.10 +/- .2, and 4.17 +/- 1.2]. Small but detectable binding was identified in the substantia nigra/ventral tegmental area. Preliminary test-retest data in two subjects suggests BP-estimates to be reliable. Pre-treatment with haloperidol reduced BPs in regions showing specific binding with no detectable changes in cerebellum. Parallel imaging with [11C]-raclopride showed substantial differences in the globus pallidus. CONCLUSIONS: [11C]-(+)-PHNO proved to be a D2/3-receptor agonist-radioligand with good brain uptake and favorable kinetics for PET in humans. [11C]-(+)-PHNO delineated D2/3-receptor rich brain regions with high signal-to-noise ratio. This is the first demonstration of a viable agonist-radioligand for D2 receptors in humans and opens the door for investigating D2(high) in health and disease.     

Distribution of dopamine D1 and D2 receptors in rabbit cortical areas, hippocampus, and neostriatum in relation to dopamine contents

The densities of dopamine D1 and D2 receptors were measured by using [3H]SCH23390 and [3H]raclopride, respectively, in the rabbit cingulate, visual, sensorimotor, and entorhinal-piriform cortical areas; the dorsal and ventral hippocampus; and the putamen as well as the medial and lateral caudate. Endogenous dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), 4-hydroxy-3-methoxyphenylacetic acid (HVA), and 3-methoxytyramine (3-MT) were assayed by HPLC with electrochemical detection. The distributions of [3H]SCH23390 and [3H]raclopride binding were heterogenous with the greatest densities in the neostriatum. The concentrations of DA and its metabolites were also highest in this structure. Regions with low DA content, i.e., cortex and hippocampus, had lower densities of [3H]SCH23390 and [3H]raclopride binding. Furthermore, these sites were differentially localized within the various regions and there were substantially more D1 than D2 receptors. The functional significance and heterogeneities in the distribution of D1 and D2 receptors are discussed in relation to the dopaminergic innervation and the turnover estimated by the ratios between endogenous DA and its metabolites.     

Effects of antipsychotics on D3 receptors: a clinical PET study in first episode antipsychotic naive patients with schizophrenia using [11C]-(+)-PHNO

Most antipsychotics are thought to have an effect on D(2) and D(3) receptors, although their D(3), versus D(2) binding has not been clearly established in vivo in humans. However, the development of [(11)C]-(+)-PHNO now permits the differentiation of antipsychotic activity on these two receptor subtypes. In this study we examined the effects of antipsychotics on D(2) and D(3) receptors by comparing [(11)C]-(+)-PHNO in D(2)-rich (caudate, CAU and putamen, PUT), mixed (ventral striatum) and D(3)-rich (globus-pallidus, GP and substantia nigra, SN) regions before and after the initiation of antipsychotic medication. The investigation therefore represents a longitudinal within-subject follow-up design wherein antipsychotic-naive patients with schizophrenia spectrum disorders were first scanned in a drug-na?ve state and then again after ~2.5 weeks of antipsychotic treatment (risperidone or olanzapine). Binding potential (non displaceable or BP(ND)) was obtained to derive estimates of drug occupancy in the identified brain regions. Antipsychotic treatment was associated with the expected occupancies in the D(2)-rich regions; unexpectedly though, patients showed a higher, rather than the expected lower, [(11)C]-(+)-PHNO BP(ND) in the GP and SN despite simultaneous evidence for ongoing D(2) blockade in the other regions (CAU and PUT). In conclusion, patients treated with atypical antipsychotics demonstrated no evidence of D(3) receptor occupancy, but instead possible D(3) up-regulation following short-term treatment. The present findings add to a very limited body of evidence related to D(3) binding in vivo. [(11)C]-(+)-PHNO offer new opportunities for exploring the potential therapeutic significance of the D(3) receptor in schizophrenia and the action of antipsychotics.     

Increased dopamine D2/D3 receptor binding after recovery from anorexia nervosa measured by positron emission tomography and [11c]raclopride.

BACKGROUND: Several lines of evidence support the possibility that disturbances of dopamine (DA) function could contribute to alterations of weight, feeding, motor activity, and reward in anorexia nervosa (AN). METHODS: To assess possibly trait-related disturbances but avoid confounding effects of malnutrition, 10 women who were recovered from AN (REC AN) were compared with 12 healthy control women (CW). Positron emission tomography with [(11)C]raclopride was used to assess DA D2/D3 receptor binding. RESULTS: The women who were recovered from AN had significantly higher [(11)C]raclopride binding potential in the antero-ventral striatum than CW. For REC AN, [(11)C]raclopride binding potential was positively related to harm avoidance in the dorsal caudate and dorsal putamen. CONCLUSIONS: These data lend support for the possibility that decreased intrasynaptic DA concentration or increased D2/D3 receptor density or affinity is associated with AN and might contribute to the characteristic harm avoidance or increased physical activity found in AN. Most intriguing is the possibility that individuals with AN might have a DA related disturbance of reward mechanisms contributing to altered hedonics of feeding behavior and their ascetic, anhedonic temperament.     

Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria.

BACKGROUND: Studies in experimental animals have implicated the mesolimbic dopaminergic projections into the ventral striatum in the neural processes underlying behavioral reinforcement and motivated behavior; however, understanding the relationship between subjective emotional experience and ventral striatal dopamine (DA) release has awaited human studies. Using positron emission tomography (PET), we correlated the change in endogenous dopamine concentrations following dextroamphetamine (AMPH) administration with the associated hedonic response in human subjects and compared the strength of this correlation across striatal subregions. METHODS: We obtained PET measures of [(11)C]raclopride specific binding to DA D2/D3 receptors before and after AMPH injection (0.3 mg/kg IV) in seven healthy subjects. The change in [(11)C]raclopride binding potential (DeltaBP) induced by AMPH pretreatment and the correlation between DeltaBP and the euphoric response to AMPH were compared between the anteroventral striatum (AVS; comprised of accumbens area, ventromedial caudate, and anteroventral putamen) and the dorsal caudate (DCA) using an MRI-based region of interest analysis of the PET data. RESULTS: The mean DeltaBP was greater in the AVS than in the DCA (p <.05). The AMPH-induced changes in euphoria analog scale scores correlated inversely with DeltaBP in the AVS (r = -.95; p <.001), but not in the DCA (r =.30, ns). Post hoc assessments showed that changes in tension-anxiety ratings correlated positively with DeltaBP in the AVS (r =.80; p [uncorrected] <.05) and that similar relationships may exist between DeltaBP and emotion ratings in the ventral putamen (as were found in the AVS). CONCLUSIONS: The preferential sensitivity of the ventral striatum to the DA releasing effects of AMPH previously demonstrated in experimental animals extends to humans. The magnitude of ventral striatal DA release correlates positively with the hedonic response to AMPH.     

NMDA antagonist effects on striatal dopamine release: positron emission tomography studies in humans.

Previous brain imaging studies with [(11)C]raclopride have suggested that the psychotogenic effects of the noncompetitive N-methyl-D-aspartate antagonist ketamine in humans might be mediated by increased dopamine (DA) release and increased stimulation of DA D(2) receptors in the striatum. The goal of the present study was to assess the effect of ketamine on D(2) receptor availability in subregions of the striatum (dorsal caudate, DCA; dorsal putamen, DPU; ventral striatum, VST) in humans. Ten healthy subjects were studied twice. In a first group of five subjects, PET scanning was obtained twice for 90 min during bolus plus constant infusion of [(11)C]raclopride. No significant differences were observed in [(11)C]raclopride specific-to-nonspecific activity ratios (V(")(3)) measured during an early interval (30-50 min) and late interval (70-90 min), confirming that a state of sustained equilibrium had been established from 30-90 min (end of infusion). In a second group of five subjects, a similar experiment was performed twice, except that ketamine was administered beginning at 50 min (0.12 mg/kg i.v. bolus followed by 0.65 mg/kg/h i.v. infusion for 70 min). Raclopride V(")(3) measured before ketamine (30-50-min interval) was compared to [(11)C]raclopride V(")(3) measured during ketamine infusion (70-90-min interval). Ketamine induced a robust dissociative state. However, no significant differences were observed in D(2) receptor availability measured before and during the ketamine infusion (n = 10) in any of the regions examined (DCA, DPU, and VST). These data fail to demonstrate an effect of ketamine on [(11)C]raclopride BP and are consistent with microdialysis studies in rodents and nonhuman primates which reported only small effects of acute NMDA receptor blockade on extracellular striatal DA concentration.     

Increased affinity of dopamine for D(2) -like versus D(1) -like receptors. Relevance for volume transmission in interpreting PET findings

Evidence indicates that dopamine (DA) mainly acts as a volume transmission (VT) transmitter through its release into the extracellular fluid where the D(1) -like and D(2) -like receptors are predominantly extrasynaptic. It was therefore of interest to compare the affinities of the two major families of DA receptors. [(3)H] raclopride /DA and [(3)H] SCH23390/DA competition assays compared the affinity of DA at D(2) -like and D(1) -like receptors in rat dorsal striatal membrane preparations as well as in membrane preparations from CHO cell lines stably transfected with human D(2L) and D(1) receptors. The IC(50) values of DA at D(2) -like receptors in dorsal striatal membranes and CHO cell membranes were markedly and significantly reduced compared with the IC(50) values of DA at D(1) -like receptors. These IC(50) values reflect differences in both the high and low affinity states. The K(iH) value for DA at [(3)H] raclopride-labeled D(2) -like receptors in dorsal striatum was 12 nM, and this can help explain PET findings that amphetamine-induced increases in DA release can produce an up to 50% decrease of [(11)C] raclopride binding in the dorsal striatum in vivo. These combined results give indications for the existence of striatal D(2) -like receptor-mediated DA VT at the local circuit level in vivo. The demonstration of a K(iH) value of 183 nM for DA at D(1) antagonist-labeled D(1) -like receptors instead gives a likely explanation for the failure of a reduction of D(1) -like receptor binding after amphetamine-induced DA release in PET studies using the D(1) -like antagonist radioligands [(11)C] SCH23390 and [(11)C] NNC. It seems difficult to evaluate the role of the extrasynaptic D(1) receptors in VT in vivo with the PET radioligands available for this receptor.     

Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and precision of D(2) receptor parameter measurements in ventral striatum.

Dopamine transmission in the ventral striatum (VST), a structure which includes the nucleus accumbens, ventral caudate, and ventral putamen, plays a critical role in the pathophysiology of psychotic states and in the reinforcing effects of virtually all drugs of abuse. The aim of this study was to assess the accuracy and precision of measurements of D(2) receptor availability in the VST obtained with positron emission tomography on the high-resolution ECAT EXACT HR+ scanner (Siemens Medical Systems, Knoxville, TN, U.S.A.). A method was developed for identification of the boundaries of the VST on coregistered high-resolution magnetic resonance imaging scans. Specific-to-nonspecific partition coefficient (V(3)") and binding potential (BP) of [(11)C]raclopride were measured twice in 10 subjects, using the bolus plus constant infusion method. [(11)C]Raclopride V(3)" in the VST (1.86 +/- 0.29) was significantly lower than in the dorsal caudate (DCA, 2.33 +/- 0.28) and dorsal putamen (DPU, 2.99 +/- 0.26), an observation consistent with postmortem studies. The reproducibility of V(3)" and BP were appropriate and similar in VST (V(3)" test-retest variability of 8.2% +/- 6.2%, intraclass correlation coefficient = 0.83), DCA (7.7% +/- 5.1%, 0.77), DPU (6.0% +/- 4.1%, 0.71), and striatum as a whole (6.3% +/- 4.1%, 0.78). Partial volume effects analysis revealed that activities in the VST were significantly contaminated by counts spilling over from the adjacent DCA and DPU: 70% +/- 5% of the specific binding measured in the VST originated from D(2) receptors located in the VST, whereas 12% +/- 3% and 18% +/- 3% were contributed by D(2) receptors in the DCA and DPU, respectively. Thus, accuracy of D(2) receptor measurement is improved by correction for partial voluming effects. The demonstration of an appropriate accuracy and precision of D(2) receptor measurement with [(11)C]raclopride in the VST is the first critical step toward the use of this ligand in the study of synaptic dopamine transmission at D(2) receptors in the VST using endogenous competition techniques.     

Distribution of D1 and D2 dopamine receptors in the basal ganglia of the cat determined by quantitative autoradiography

The patterns of dopamine D1 and D2 receptors were examined in the corpus striatum and related structures in the cat brain by quantitative autoradiography after in vitro radioligand binding with [3H]SCH23390 (D1 antagonist) and [3H]spiperone (D2 antagonist). Highly specific binding for both radioligands occurs in striatal structures known to receive dopaminergic input: the caudate nucleus, putamen, nucleus accumbens, and olfactory tubercle. However, the density of binding varies from one structure to another, and the density distribution within striatal nuclei is heterogeneous. In all but one portion of the striatum, the concentration of bound D1 radioligand ranges from 46 to 230% more than that of the D2 radioligand. The exception to this difference occurs at caudal putamenal levels where the two radioligands bind in equal concentrations (approximately equal to 220 fmol/mg tissue wet-weight). The highest density of both D1 and D2 radioligand binding occurs in irregular zones in the head and body of the caudate nucleus. Such high-density zones of D2 radioligand binding appear mainly in the dorsolateral part of the caudate's head. For the D1 radioligand, the high-density zones are more widespread throughout the caudate nucleus, nucleus accumbens, and putamen. The D2 radioligand binding (but not the D1) also exhibits low-density zones at more caudal levels of the caudate nucleus, and these are often in register with the high-density zones of D1 radioligand binding. In the putamen, inverted concentration gradients exist for the two radioligands: the [3H]SCH23390 gradient runs from higher levels rostrally to lower levels caudally. The lowest levels of bound [3H]spiperone in the striatum occur in the nucleus accumbens-olfactory tubercle area, whereas the lowest binding of [3H]SCH23390 occurs in the caudal putamen. Pallidal and nigral structures show marked disparities in binding of the two different radioligands. The D2 radioligand binding in the globus pallidus (80 +/- 8 fmol/mg tissue wet-weight) is about twice that in the entopedunuclear nucleus and pars reticulata of the substantia nigra, the latter two having equal levels (35 +/- 3 fmol/mg). No specific binding of the D2 radioligand occurs in the ventral pallidum. In contrast, D1 radioligand binding is highest in the entopeduncular nucleus (217 +/- 6 fmol/mg) and in the pars reticulata of the substantia nigra (198 +/- 2 fmol/mg) and moderate in the ventral pallidum (135 +/- 15 fmol/mg). In the globus pallidus, no detectable D1 radioligand binding occurs.(ABSTRACT TRUNCATED AT 400 WORDS)     

Changes of GABA receptors and dopamine turnover in the postmortem brains of parkinsonians with levodopa-induced motor complications.

Brain samples from 14 Parkinson's disease patients, 10 of whom developed motor complications (dyskinesias and/or wearing-off) on dopaminomimetic therapy, and 11 controls were analyzed. Striatal 3beta-(4-(125)I-iodophenyl)tropane-2beta-carboxylic acid isopropyl ester ([(125)I]RTI-121) -specific binding to dopamine transporter and concentration of dopamine were markedly decreased, but no association between level of denervation and development of motor complications was observed. The homovanillic acid/dopamine ratio of concentrations was higher in putamen of patients with wearing-off compared to those without. Striatal (35)S-labeled t-butylbicyclophosphorothionate ([(35)S]TBPS) and [(3)H]flunitrazepam binding to GABA(A) receptors were unchanged in patients with Parkinson's disease, whereas [(125)I]CGP 64213 -specific binding to GABA(B) receptors was decreased in the putamen and external segment of the globus pallidus of parkinsonian patients compared with controls. [(3)H]Flunitrazepam binding was increased in the putamen of patients with wearing-off compared to those without. [(35)S]TBPS-specific binding was increased in the ventral internal globus pallidus of dyskinetic subjects. These data suggest altered dopamine metabolism and increased GABA(A) receptors in the putamen related to the pathophysiology of wearing-off. The present results also suggest that an up-regulation of GABA(A) receptors in the internal globus pallidus is linked to the pathogenesis of levodopa-induced dyskinesias.     

Positron emission tomography quantification of [11C]-(+)-PHNO binding in the human brain.

The kinetic modeling of [11C]-(+)-PHNO binding to the dopamine D2/3 receptors in six human volunteers using positron emission tomography (PET) is described. [11C]-(+)-PHNO is the first agonist radioligand for the D2/3 in humans and as expected showed high uptake in caudate, putamen, globus pallidus (GP) and ventral striatum, and low uptake in cerebellum. A two-tissue compartment model (2CM) with four parameters was necessary to adequately fit time-activity data in all regions. Although a 2CM provided an excellent estimation of total distribution volumes, which were highly correlated with those obtained with the invasive Logan approach, it provided a poor identification of the k3/k4 ratios. Coupling K1/k2 between brain regions (Method C) or fixing K1/k2 to the value obtained in cerebellum (Method D) enabled more stable estimates of k3/k4 as compared with an unconstrained 2CM. The k3/k4 obtained with Method D ranged from 0.12+/-0.03 in cerebellum to 3.93+/-0.77 in GP and were similar to those obtained when coupling K1/k2. Binding potentials (BPs) obtained using the simplified reference tissue model (BP(SRTM)) ranged from 2.08+/-0.34 in caudate to 3.55+/-0.78 in GP and were highly correlated with k3/k4 estimates obtained with Method D (r=0.98). However, BP(SRTM) were 11%+/-5% lower than values obtained with Method D. BPs derived using the noninvasive Logan approach were slightly lower but not significantly different than BP(SRTM). This study demonstrates that [11C]-(+)-PHNO can be used for the quantitative measurement of D2/3 densities and should enable further studies of potential D2/3 dysregulation in several important psychiatric and neurologic illnesses.     

Behavioral and neurochemical consequences of ibotenic acid lesion in the subthalamic nucleus of the common marmoset

Five marmosets were unilaterally lesioned within the subthalamic nucleus (STN) by injection of 10 μg ibotenic acid. Seven marmosets served as saline injected controls. The lesioned marmosets showed an increased locomotor activity, occasional tongue protrusions, posture asymmetry, and abnormal movements of the contralateral legs and arms. The animals were sacrificed 21 days after the lbotenic acid injection and markers of γ-aminobutyric acid (GABA), dopamine (DA), and acetylcholine were studied in a variety brain regions. There was a bilateral increase in the activity of glutamic acid decarboxylase (GAD) in the caudate, putamen, globus pallidus, superior colliculus, and the ventral anterior/ventral lateral (VANL) thalamus, whereas GABA concentrations were only increased ipsilaterally in the ventral posterior medial/centromedial/parafasciculus (VPM/CM/Pf) complex of the thalamus. Tyrosine hydroxylase (TH) activity was bilaterally increased in the medial segment of globus pallidus and nucleus accumbens. However, there were also changes restricted to the side contralateral to the lesion. TH activity and DA concentrations were increased contralateral to the lesion in the putamen. Choline acetyltransferase (CAT) activity was bilaterally increased in the medial segment of globus pallidus and hypothalamus. The lbotenic acid induced STN-lesion in the marmoset, thus, seemed to cause a widespread bilateral activation of neurons within the basal ganglia.     

In vivo PET studies of the dopamine D2 receptors in rhesus monkeys with long-term MPTP-induced parkinsonism

Studies of dopamine (DA) receptor binding in early parkinsonian patients, or in models of Parkinson's disease, have revealed a supersensitivity of the D2-like receptor subtype as compared to age-matched controls. The lack of upregulation in advanced patients is often attributed to the effects of prolonged antiparkinsonian therapy, but the impact of therapy vs. intrinsic mechanisms in untreated patients or animals with long-term lesions of the DA nigrostriatal pathway has been difficult to address. We studied, in vivo, by PET using the DA D2 receptor ligand raclopride, the status of the DA receptors in normal rhesus monkeys and those with acute (3 months) or long-term (10 years) MPTP-induced nigrostriatal lesions. Compared to age-matched controls, there was no change in raclopride binding in MPTP-treated animals without parkinsonian symptoms. There was a significant increase in raclopride binding in the putamen (but not caudate nucleus) of all the animals displaying rigidity, hypo- and bradykinesia. This increase was greater in the animals with acute lesions (32%) than with established, long-term lesions (18%). There was no correlation between the postmortem striatal DA concentrations and in vivo raclopride binding but there was a correlation between PET raclopride binding and [(3)H]raclopride binding in vitro. Complex changes in D2 receptor binding occur in various stages of parkinsonism. Antiparkinsonian therapy is unlikely to be solely responsible for the lack of upregulation found in advanced parkinsonian patients but may be a contributing factor.     

Higher binding of the dopamine D3 receptor-preferring ligand [11C]-(+)-propyl-hexahydro-naphtho-oxazin in methamphetamine polydrug users: a positron emission tomography study

Positron emission tomography (PET) findings suggesting lower D2-type dopamine receptors and dopamine concentration in brains of stimulant users have prompted speculation that increasing dopamine signaling might help in drug treatment. However, this strategy needs to consider the possibility, based on animal and postmortem human data, that dopaminergic activity at the related D3 receptor might, in contrast, be elevated and thereby contribute to drug-taking behavior. We tested the hypothesis that D3 receptor binding is above normal in methamphetamine (MA) polydrug users, using PET and the D3-preferring ligand [11C]-(+)-propyl-hexahydro-naphtho-oxazin ([11C]-(+)-PHNO). Sixteen control subjects and 16 polydrug users reporting MA as their primary drug of abuse underwent PET scanning after [11C]-(+)-PHNO. Compared with control subjects, drug users had higher [11C]-(+)-PHNO binding in the D3-rich midbrain substantia nigra (SN; +46%; p<0.02) and in the globus pallidus (+9%; p=0.06) and ventral pallidum (+11%; p=0.1), whereas binding was slightly lower in the D2-rich dorsal striatum (approximately -4%, NS; -12% in heavy users, p=0.01) and related to drug-use severity. The [11C]-(+)-PHNO binding ratio in D3-rich SN versus D2-rich dorsal striatum was 55% higher in MA users (p=0.004), with heavy but not moderate users having ratios significantly different from controls. [11C]-(+)-PHNO binding in SN was related to self-reported "drug wanting." We conclude that the dopamine D3 receptor, unlike the D2 receptor, might be upregulated in brains of MA polydrug users, although lower dopamine levels in MA users could have contributed to the finding. Pharmacological studies are needed to establish whether normalization of D3 receptor function could reduce vulnerability to relapse in stimulant abuse.     

The striatum of the opossum, Didelphis virginiana. Description and experimental studies

The relationships and cytoarchitecture of the putamen, the caudate, the claustrum, the globus pallidus and the entopeduncular nuclei have been described for the opossum. The neocortical projections to these nuclei have ben studied by employing the Nauta-Gygax technique ('54) and the Swank Davenport modification of the Marchi technique ('34) on animals in which neocortical lesions were previously placed. Degenerating fibers from every cortical lesion were observed to terminate in both the putamen and the caudate with the Nauta-Gygax technique, whereas such connections were traced only to putamen woth the Marchi method. Terminations were present within the claustrum, but equivocal in the globus pallidus. In general, fibers from the more rostral cortices terminate in the rostral parts of both striatal nuclei, whereas fibers from more caudal neocortical areas project to more caudal parts of these same nuclei. In addition, the more dorsal or dorsomedial neocortical areas distribute more fibers to the caudate than to the putamen, whereas the opposite is true for the ventral or ventrolateral neocortical areas. Neocortical fibers did not project to the ventral, medial part of the head of the caudate which was cytoarchitectually different from the rest of the nucleus. A few fascicles of frontal, orbital and parietal origin terminated in the contralateral putamen and caudate after having decussated in the anterior commissure.     

Regional distribution of the dopamine D2 receptors in the mesotelencephalic dopamine neuron system of human brain

Using the [3H]spiroperidol binding technique, we performed a regional distribution of the D2 receptors in the human mesotelencephalic dopamine neuron system. D2 receptors were found in decreasing order of concentration in caudate nucleus greater than putamen greater than nucleus accumbens greater than globus pallidus greater than amygdala greater than substantia nigra. D2 receptors could not be detected in any cortical region. The nigrostriatal and mesolimbic components of the mesotelencephalic dopamine neuron system are easily to reconstitute. If there exists a mesocortical component in man, its actions appear not to be mediated by D2 receptors.     

PET shows that striatal dopamine D1 and D2 receptors are differentially affected in AD

OBJECTIVE: To study dopamine D1 and D2 receptors in the putamen and the caudate nucleus in patients with AD and age-matched healthy controls by means of PET. METHODS: A dopamine D1 receptor antagonist ([11C]NNC 756) and a D2 receptor antagonist ([11C]raclopride) were used as ligands. The uptake of these ligands was calculated as a distribution volume ratio of the putamen and the caudate nucleus to the cerebellum. RESULTS: The mean [11C]NNC 756 uptake in AD was reduced by 14% from the mean control value both in the putamen (p = 0.004) and the caudate nucleus (p = 0.009). There was no significant reduction in the mean [11C]raclopride uptake in either the putamen or the caudate nucleus in AD. There was no correlation between [11C]NNC 756 or [11C]raclopride uptake and Mini-Mental State Examination or motor Unified PD Rating Scale scores in patients with AD. CONCLUSIONS: There are changes in striatal D1 but not in D2 receptors in AD.