Interactions between D1 and D2 dopamine receptor family agonists and antagonists: the effects of chronic exposure on behavior and receptor binding in rats and their clinical implications

Summary Functional interactions between dopamine receptor subtypes may affect behavioral and biochemical responses which serve as models for neuropsychiatric illnesses and the clinical effects of drug therapy. We evaluated the effects of chronic exposure to the selective D1 receptor antagonist SCH 23390, and the selective D2 receptor antagonist metoclopramide, on spontaneous and drug-induced behavior and receptor density in rats, and then determined how these effects would be modified by concurrent administration of antagonists or agonists [SKF 38393, LY 171555 (quinpirole)] selective for the complementary receptor subtype. Administered alone, both the D1 and D2 antagonists had acute cataleptic effects to which animals became tolerant following chronic treatment, but the selective antagonists had opposing effects on spontaneous locomotor activity. Both antagonists produced equivalent, supersensitive behavioral responses to apomorphine, and resulted in an increase in D2 receptor density. Coadministration of the D1 and D2 antagonists had a synergistic effect on catalepsy, attenuated the effects on spontaneous locomotor activity observed with either drug alone, and had an additive effect on both apomorphine-induced stereotypic behavior and D2 receptor proliferation. On the other hand, when either selective antagonist was combined with the agonist selective for the complementary receptor subtype, both D2 receptor proliferation and behavioral supersensitivity were completely blocked. Combined antagonist-agonist treatments had opposing effects on the development of tolerance to antagonist-induced catalepsy. D2 —but not D1 — receptor densities were correlated with animals' behavioral responses to apomorphine. There results support and extend the notion that complex functional interactions between D1 and D2 receptor families occur within the central nervous system, and suggest that novel effects might be derived from combined administration of receptor selective agonists and antagonists.     

Relationship between regional gray matter volumes and dopamine D2 receptor and transporter in living human brains

Although striatal dopamine neurotransmission is believed to be functionally linked to the formation of the corticostriatal network, there has been little evidence for this regulatory process in the human brain and its disruptions in neuropsychiatric disorders. Here, we aimed to investigate associations of striatal dopamine transporter (DAT) and D₂ receptor availabilities with gray matter (GM) volumes in healthy humans. Positron emission tomography images of D₂ receptor (n = 34) and DAT (n = 17) captured with the specific radioligands [¹¹C]raclopride and [¹⁸F]FE‐PE2I, respectively, were acquired along with T1‐weighted magnetic resonance imaging data in our previous studies, and were re‐analyzed in this work. We quantified the binding potentials (BP _ND) of these radioligands in the limbic, executive, and sensorimotor functional subregions of the striatum. Correlations between the radioligand BP _ND and regional GM volume were then examined by voxel‐based morphometry. In line with the functional and anatomical connectivity, [¹¹C]raclopride BP _ND in the limbic striatum was positively correlated with volumes of the uncal/parahippocampal gyrus and adjacent temporal areas. Similarly, we found positive correlations between the BP _ND of this radioligand in the executive striatum and volumes of the prefrontal cortices and their adjacent areas as well as between the BP _ND in the sensorimotor striatum and volumes of the somatosensory and supplementary motor areas. By contrast, no significant correlation was found between [¹⁸F]FE‐PE2I BP _ND and regional GM volumes. Our results suggest unique structural and functional corticostriatal associations involving D₂ receptor in healthy humans, which might be partially independent of the nigrostriatal pathway reflected by striatal DAT.     

Rat-PET study without anesthesia: anesthetics modify the dopamine D1 receptor binding in rat brain

Positron emission tomography (PET) measurements in 6-month-old F344/N rats were performed in the conscious state and the influence of chloral hydrate, ketamine, and pentobarbital anesthesia on dopamine D(1) (DA-D(1)) receptor binding was evaluated using [(11)C]SCH23390, a selective DA-D(1) receptor ligand. To perform the PET study in conscious rats, an original fixation apparatus was developed and the animals were trained to acclimate to the scanning atmosphere for 3 h. This training was carried out twice a day for 2 weeks. PET measurements in conscious rats were successful, since the trained rats scarcely moved during the scanning (as monitored by video camera) and since highly reproducible measurements of binding potential (BP) were derived from their scanning. Chloral hydrate and ketamine anesthesia significantly increased the striatal BP of DA-D(1) receptors by 36% and 46%, respectively, compared to that observed in the conscious state. In contrast, pentobarbital markedly decreased the BP by 41%. These BP values of DA-D(1) receptors were calculated using a curve-fitting method. Our results indicate that PET studies in rats should be performed in the conscious state since the anesthetics dramatically modified ligand-receptor bindings, such as DA-D(1) receptor binding, in rat brain.     

D1 receptor binding in rat striatum: modification by various D1 and D2 antagonists,but not by sibutramine hydrochloride,antidepressants or treatments which enhance central dopaminergic function

Summary [³H]SCH 23390 is a selective high affinity ligand for D₁ receptors in vitro. Using this ligand persistent blockade of D₁ receptors by SCH 23390 and cis-flupenthixol was shown to significantly increase the number of D₁ receptor binding sites in rat striatum. In contrast, repeated administration of the D₂-selective antagonist, clebopride, resulted in a small, but significant, reduction in number. No differences in binding affinity were observed and a single dose of these compounds was without effect. The D₂-selective antagonist, haloperidol, the non-selective D₁/D₂ receptor antagonist, chlorpromazine, the dopamine reuptake inhibitors, bupropion, GBR 12909 and nomifensine, and the dopamine releasing agent, d-amphetamine, had no effect on D₁ receptors. The antidepressant treatments, desipramine, zimeldine, amitriptyline, tranylcypromine, mianserin and ECS and the monoamine reuptake inhibitor, sibutramine, similarly did not alter striatal D₁ sites. Thus, of the treatments investigated only chronic receptor blockade by high affinity antagonists altered D₁ receptor binding in rat striatum.     

Characterization of [3H]nemonapride binding to mouse brain dopamine D2 receptors assessedin vivo andex vivo for metabolic modeling in PET studies

Summary We characterized [³H]nemonapride ([³H]NEM, [³H]YM-09151-2) binding to dopamine D₂ receptors. In mice given [³H]NEM with and without sulpiride, thein vivo specific binding of the [³H]NEM to the D₂ receptors in the striatum was assessed: SB_{in vivo-1}, striatal uptake minus cerebellar uptake; and SB_{in vivo-2}, uptake in the control mice minus uptake in the sulpiride-treated mice. Tissue homogenates were divided into cytosol and the membrane binding fraction (MB). When the MB was incubatedin vitro with sulpiride, the dissociated and nondissociated fractions were defined as theex vivospecific binding (SB_{ex vivo}) and theex vivo nonspecific binding (NB_{ex vovo}), respectively. HPLC revealed that most of the radioactivity in the MB was [³H]NEM, whereas metabolites were found in the cytosol. In the striatum, the SB_{ex vivo} increased with time (50% of the total tissue uptake at 60 min), and was equivalent to the SB_{in vivo-2}. The SB_{in vivo-1} was comparable to the MB. In the cerebral cortex and cerebellum, the SB_{ex vivo} decreased with time and the SB_{ex vivo}/free [³H]NEM ratios were smaller than those in the striatum.     

Effects of D2 dopamine receptor agonist and antagonist on brain activity in the rat assessed by functional magnetic resonance imaging

The effects of D₂ dopamine receptor agonist, bromocriptine (BROMO), and antagonist, haloperidol (HPD), on brain activity were investigated in rats by functional magnetic resonance imaging. T2^*-weighted signal intensity was increased in the hypothalamus at 120 min after acute administration of BROMO, and in the ventral posterior and dorsomedial nuclei of the thalamus from 30 to 120 min. In contrast, the signal intensity was decreased in the caudate–putamen at 30 min after acute administration of HPD, in the hypothalamus from 30 to 60 min, and in the perirhinal cortex at 30 min. After chronic (2 weeks) HPD treatment, acute administration of HPD decreased signal intensity in the caudate–putamen at 60 min, in the hypothalamus at 30 min, the perirhinal cortex from 2 to 120 min, the dorsomedial and ventral posterior nuclei of the thalamus from 2 to 120 min, and the medial nucleus of the amygdala from 60 to 120 min. These results suggest that (1) the D₂ receptor agonist increased the activity of the thalamic nuclei and the hypothalamus, while the D₂ receptor antagonist suppressed brain activity in the regions where D₂ receptors were present, (2) the suppression of brain activity in the thalamic nuclei and the perirhinal cortex by acute HPD administration was enhanced by chronic HPD treatment, and (3) the effects of antipsychotic drugs on the thalamus, amygdala, and perirhinal cortex may be related to their therapeutic efficacy, since clinical improvement in schizophrenic patients appears several days after the start of HPD treatment.     

Computer-assisted image analysis of caveolin-1 involvement in the internalization process of adenosine A2A-dopamine D2 receptor heterodimers

A functional aspect of horizontal molecular networks has been investigated experimentally, namely the heteromerization between adenosine A_2A and dopamine D₂ receptors and the possible role of caveolin-1 in the cotrafficking of these molecular complexes. This study has been carried out by means of computer-assisted image analysis procedure of laser images of membrane immunoreactivity of caveolin-1, A_2A, D₁, and D₂ receptors obtained in two clones of Chinese hamster ovary cells—one transfected with A_2A and dopamine D₁ receptors and the other one with A_2A and D₂ receptors. Cells were treated for 3 h with 10 μM D₁ receptor agonist SKF 38393, 50 μM D₂-D₃ receptor agonist quinpirole, and 200 nM A_2A receptor agonist CGS 21680. In A_2A-D₁-cotransfected cells, caveolin-1 was found to colocalize with both A_2A and D₁ receptors and treatment with SKF 38393 induced internalization of caveolin-1 and D₁ receptors, with a preferential internalization of D₁ receptors colocalized with caveolin-1. In A_2A-D₂-cotransfected cells, caveolin-1 was found to colocalize with both A_2A and D₂ receptors and either CGS 21680 or quinpirole treatment induced internalization of caveolin-1 and A_2A and D₂ receptors, with a preferential internalization of A_2A and D₂ receptors colocalized with caveolin-1. The results suggest that A_2A and D₂ receptors and caveolin-1 likely interact forming a macrocomplex that internalizes upon agonist treatment. These observations are discussed in the frame of receptor oligomerization and of the possible functional role of caveolin-1 in the process of co-internalization and, hence, in controlling the permanence of receptors at the plasma membrane level (prerequisite for receptor mosaic organization and plastic adjustments) and in the control of receptor desensitization. This paper is dedicated to Luciano Martini, Professor of Endocrinology in Milano and to Faustino Savoldi, Professor of Neurolgy in Pavia. Department of Human Anatomy and Physiology, Section of Antomy, University of Padova, 35121 Padova, Italy     

Frontal dopamine D(2/3) receptor binding in drug-naive first-episode schizophrenic patients correlates with positive psychotic symptoms and gender.

BACKGROUND: The aim of the study was to examine extrastriatal dopamine D(2/3) receptor binding and psychopathology in schizophrenic patients, and to relate binding potential (BP) values to psychopathology. METHODS: Twenty-five drug-naive schizophrenic patients and 20 healthy controls were examined with single-photon emission computerized tomography (SPECT) using the D(2/3)-receptor ligand [123I]epidepride. RESULTS: In the hitherto largest study on extrastriatal D(2/3) receptors we detected a significant correlation between frontal D(2/3) BP values and positive schizophrenic symptoms in the larger group of male schizophrenic patients, higher frontal BP values in male (n = 17) compared to female (n = 8) patients, and - in accordance with this - significantly fewer positive schizophrenic symptoms in the female patients. No significant differences in BP values were observed between patients and controls; the patients, however, had significantly higher BP in the right compared to the left thalamus, whereas no significant hemispheric imbalances were observed in the healthy subjects. CONCLUSIONS: The present data are the first to confirm a significant correlation between frontal D(2/3) receptor BP values and positive symptoms in male schizophrenic patients. They are in agreement with the hypothesis that frontal D(2/3) receptor activity is significant for positive psychotic symptoms. Additionally, the data support a thalamic hemispheric imbalance in schizophrenia.     

Genetic control of dopamine and serotonin receptors in brain regions of inbred mice

In this report the genetic determinants of dopamine and serotonin receptors are investigated. We have used two types of radioreceptor binding assays to identify and quantify these neurotransmitter receptors in various brain regions of inbred mice. In the first method dopamine and serotonin sites are quantified using [3H]spiperone in the presence of appropriate blanking agents. These results are compared with those obtained by the use of [3H]domperidone and [3H]mianserin to label D2 and S2 sites, respectively. Both methods yield nearly identical results. Strain differences in D2 sites are found in the striatum, olfactory tubercle and pituitary. The density of dopaminergic sites is uncorrelated in the 3 brain regions in all mouse strains studied, suggesting that genetic determination of receptor density is independently regulated in each region. Similar observations have been made for S2 receptors in the striatum, hypothalamus, olfactory tubercle and frontal cortex. Analysis of D3 and D2 binding sites in recombinant inbred lines suggests that each site may be determined monogenically.     

Effects of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin on the dopaminergic and cholinergic receptors as evaluated by positron emission tomography in the Rhesus monkey

Summary The effects of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (R-THBP) on the central cholinergic and dopaminergic systems in the Rhesus monkey brain were investigated by positron emission tomography (PET) with the muscarinic cholinergic receptor ligands (N-[¹¹C]methyl-benztropine) and dopaminergic receptor ligands selective for D₁ D₂, and D₃ subtypes ([¹¹C]SCH23390, N-[¹¹C]methyl-spiperone, and (+)[¹¹C]UH232, respectively). None of the doses (3, 10, and 30 mg/kg i.v.) of R-THBP used significantly affected the regional cerebral blood flow (rCBF as determined by Raichle's H₂ ¹⁵O method), and 10 mg/kg of R-THBP had little effect on the regional cerebral metabolic rate of glucose (rCMRglc) in the Rhesus monkey brain, as assessed by the graphical [¹⁸F]fluoro-deoxyglucose method. The effect of R-THBP on the muscarinic cholinergic system was dose dependent; while 3 mg/kg of R-THBP did not significantly alter the uptake ratio of N-[¹¹C]methyl-benztropine in several brain regions to that in the cerebellum, 10 and 30 mg/kg of R-THBP significantly reduced the uptake ratio in the thalamus, as well as in the frontal and temporal cortices. None of the doses (3, 10, and 30 mg/kg i.v.) of R-THBP tested affected [¹¹C]SCH23390 (dopamine D₁ receptor) binding. However, the k3 value for N-[¹¹C]methyl-spiperone (dopamine D₂ receptor) binding, which represents the association rate × B_max value, was significantly decreased in the striatum. The uptake ratio of (+)[¹¹C]UH232 (dopamine D₃ receptor) in the striatum to that in the cerebellum was also decreased by administration of R-THBP (3 and 30 mg/kg i.v.). These findings suggest that R-THBP acts on dopamine D₂ and D₃ receptors selectively without markedly affecting dopamine D₁ receptor binding. Furthermore, the changes in cholinergic and dopamine D₂ and D₃ receptors in vivo can not be attributed to a change in rCBF but may depend on the action of R-THBP.Abbreviations R-THBP 6R-L-erythro-5,6,7,8-tetrahydrobiopterin - PET positron emission tomography - rCBF regional cerebral blood flow - rCMRglc regional cerebral metabolic rate of glucose     

Association between a promoter dopamine D2 receptor gene variant and the personality trait detachment.

BACKGROUND: Personality traits have shown considerable heritable components. Striatal dopamine D(2) receptor density, as determined by positron-emission tomography, has been associated with detached personality, as assessed by the Karolinska Scales of Personality. A putative functional promoter polymorphism in the dopamine D(2) receptor gene (DRD2), -141C ins/del, has been associated with dopamine D(2) receptor density. METHODS: In this study healthy subjects (n = 235) who filled in at least one of several personality questionnaires (Karolinska Scales of Personality, Swedish Universities Scales of Personality, Health-relevant Five-factor Personality Inventory, and Temperament and Character Inventory) were analyzed with regard to the DRD2 -141C ins/del variant. RESULTS: There was an association (p =.001) between the DRD2 -141C ins/del variant and Karolinska Scales of Personality Detachment scale, indicating higher scores in subjects with the -141C del variant. There were also associations between the DRD2 -141C ins/del variant and a number of Karolinska Scales of Personality and Swedish Universities Scales of Personality Neuroticism-related scales, but of these only Swedish Universities Scales of Personality Lack of Assertiveness scale (p =.001) survived correction for multiple testing. CONCLUSIONS: These results add further support for the involvement of dopamine D(2) receptor in certain personality traits. The results should be treated with caution until replicated.     

Evidence of dopamine dysfunction in the hypothalamus of patients with Parkinson's disease: an in vivo 11C-raclopride PET study

A mild to moderate reduction in dopamine, noradrenaline and serotonin levels alongside a progressive loss of hypocretin cells and melanin hormone concentrating cells has been reported in the hypothalamus of PD at postmortem. Hypothalamic uptake of ¹⁸F-dopa PET, an in vivo marker of dysfunction of monoaminergic neurons, is also significantly reduced in these patients. These data indicate a general impairment of hypothalamic function in PD. Dopamine receptors play an important role in the regulation of hypothalamic pathways. To date, possible changes in hypothalamic D₂ receptor availability have not been investigated in PD. The objective in this study was to assess dopamine D₂ receptor availability in hypothalamus of patients with idiopathic Parkinson's disease (PD) using positron emission tomography (PET) with ¹¹C-raclopride (RAC). We evaluated D₂ binding in RAC PET images of 14 PD patients using both region of interest (ROI) analysis and a voxel based approach. ROIs for the hypothalamus were traced on the subject's MRI co-registered to the PET image. ¹¹C-raclopride binding potentials (BP) for hypothalamus were obtained by applying ROIs onto parametric images. Findings were compared with those of 9 normal controls. We found a significant reduction in the mean hypothalamic RAC BP of the PD patients compared with the normal controls (0.2714 ± 0.06 vs. 0.3861 ± 0.04; mean ± SD; p = 0.0005). ROI results were confirmed with statistical parametric mapping (SPM). Individual hypothalamic BP values of PD patients did not correlate with age, disease duration, disease severity and levodopa equivalent dose. It remains to be ascertained whether the reductions in hypothalamic D₂ receptor availability seen in PD are disease related, the results of chronic exposure to levodopa or both. Our results provide further evidence of dopaminergic dysfunction in the hypothalamus in PD, and this may contribute to the development of sleep, endocrine and autonomic disorders.     

Effects of alkylating agents on dopamine D(3) receptors in rat brain: selective protection by dopamine

Dopamine D₃ receptors are structurally highly homologous to other D₂-like dopamine receptors, but differ from them pharmacologically. D₃ receptors are notably resistant to alkylation by 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), which readily alkylates D₂ receptors. We compared EEDQ with N-(p-isothiocyanatophenethyl)spiperone (NIPS), a selective D₂-like receptor alkylating agent, for effects on D₃ and D₂ receptors in rat brain using autoradiographic analysis. Neither agent occluded D₃ receptors in vivo at doses that produced substantial blockade of D₂ receptors, even after catecholamine-depleting pretreatments. In vitro, however, D₃ receptors were readily alkylated by both NIPS (IC₅₀=40 nM) and EEDQ (IC₅₀=12 μM). These effects on D₃ sites were blocked by nM concentrations of dopamine, whereas μM concentrations were required to protect D₂ receptors from the alkylating agents. The findings are consistent with the view that alkylation of D₃ receptors in vivo is prevented by its high affinity for even minor concentrations of endogenous dopamine.     

Regulation of dopamine receptor and neuropeptide expression in the basal ganglia of monkeys treated with MPTP

In Parkinson's disease (PD), striatal dopamine deficiency has been associated with complex changes in the functional and neurochemical anatomy of the basal ganglia. In this study, we simultaneously analyzed the regulation of D1 and D2 dopamine receptors and levels of the neuropeptides, substance P, and enkephalin (ENK) in various basal ganglia nuclei following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic denervation of striatum in nonhuman primates. Both unilateral and bilateral lesioned animals were used for this study. Striatal dopamine deficiency resulted in distinct alterations in D1, D2, substance P, and enkephalin levels and distribution: (1) Both D1 and D2 protein levels were significantly up-regulated in striatum. (2) There was an overall up-regulation of striatal substance P expression following dopamine denervation. (3) Substance P distribution was 'reversed' in dopamine depleted striatum: striosomes, which normally express higher levels of substance P, showed decreased expression, whereas substance P expression was up-regulated in the matrix. (4) Substance P expression was up-regulated in the internal segment of the globus pallidus (GPi), but remained unchanged in substantia nigra (SN). (5) Enkephalin levels were increased in striatum and the external segment of the globus pallidus (GPe), but not in substantia nigra. All the changes were more pronounced in the bilateral lesioned monkeys, though the data represent a pooled statistical evaluation of unilateral and bilateral lesioned monkeys. Our studies indicate that D1 and D2 dopamine receptors and substance P and enkephalin undergo regulatory changes in response to nigrostriatal dopamine denervation. Simultaneous study of the alterations in these various components of the 'direct' and 'indirect' pathways in the same animals will enable better understanding of the pathophysiology of PD and its therapeutic targets.     

Binding characteristics of high-affinity dopamine D2/D3 receptor agonists, 11C-PPHT and 11C-ZYY-339 in rodents and imaging in non-human primates by PET

We have evaluated the in vitro autoradiographic binding characteristics and in vivo brain distribution of two high-affinity dopamine D2/D3 receptor agonists, (+/-)-2-(N-phenethyl-N-1'-11C-propyl)amino-5-hydroxytetralin (11C-PPHT) and (+/-)-2-(N-cyclohexylethyl-N-1'-11C-propyl)amino-5-hydroxytetralin (11C-ZYY-339) in rodents and in monkeys using positron emission tomography (PET). In vitro autoradiograms in rat brain slices with (11)C-PPHT and 11C-ZYY-339 revealed binding to dopaminergic regions in the striata, which was substantially (>90%) displaced by 10 microM sulpiride. Striatal binding was also removed in the presence of 5-guanylylimidophosphate (Gpp(NH)p), indicative of binding of these radiotracers to the high-affinity (HA) state. The results of in vivo studies in rats exhibited binding of the two radiotracers to the striata (striata/cerebellum approached 2 in 30 min). The regional selectivity to the striata was reduced by preadministration of haloperidol. PET studies in male rhesus monkeys using an ECAT EXACT HR+ scanner indicated localization of 11C-PPHT and 11C-ZYY-339 in the striata and thalamus. Striata to cerebellum and thalamus to cerebellum ratios were low (1.5 and 1.3, respectively, at 30 min postinjection) for both 11C-PPHT and 11C-ZYY-339, apparently due to the slower nonspecific clearance from cerebellum. These findings with 11C-PPHT and 11C-ZYY-339 indicate the possibility of in vivo imaging of high-affinity state of dopamine D2/D3 receptors in both the striata and the thalamus.     

Anatomical relationship between opioid peptides and receptors in rhesus monkey brain

To determine whether opioid peptide-receptor pharmacological association found in vitro (e.g., enkephalin-delta, dynorphin-kappa) predict anatomical relationships in situ, immunocytochemical and receptor autoradiographic studies were carried out on adjacent sections from the same brains of formaldehyde-perfused rhesus monkeys. Apparent mu and kappa opioid receptors (labeled, respectively, by [3H] naloxone and [3H]bremazocine under different incubation conditions), but not delta opioid receptors (labeled by [3H]D-Ala2, D-Leu5-enkephalin), survived the fixation procedure, and were found to be colocalized throughout the brain. We have observed complex associations between these binding sites and one, two, or all three opioid peptide systems (i.e., proopiomelanocortin, proenkephalin, and prodynorphin) in different brain regions. These multiple opioid peptide-receptor subtype associations are apparent, for example, in neural systems involved in the processing of pain stimuli, and may be important for mediating different types of analgesia. Since differential processing of proenkephalin and prodynorphin can give rise to opioids of varying receptor selectivities, the colocalization of opioid receptor subtypes may signify that such processing is a key regulatory event in determining which receptor subtype is activated and, thus, the physiological consequences of opioid neurotransmission.     

Dopamine D1 and D2 receptor binding sites in brain samples from depressed suicides and controls

Dopamine D₁ and D₂ receptors were measured (by saturation binding of [³H]SCH23390 and [³H]raclopride) in caudate, putamen and nucleus accumbens, obtained at post-mortem from suicide victims with a firm retrospective diagnosis of depression and matched controls. There were no differences in the number or affinity of D₁ or D₂ receptors between suicides who had been free of antidepressants for at least three months prior to death, and controls. Increased numbers and decreased affinity of D₂ receptors were however found in each brain region of antidepressant-treated suicides. We argue that these increases are related to concurrent treatment with neuroleptics rather than a direct effect of antidepressants. Increased numbers of D₁ receptors in antidepressant-treated suicides were seen only in nucleus accumbens. This increase could not be clearly attributed to neuroleptics and may be related to antidepressant treatment.     

Measurement error analysis for the determination of dopamine D2 receptor occupancy using the agonist radioligand [11C]MNPA

The purpose of this study is to investigate errors in quantitative analysis for estimating dopamine D₂ receptor occupancy of antipsychotics with agonist radioligand [¹¹C]MNPA by numerical simulation, with particular attention to the validity of a quantitative approach based on the use of a reference region. Synthetic data were validated using clinical data combined with a bootstrap approach. Time–activity curves (TACs) of [¹¹C]MNPA were simulated, and the reliability of binding potential (BP_ND) and occupancy estimated by nonlinear least square (NLS) fitting and a simplified reference tissue model (SRTM) were investigated for various noise levels and scan durations. In the human positron emission tomography (PET) study with and without antipsychotic, risperidone, the uncertainty of BP_ND and occupancy estimated by SRTM was investigated using resampled TACs based on bootstrap approach with weighted residual errors of fitting. For both NLS and SRTM, it was possible to have <3% of bias in occupancy estimates of [¹¹C]MNPA by 60 mins. However, shortened scan duration degrades the quantification of very small binding potentials, especially in case of SRTM. Observations were replicated on the clinical data. Results showed that dopamine D₂ receptor occupancy by antipsychotics can be estimated precisely in region of interest analysis by SRTM with a longer than 60-min [¹¹C]MNPA PET scan duration.     

Ketamine increases the striatal N-[C]methylspiperone binding in vivo: positron emission tomography study using conscious rhesus monkey

A system for positron emission tomography study of conscious monkeys was newly developed. By use of this system in combination with a microdialysis technique, the effect of ketamine on the binding and release of dopamine was investigated. The administration of ketamine (5 mg/kg) caused sedation accompanied by psychotic symptoms such as nystagmus and stereotyped movements of extremities. During this psychotomimetic period produced by ketamine, a significant increase in the accumulation of the dopamine D₂ receptor ligand N-[¹¹C]methylspiperone was observed in the striatum compared with the level in the conscious state, while no significant change was observed in the frontal cortex and cerebellum. In contrast to the use of ketamine as the anesthetic, pentobarbital (25 mg/kg), which produced deeper anesthesia but no psychotic symptoms, caused a decrease in the accumulation of N-[¹¹C]methylspiperone in the striatum. Kinetic analysis, conducted by a graphical method, revealed that the value of the association constant (K3) for N-[¹¹C]methylspiperone binding in the striatum was increased to approximately 130% by ketamine and decreased to approximately 70% by pentobarbital compared with the control values. Furthermore, the release of dopamine from the striatum measured by microdialysis was not affected by ketamine anesthesia. These results indicate that ketamine facilitates striatal dopaminergic neurotransmission through increasing the binding activity of dopamine D₂ receptors in the striatum, and suggest that these changes may be related to the psychotomimetic behavioral symptoms of this drug.