In vivo imaging of D2 dopamine receptors in schizophrenia: the ups and downs of neuroimaging research.
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Disruption of the cytochrome c gene in xylose-utilizing yeast Pichia stipitis leads to higher ethanol production.
The xylose-utilizing yeast, Pichia stipitis, has a complex respiratory system that contains cytochrome and non-cytochrome alternative electron transport chains in its mitochondria. To gain primary insights into the alternative respiratory pathway, a cytochrome c gene (PsCYC1, Accession No. AF030426) was cloned from wild-type P. stipitis CBS 6054 by cross-hybridization to CYC1 from Saccharomyces cerevisiae. The 333 bp open reading frame of PsCYC1 showed 74% and 69% identity to ScCYC1 and ScCYC7, respectively, at the DNA level. Disruption of PsCYC1 resulted in a mutant that uses the salicylhydroxamic acid (SHAM)-sensitive respiratory pathway for aerobic energy production. Cytochrome spectra revealed that cytochromes c and a.a(3) both disappeared in the cyc1-Delta mutant, so no electron flow through the cytochrome c oxidase was possible. The cyc1-Delta mutant showed 50% lower growth rates than the parent when grown on fermentable sugars. The cyc1-Delta mutant was also found to be unable to grow on glycerol. Interestingly, the mutant produced 0.46 g/g ethanol from 8% xylose, which was 21% higher in yield than the parental strain (0.38 g/g). These results suggested that the alternative pathway might play an important role in supporting xylose conversion to ethanol under oxygen-limiting conditions.
Antifungal Agents↗
Distribution of dopamine D1-D4 receptor subtypes in human dorsal vagal complex.
The distribution of D1/D5, D2/D3, D2/D3/D4, and individually, putative D2-D4 receptors across the dorsal vagal complex of the human medulla was assessed with quantitative receptor autoradiography. D1/D5 receptors were found in very low levels. D2 receptors were concentrated in the intermediate and medial subnuclei of the nucleus of the solitary tract (NTS), and in the dorsal motor nucleus of the vagus (DMN), while D3 receptors were more homogeneous across the entire NTS, area postrema (AP), and DMN. In contrast, D4 receptors were found almost exclusively in the intermediate and medial subnuclei of the NTS, and in the DMN. These findings suggest that the "D2 family" of receptors is an important component of brain stem mechanisms regulating visceral function, including gastrointestinal systems, such as emesis, along with cardiovascular and pulmonary systems. Compounds with individual selectivity for D2, D3, or D4 receptors may be useful in the manipulation of neural networks regulating these visceral systems.
Adolescent↗
Effect of reserpine-induced depletion of synaptic dopamine on [11C]raclopride binding to D2-dopamine receptors in the monkey brain.
Positron emission tomography was used to examine the in vivo binding of [11C]raclopride to D2-dopamine (DA) receptors in the striatum of two Cynomolgus monkeys after a single dose of reserpine (1 mg/kg, i.v.). A Scatchard procedure was repeated five times to follow D2 receptor density and apparent affinity for 7 weeks after reserpine. Reserpine-induced depletion of DA lead to a marked increase in [11C]raclopride binding, which was still detectable 20 days after treatment. Scatchard analyses indicated that the measured increase in [11C]raclopride binding reflected an increase in receptor affinity but no evident change in receptor density (Bmax). Thus, the increase in [11C]raclopride binding after reserpine should correspond to a reduced competition with endogenous DA for binding to D2 receptors. The results were used to estimate the DA-induced D2 occupancy to be about 40% at physiological conditions.
Animals↗
Long-term stability of neurotransmitter activity investigated with 11C-raclopride PET.
There is evidence for the shift of regulatory setpoints of functionally linked neurotransmitter systems as a basis of psychiatric disorders. 11C-raclopride PET, which has been shown to be sensitive to changes in endogenous dopamine and has a high short-term test-retest reliability, can be used to investigate different regulatory states of the dopaminergic system with respect to psychiatric diseases and pharmacological influences. Prior to these studies, the reliability of the method over time has to be established. The current study was performed in order to evaluate the long-term stability of the striatal dopaminergic system. Eight normal healthy subjects (mean age: 48.1 years; range: 24-75) were studied twice with 11C-raclopride PET two times under resting conditions with a mean time interval between the scans of 11.3 months (range: 1-19). The ratio of basal ganglia (BG) to cerebellar (CB) distribution volumes (DVs) revealed a mean absolute change of 6.94 (range: 0.0-12.87%) between study A and B. BG DVs mean absolute change was 6.30% (range: 0.55-30.46%), CB DVs mean absolute change was 8.65% (range: 3.51-16.33%). The mean change of the BG/CB ratio was -0.33% (range: 12.87-12.34%). BG DVs mean change was 4.55% (range: 4.2-30.46%), CB DVs mean change was 5.10% (range: -10.71-16.33%). The intraindividual differences between the two scans in our study were not significantly different as compared to the 24 hour interval test-retest data, which have been published earlier (repeated measures ANOVA with df = 11; F = 0.49; P = 0.50) [Volkow et al. (1993) J. Nucl. Med., 34:609-613]. The intraclass correlation of the DV ratio index was r = 0.81. The binding potential in the baseline scans and repeated scans showed a non-significant correlation with age (r = -0.58, P = 0.13). Interindividually, the DV ratio index revealed a mean of 3.18 (range = 2.55-3.68, SD = 0.42 in study A and of 3.16 (range 2.37-3.57, SD = 0.41) in study B. The intrasubject stability of the 11C-raclopride binding over a long-term period in normal human subjects suggests the feasibility of study designs investigating the long-term changes of the dopaminergic responsivity after pharmacological challenges. The baseline stability will also serve as a necessary reference for further dose-response studies and investigations of subchronical pharmacological interventions.
Adult↗
D1 dopamine receptors mediate neuroleptic-induced Fos expression in the islands of Calleja.
Systemic injections of the selective, full, D1 agonists A-77636 and SKF-82958 induced pronounced Fos-like immunoreactivity in the islands of Calleja in the olfactory tubercle of intact rats. Fos expression in this region could also be induced by injections of the D2-like dopamine antagonist raclopride (0.5 mg/kg). Pretreatment with the selective D1 dopamine antagonist SCH-23390 (0.2 mg/kg) completely abolished this response, but was without significant effect on raclopride-induced Fos expression in the dorsolateral region of the striatum. SCH-23390 was also able to prevent the atypical neuroleptic clozapine (30 mg/kg) from inducing Fos expression in the islands of Calleja. These findings demonstrate that stimulation of D1 dopamine receptors plays an essential role in neuroleptic induction of Fos-like immunoreactivity in the islands of Calleja, but not in the dorsal striatum, and thus suggest that different mechanisms underlie neuroleptic stimulation of immediate early gene expression in these two structures.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Effects of NMDA antagonism on striatal dopamine release in healthy subjects: application of a novel PET approach.
Agents that antagonize the glutamatergic N-methyl-d-aspartate (NMDA) receptor, such as phenylcyclidine (PCP) and ketamine, produce a behavioral state in healthy volunteers that resembles some aspects of schizophrenia. A dysfunction in NMDA-dopaminergic interactions has been proposed as a mechanism for these behavioral effects. In this study, we examined the effects of ketamine on striatal dopamine release in healthy human subjects with a novel 11C-raclopride/PET displacement paradigm and compared these effects to administration of saline and the direct-acting dopamine agonist amphetamine. We found that the percent decreases (mean +/- SD) in specific 11C-raclopride binding from baseline for ketamine (11.2 +/- 8.9) was greater than for saline (1.9 +/- 3.7) (t = 2.4, df = 13, P = 0.003) indicating that ketamine caused increases in striatal synaptic dopamine concentrations. Ketamine-related binding changes were not significantly different than the decreases in percent change (mean +/- SD) in specific 11C-raclopride binding caused by amphetamine (15.5 +/- 6.2) (t = 1.3, df = 19, P = 0.21). Ketamine-induced changes in 11C-raclopride-specific binding were significantly correlated with induction of schizophrenia-like symptoms. The implications of this brain imaging method for studies of schizophrenia and the mechanism of action of antipsychotic drugs are discussed.
Adult↗
Differential modulation of dopamine D1-receptor binding and mRNA expression in the basal ganglia by the D1-receptor antagonist, SCH-23390.
Dopamine D1-receptor binding in the basal ganglia is differentially regulated by subtype nonspecific dopamine antagonists such as the antipsychotic, Fluphenazine. The purpose of the present study was to determine the relative contributions of D1 and D2 receptor systems in the regulation of basal ganglia D1-receptor binding. Rats were injected twice daily for 21 days with saline, the D1-receptor antagonist, SCH-23390, the D2-receptor antagonist, Raclopride, or both SCH-23390 and Raclopride. Dopamine D1-receptor levels (as indicated by [125I]SCH-23982 binding) and mRNA expression were measured using receptor autoradiographic and in situ hybridization histochemical techniques. [125I]NCQ-298 binding to D2-receptors was also measured as a positive control for the effects of Raclopride. SCH-23390 administration independently increased [125I]SCH-23982 binding in a region-dependent manner with the greatest increases occurring in the entopeduncular nucleus. SCH-23390 also increased D1-receptor mRNA expression in specific striatal subregions suggesting that increases in binding were related to changes in receptor synthesis. In addition, Raclopride independently enhanced D2 binding with comparable increases observed in extrastriatal regions and increases of a lesser magnitude in the striatum. These data show that the modulation of basal ganglia D1-receptor binding observed in animals treated with nonselective antagonists is due primarily to the blockade of D1-receptors. The differential enhancement in basal ganglia D1 binding observed after D1-receptor blockade may be due to anatomical or phenotypic heterogeneity within the population of striatal D1-receptor synthesizing neurons. Similarly, the differential enhancement in striatal and extrastriatal D2-receptor binding may be due to differences in the regulation of striatal and extrastriatal D2-receptor synthesizing neurons.
Animals↗
Effect of cocaine self-administration on dopamine D2 receptors in rhesus monkeys.
The present study used autoradiography to examine the effects of chronic self-administration of cocaine on the density of dopamine D2 receptors in nonhuman primates. Three rhesus monkeys intravenously self-administered an average of 1.35 mg/kg cocaine per day for 18-22 months until they were euthanized immediately after a self-administration session. Binding site density of the D2 ligand [3H]raclopride (2 nM) was assessed in these monkeys as well as three untreated controls, using quantitative in vitro receptor autoradiography. As compared to untreated controls, D2 binding site density was significantly lower in the animals that self-administered cocaine in all regions of the striatum rostral to the anterior commissure. These regions include the anterior and central regions of the caudate nucleus, putamen, olfactory tubercle, and both the shell and core of the nucleus accumbens. Within the substantia nigra and ventral tegmental area, by contrast, no differences were found in the density of D2 binding sites. These findings suggest a pervasive effect of cocaine on the regulation of D2 receptors in the striatum. The lack of change within the ventral midbrain, however, suggests a differential regulation of D2 receptors in the striatum and ventral midbrain. This study confirms and extends our knowledge of the neurobiological changes in the mesolimbic dopamine system that result from chronic exposure to cocaine.
Animals↗
Imaging dopamine D4 receptors in the living primate brain: a positron emission tomography study using the novel D1/D4 antagonist [11C]SDZ GLC 756.
The dopamine D4 receptor has lately attracted interest since it has been hypothesized to be involved in the pathogenesis and pharmacotherapy of neuropsychiatric diseases. The present study provides first in vivo evidence of dopamine D4 receptors in primate brain using a [11C]benzo[g]quinoline, the novel radioligand [11C]SDZ GLC 756 ([11C]GLC: in vitro dissociation constants at human receptor clones [nM]: 1.10 at D1; 0.40 at D2; 25 at D3; 0.18 at D4.2; 6.03 at D5). Dynamic positron emission tomography scans were performed on healthy baboons (Papio hamadryas, n = 3). Specific receptor binding (SB) was calculated for striatum and neocortex (frontal, temporal, parietal, and occipital) based on the differences between the regional and the cerebellar concentration of [11C]. Blockade of D1 and D5 receptors by SCH23390 (1.7 pmol/kg) diminished SB in the striatum by 55 +/- 4% (mean +/- standard deviation, P < 0.05) and in the frontal cortex by 13 +/- 8% (P < 0.05) when compared to SB in the unblocked state (SB(D1-D5)). In the presence of the dopamine antagonists SCH23390 (1.7 micromol/kg) and raclopride (5.7 pmol/kg)--which mask the D1, D2, D3, and D5 subtypes--SB of [11C]GLC to D4 receptors (SB(D4)) was demonstrated in the striatum and all cortical regions of interest. In the striatum, the ratio of SB(D4)/SB(D1-D5) was 0.13 +/- 0.07. In the neocortex, SB(D4)/SB(D1-D5) was notably higher (0.77 +/- 0.29; mean of all cortical regions of interest). The widespread distribution of dopamine D4 receptors suggests a basic functional role of this receptor subtype in the modulation of cortical and subcortical neuronal activity.
Animals↗
Changes in striatal D2-receptor density following chronic treatment with amphetamine as assessed with PET in nonhuman primates.
Recent brain imaging studies suggest that schizophrenia may be related to abnormally high amphetamine-induced dopamine release. It is known that repeated use of amphetamine may cause paranoid psychosis and persisting stereotypies. The biochemical background for these signs and symptoms has not been clarified. In this study, positron emission tomography and [11C]raclopride were used to determine central D2-dopamine receptor density (Bmax) and apparent affinity (K(D)app) in Cynomolgus monkeys before and after 14 days of treatment with d-amphetamine sulphate (2 mg/kg/day; s.c.). One day after withdrawal from amphetamine, K(D)app was increased, suggesting [11C]raclopride competition with elevated concentration of dopamine. At 7 and 14 days after withdrawal, there was a 19-26% decrease in Bmax but no change in K(D)app as compared to baseline. Although this study was performed on two monkeys only, there was thus no support for the view that chronic intermittent hyperactivity of the dopamine system may be related to an upregulation of striatal D2-dopamine receptors. Repeated administration of amphetamine may, rather, cause a long-lasting downregulation of the D2-receptor density, which may be a neurochemical correlate to the abnormal movements, anhedonia, anxiety, and depression seen in psychostimulant abusers.
Amphetamine-Related Disorders↗
Plasticity of responses to synaptic inputs in rat ventral striatal neurons after repeated administration of the dopamine D2 antagonist raclopride.
The effects of acute and repeated systemic administration of the dopaminergic D2 antagonist raclopride on responses of ventral striatal neurons were examined in chloral hydrate-anesthetized rats. Stimulating electrodes were placed in the entorhinal and perirhinal cortices, medial thalamus, and prelimbic cortex. Stimulation in water-injected control rats evoked one or occasionally two action potentials. Results were similar in rats injected acutely with raclopride (4 or 8 mg/kg) except that a small proportion of cells (5%) produced burst responses (defined as three or more evoked action potentials). In rats injected with raclopride daily for 7-14 days, burst responses were seen in a larger proportion of cells (17%) and bursts of up to nine action potentials could be evoked. The results suggest that repeated administration of dopaminergic agents can induce striking plastic changes of excitatory responses in a subset of ventral striatal neurons.
Animals↗
PET studies of binding competition between endogenous dopamine and the D1 radiotracer [11C]NNC 756.
NNC 756 ((+)-8-chloro-5-(2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl-2,3,4,5- tetrahydro-1H-3-benzazepine) is a new high affinity dopamine (DA) D1 receptor antagonist. Labeled with C-11, it has been used as a PET radiotracer to visualize D1 receptors both in striatal and extrastriatal areas, such as the prefrontal cortex. The goal of this study was to evaluate several methods for derivation of D1 receptor binding potential (BP) with [11C]NNC 756 in baboons, and to use these methods to assess the vulnerability of [11C]NNC 756 binding to competition by endogenous DA. A three-compartment model provided a good fit to PET data acquired following a single bolus injection. BP values obtained with this analysis were in good agreement with values derived from in vitro studies. BP values measured following injection of the potent DA releaser amphetamine (1 mg/kg, n=2) were similar to values measured under control conditions. Kinetic parameters derived from single bolus experiments were used to design a bolus plus continuous infusion administration protocol aimed at achieving a state of sustained binding equilibrium. Injection of amphetamine during sustained equilibrium did not affect [11C]NNC 756 binding. Similar results were observed with another D1 radiotracer, [11C]SCH 23390. Doses of amphetamine used in this study are known to reduce by 20-40% the binding potential of several D2 receptors radiotracers. Therefore, the absence of displacement of [11C]NNC 756 by an endogenous DA surge may indicate important differences between D1 and D2 receptors in vivo, such as differences in proportion of high affinity states not occupied by DA at baseline. These findings may also imply that a simple binding competition model is inadequate to account for the effects of manipulation of endogenous DA levels on the in vivo binding of radiolabeled antagonists.
Amphetamine↗
GBR12909 attenuates amphetamine-induced striatal dopamine release as measured by [(11)C]raclopride continuous infusion PET scans.
Major neurochemical effects of methamphetamine include release of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) via a carrier-mediated exchange mechanism. Preclinical research supports the hypothesis that elevations of mesolimbic DA mediate the addictive and reinforcing effects of methamphetamine and amphetamine. This hypothesis has not been adequately tested in humans. Previous in vivo rodent microdialysis demonstrated that the high affinity DA uptake inhibitor, GBR12909, attenuates cocaine- and amphetamine-induced increases in mesolimbic DA. The present study determined the ability of GBR12909 to attenuate amphetamine-induced increases in striatal DA as measured by [(11)C]raclopride continuous infusion positron emission tomography (PET) scans in two Papio anubis baboons. [(11)C]Raclopride was given in a continuous infusion paradigm resulting in a flat volume of distribution vs. time for up to 45 min postinjection. At that time, a 1.5 mg/kg amphetamine i.v. bolus was administered which caused a significant (30.3%) reduction in the volume of distribution (V(3)"). The percent reduction in the volume of distribution and, hence, a measure of the intrasynaptic DA release ranged between 22-41%. GBR12909 (1 mg/kg, slow i.v. infusion) was administered 90 min before the administration of the radiotracer. The comparison of the volume of distribution before and after administration of GBR12909 showed that GBR12909 inhibited amphetamine-induced DA release by 74%. These experiments suggest that GBR12909 is an important prototypical medication to test the hypothesis that stimulant-induced euphoria is mediated by DA and, if the DA hypothesis is correct, a potential treatment agent for cocaine and methamphetamine abuse. Furthermore, this quantitative approach demonstrates a way of testing various treatment medications, including other forms of GBR12909 such as a decanoate derivative.
Amphetamine↗
Neurochemical changes in the entopeduncular nucleus and increased oral behavior in rats treated subchronically with clozapine or haloperidol.
The purpose of the present experiment was to test the possibility that atypical antipsychotics and classical antipsychotics differentially regulate specific neurochemical processes within the entopeduncular nucleus. For these experiments, rats were administered clozapine (25 mg/kg), haloperidol (1 mg/kg), or Tween-80 (control) daily for 21 days. Dopamine D(1)-receptor binding was assessed with in vitro receptor autoradiographic methods and the mRNAs corresponding to the two forms of glutamate decarboxylase (glutamate decarboxylase-65 and glutamate decarboxylase-67) were analyzed using in situ hybridization histochemical methods. In addition, vacuous chewing movements (VCM) were measured throughout the drug administration period as a functional indicator of drug action and changes in striatal dopamine D(2)-receptor binding were measured as a positive control for D(2)-receptor antagonist properties of haloperidol and clozapine. In agreement with previous reports, haloperidol increased D(2)-receptor binding throughout the striatum while clozapine had a more limited impact on D(2)-receptors. Behavioral analysis revealed that both haloperidol and clozapine enhanced the display of vacuous chewing movements to a similar extent but with a different postinjection latency. In the entopeduncular nucleus, clozapine increased D(1)-receptor binding compared to controls while haloperidol was without effect. With respect to the regulation of GAD mRNAs, haloperidol increased glutamate decarboxylase-65 and glutamate decarboxylase-67 mRNA levels throughout the entopeduncular nucleus. The effects of clozapine were restricted to increases in glutamate decarboxylase-65 mRNA. These studies show that clozapine and haloperidol, both of which increase the occurrence of VCM, differentially modulate the neurochemistry of the entopeduncular nucleus.
Animals↗
High sensitivity determination of the remoxipride hydroquinone metabolite NCQ-344 in plasma by coupled column reversed-phase liquid chromatography and electrochemical detection.
An HPLC method for the determination of NCQ-344, a remoxipride metabolite with a hydroquinone structure, in human plasma is described. Special precautions for the sampling were necessary as the compound rapidly decomposes. An efficient clean-up of the plasma samples was necessary to make use of the inherent sensitivity of the electrochemical detector. This was accomplished by a fast and simple liquid-liquid extraction at pH 7.05 combined with further cleaning on-line by using a short cyanopropyl column as the first column in a column switching system. A heart-cut from the cyanopropyl column containing the NCQ-344 fraction was then injected onto the analytical octadecyl silica column and NCQ-344 was detected at an oxidation potential of 0.70 V. The absolute recovery was > 95% and concentrations down to 0.10 nM could be determined with acceptable precision. The NCQ-344 levels in a limited number of samples from patients given remoxipride were found to be between 0.10 and 1 nM. The remoxipride concentrations in the same samples were 5,000-20,000 nM.
Chromatography, High Pressure Liquid↗
Myeloperoxidase-based chemiluminescence of polymorphonuclear leukocytes and monocytes.
Luminol and lucigenin chemiluminescence (CL) responses produced by separated human blood polymorphonuclear leukocytes (pmn) and monocytes (mono) have been studied following stimulation with the surface-receptor agonist fMLP (a synthetic chemotactic peptide) and the protein kinase C activator phorbol myristate acetate (PMA). Pmn produced two- to threefold the luminol CL and superoxide anion (O2-) levels of mono; lucigenin CL was similar for both cell-types. The myeloperoxidase (MPO) inhibitor salicylhydroxamic acid (SHA) abrogated luminol but not lucigenin CL in both cell types, but did not further inhibit the already grossly subnormal luminol CL responses seen with MPO-deficient cells which produced normal lucigenin CL. SHA also profoundly inhibited the luminol CL response in a cell-free MPO-H2O2 system. Mono lucigenin CL does not appear to specifically measure O2- production. These data show that luminol CL provides a useful measure of pmn and also mono MPO activity. However, analysis of the effects of various reactive oxygen species (ROS) scavengers, assessed on phagocyte and cell-free CL systems (both MPO-H2O2 and superoxide generating) suggest that the luminol CL signal is not entirely dependent on MPO activity.
Acridines↗
Effect of amphetamine on extrastriatal D2 dopamine receptor binding in the primate brain: a PET study.
[(11)C]raclopride binding to D2 dopamine receptors in the striatum is sensitive to drug-induced changes of endogenous dopamine concentration. We recently developed the new radioligand [(11)C]FLB 457, which is suitable for positron emission tomography (PET) studies of extrastriatal D2 dopamine receptors. The purpose of this PET study was to examine the effect of amphetamine on [(11)C]FLB 457 binding in extrastriatal regions. Each of three cynomolgus monkeys was examined at baseline conditions, 15 min and 3 h after I.V. injection of amphetamine (2 mg/kg). The effect of amphetamine was calculated from the ratio of specific [(11)C]FLB 457 binding to the binding in the cerebellum, a region which was used as reference for free and nonspecific binding in the brain. The changes of the ratio in the striatum, the thalamus, and the neocortex were between -1.2% and -15.5% at 15 min and -2.1% and -16.3% at 3 h, respectively, after amphetamine administration. The reductions of the binding ratios in the extrastriatal regions are similar to those reported for [(11)C]raclopride binding in the striatum. These data in a limited series of monkeys suggest that [(11)C]FLB 457 binding to D2 dopamine receptors in extrastriatal regions is sensitive to changes in the concentration of endogenous dopamine.
Amphetamine↗