Competition for sulphate during detoxification in the gut wall.
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Animals↗
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New approach to screening drugs for activity against African trypanosomes.
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Drug Evaluation, Preclinical↗
Evidence for striatal dopamine release during a video game.
Dopaminergic neurotransmission may be involved in learning, reinforcement of behaviour, attention, and sensorimotor integration. Binding of the radioligand 11C-labelled raclopride to dopamine D2 receptors is sensitive to levels of endogenous dopamine, which can be released by pharmacological challenge. Here we use 11C-labelled raclopride and positron emission tomography scans to provide evidence that endogenous dopamine is released in the human striatum during a goal-directed motor task, namely a video game. Binding of raclopride to dopamine receptors in the striatum was significantly reduced during the video game compared with baseline levels of binding, consistent with increased release and binding of dopamine to its receptors. The reduction in binding of raclopride in the striatum positively correlated with the performance level during the task and was greatest in the ventral striatum. These results show, to our knowledge for the first time, behavioural conditions under which dopamine is released in humans, and illustrate the ability of positron emission tomography to detect neurotransmitter fluxes in vivo during manipulations of behaviour.
Adult↗
Dopamine D4 receptors elevated in schizophrenia.
Although the biological basis of schizophrenia is not known, possible causes include genetic defects, viruses, amines, brain structure and metabolism, neuroreceptors, and G proteins. The hypothesis of dopamine overactivity in schizophrenia is based on the fact that neuroleptics block dopamine D2 receptors in direct relation to their clinical antipsychotic potencies. Moreover, dopamine D2 or D2-like receptors are elevated in postmortem schizophrenia brain tissue. This elevation, however, is only found in vivo using [11C]methylspiperone but not [11C]raclopride. The dopamine D4 receptor gene has not yet been excluded in schizophrenia because the 21 gene variants of D4 have not yet been tested. Because the link between D1 and D2 receptors is reduced in schizophrenia tissue, we tested whether one component of this link was sensitive to guanine nucleotide. We report here that the binding of [3H]raclopride to D2 receptors in schizophrenia was not sensitive to guanine nucleotide. This finding permitted analysis of data on the binding of [3H]emonapride to the D2, D3 and D4 receptors. We conclude that the combined density of D2 and D3 receptors (labelled by [3H]raclopride) is increased by only 10% in schizophrenia brain, as found by Farde et al., but that it is the density of dopamine D4 receptors which is sixfold elevated in schizophrenia. These findings resolve the apparent discrepancy, mentioned above, wherein the density of [11C]methylspiperone-labelled sites (D2, D3 and D4), but not that of [11C]raclopride-labelled sites (D2 and D3), was found elevated in the schizophrenia striatum.
Aged↗
Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects.
Cocaine blocks the reuptake of dopamine, a neurotransmitter involved in the control of movement, cognition, motivation and reward. This leads to an increase in extracellular dopamine; the reinforcing effect of cocaine is associated with elevated dopamine levels in the nucleus accumbens. But addiction to cocaine involves other effects, such as craving, loss of control and compulsive drug intake; the role of the dopamine system in these effects is less well-understood. We therefore used positron emission tomography (PET) to compare the responses of cocaine addicts and normal controls to intravenous methylphenidate, a drug that, like cocaine, causes an increase in synaptic dopamine. Addicts showed reduced dopamine release in the striatum, the brain region where the nucleus accumbens is located, and also had a reduced 'high' relative to controls. In contrast, addicts showed an increased response to methylphenidate in the thalamus (a region that conveys sensory input to the cortex). This thalamic response was associated with cocaine craving and was not seen in control subjects. Thus, our findings challenge the notion that addiction involves an enhanced striatal dopamine response to cocaine and/or an enhanced induction of euphoria. Moreover, they suggest a participation of thalamic dopamine pathways in cocaine addiction, a possibility that merits further investigation.
Adult↗
Dopamine activation of endogenous cannabinoid signaling in dorsal striatum.
We measured endogenous cannabinoid release in dorsal striatum of freely moving rats by microdialysis and gas chromatography/mass spectrometry. Neural activity stimulated the release of anandamide, but not of other endogenous cannabinoids such as 2-arachidonylglycerol. Moreover, anandamide release was increased eightfold over baseline after local administration of the D2-like (D2, D3, D4) dopamine receptor agonist quinpirole, a response that was prevented by the D2-like receptor antagonist raclopride. Administration of the D1-like (D1, D5) receptor agonist SKF38393 had no such effect. These results suggest that functional interactions between endocannabinoid and dopaminergic systems may contribute to striatal signaling. In agreement with this hypothesis, pretreatment with the cannabinoid antagonist SR141716A enhanced the stimulation of motor behavior elicited by systemic administration of quinpirole. The endocannabinoid system therefore may act as an inhibitory feedback mechanism countering dopamine-induced facilitation of motor activity.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Kinetic analysis of central [11C]raclopride binding to D2-dopamine receptors studied by PET--a comparison to the equilibrium analysis.
[11C]Raclopride binding to central D2-dopamine receptors in humans has previously been examined by positron emission tomography (PET). Based on the rapid occurrence of binding equilibrium, a saturation analysis has been developed for the determination of receptor density (Bmax) and affinity (Kd). For analysis of PET measurements obtained with other ligands, a kinetic three-compartment model has been used. In the present study, the brain uptake of [11C]raclopride was analyzed further by applying both a kinetic and an equilibrium analysis to data obtained from four PET experiments in each of three healthy subjects. First regional CBV was determined. In the second and third experiment, [11C]-raclopride with high and low specific activity was used. In a fourth experiment, the [11C]raclopride enantiomer [11C]FLB472 was used to examine the concentration of free radioligand and nonspecific binding in brain. Radio-activity in arterial blood was measured using an automated blood sampling system. Bmax and Kd values for [11C]raclopride binding could be determined also with the kinetic analysis. As expected theoretically, those values were similar to those obtained with the equilibrium analysis. In addition, the kinetic analysis allowed separate determination of the association and dissociation rate constants, kon and koff, respectively. Examination of [11C]raclopride and [11C]FLB472 uptake in brain regions devoid of specific D2-dopamine receptor binding indicated a fourth compartment in which uptake was reversible, nonstereoselective, and nonsaturable in the dose range studied.
Adult↗
Decrease in human striatal dopamine D2 receptor density with age: a PET study with [11C]raclopride.
The effect of age on human striatal dopamine D2 receptors was investigated with positron emission tomography (PET) using [11C]raclopride as a radioligand. Twenty-one healthy volunteers aged from 20 to 81 years were studied. An equilibrium method was applied and two separate PET scans with different specific activities of [11C]raclopride were performed. The maximal number of receptors (Bmax) and their dissociation constant (Kd) were calculated using Scatchard analysis. There was an age-dependent decline in the Bmax (r = -0.49; p = 0.02) of striatal D2 receptors while the Kd remained unchanged. The results show that there is an age-related loss of striatal D2 receptors, which, together with other changes in the brain nigrostriatal dopaminergic system, may contribute to extrapyramidal symptoms associated with aging.
Adult↗
Effects of blood flow on [11C]raclopride binding in the brain: model simulations and kinetic analysis of PET data.
To assess the stability of different measures of receptor occupancy from [11C]raclopride (a D2 antagonist) studies with positron emission tomography, we analyze data from five test/retest studies in normal volunteers in terms of individual model parameters from a three-compartment model, the distribution volume (DV) and the ratio of DVs from a receptor-containing region of interest to a non-receptor-containing region. Large variations were found in the individual model parameters, limiting their usefulness as an indicator of change in receptor systems. The DV ratio showed the smallest variation. Individual differences were reflected in the greater intersubject variation in DV than intrasubject variation. The potential effects of blood flow on these measurements were addressed both experimentally and by simulation studies using three models that explicitly incorporate blood flow into a compartmental model that also includes receptor-ligand binding. None of the models showed any variation in the DV with changes in blood flow as long as flow was held constant during the simulation. Experimentally, blood flow was significantly reduced by hyperventilation in a human subject. The DV was found to be reduced relative to baseline in the hyperventilation study, but the DV ratio remained unchanged. The effect of elevated and reduced flow was also tested in two baboon experiments in which PCO2 was varied. Some variability in the DV ratio was observed but was not correlated with changes in blood flow. This raises the possibility that other factors indirectly related to changes in blood flow (or PCO2) may cause changes in DV, and these effects need to be considered when evaluating experimental results.
Animals↗
Analgesic nephropathy: etiology, clinical syndrome, and clinicopathologic correlations in Australia.
Analgesic abuse is a major public health hazard in Australia, and analgesic nephropathy with consequent terminal renal failure is the underlying cause in 20% of the patients requiring dialysis and transplantation. Analgesics are invariably taken in the form of compounds and mixtures. In the aspirin-phenacetin-caffeine (APC) mixture, aspirin appears to be the major nephrotoxic agent and phenacetin appears to play a secondary and synergistic role. The renal disease associated with abuse of analgesics is characteristic and is part of a much wider clinical syndrome, the analgesic syndrome, which includes peptic ulcer disease (35%), anemia (60 to 90%), hypertension (15 to 70%), ischemic heart disease (35%), psychological and psychiatric manifestations, pigmentation, and possible gonadal- and pregnancy-related effects. The primary lesion in analgesic nephropathy is renal papillary necrosis (RPN), and this is a nephrotoxic effect common to all nonsteroid antiinflammatory agents. The most important factor in the management of patients with analgesic nephropathy is the cessation of analgesic abuse, and this leads to improvement and stabilization of renal function. A small proportion of patients will, however, deteriorate in relation to accelerated hypertension, persistent proteinuria, ischemic heart disease, and complications leading to nephrectomy. Patients with analgesic nephropathy are poor risk patients and have a poor prognosis, even after dialysis and transplantation.
Adult↗
Nucleus accumbens dopamine differentially mediates the formation and maintenance of monogamous pair bonds.
The involvement of dopamine within the nucleus accumbens in the formation and maintenance of pair bonds was assessed in a series of experiments using the monogamous prairie vole. We show that dopamine transmission that promotes pair bond formation occurs within the rostral shell of the nucleus accumbens, but not in its core or caudal shell. Within this specific brain region, D1- and D2-like receptor activation produced opposite effects: D1-like activation prevented pair bond formation, whereas D2-like activation facilitated it. After extended cohabitation with a female, male voles showed behavior indicative of pair bond maintenance-namely, selective aggression towards unfamiliar females. These voles also showed a significant upregulation in nucleus accumbens D1-like receptors, and blockade of these receptors abolished selective aggression. Thus, neuroplastic reorganization of the nucleus accumbens dopamine system is responsible for the enduring nature of monogamous pair bonding. Finally, we show that this system may also contribute to species-specific social organization.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Selective effects of low-dose D2 dopamine receptor antagonism in a reaction-time task in rats.
Operant responses involving a cued discrimination are sensitively disrupted by neuroleptic drugs that block dopamine (DA) receptors in the brain; however, it is not clear which DA receptor subtypes may be involved in these effects. The role of D1 or D2 DA receptor antagonists on the execution of a conditioned reaction-time (RT) motor task was investigated in the present study. Rats were trained to release a lever after the presentation of a visual cue within a RT limit to be reinforced by a food pellet. The D1 receptor antagonist SCH-23390, at doses that significantly decrease the behavioral effects of cocaine, did not impair performance at any dose (5, 10, or 20 micrograms/kg) injected subcutaneously. In contrast, a selective D2 receptor antagonist raclopride (50, 100, or 200 micrograms/kg) induced a dose-dependent increase in the number of incorrect responses (release of the lever over the RT limit) associated with an increase in the RT. The results suggest that the dopaminergic nigrostriatal system, which has previously been shown to be specifically involved in this RT task (Amalric and Koob 1987), appears to be a sensitive site for sensorimotor integration, and that the execution of the conditioned RT motor task may depend preferentially on the activation of the dopaminergic D2 receptors in this system.
Animals↗
Risperidone inhibits 5-hydroxytryptaminergic neuronal activity in the dorsal raphe nucleus by local release of 5-hydroxytryptamine.
1. The effects of risperidone on brain 5-hydroxytryptamine (5-HT) neuronal functions were investigated and compared with other antipsychotic drugs and selective receptor antagonists by use of single cell recording and microdialysis in the dorsal raphe nucleus (DRN). 2. Administration of risperidone (25-400 micrograms kg-1, i.v.) dose-dependently decreased 5-HT cell firing in the DRN, similar to the antipsychotic drug clozapine (0.25-4.0 mg kg-1, i.v.), the putative antipsychotic drug amperozide (0.5-8.0 mg kg-1, i.v.) and the selective alpha 1-adrenoceptor antagonist prazosin (50-400 micrograms kg-1, i.v.). 3. The selective alpha 2-adrenoceptor antagonist idazoxan (10-80 micrograms kg-1, i.v.), in contrast, increased the firing rate of 5-HT neurones in the DRN, whereas the D2 and 5-HT2A receptor antagonists raclopride (25-200 micrograms kg-1, i.v.) and MDL 100,907 (50-400 micrograms kg-1, i.v.), respectively, were without effect. Thus, the alpha 1-adrenoceptor antagonistic action of the antipsychotic drugs might, at least partly, cause the decrease in DRN 5-HT cell firing. 4. Pretreatment with the selective 5-HT1A receptor antagonist WAY 100,635 (5.0 micrograms kg-1, i.v.), a drug previously shown to antagonize effectively the inhibition of 5-HT cells induced by risperidone, failed to prevent the prazosin-induced decrease in 5-HT cell firing. This finding argues against the notion that alpha 1-adrenoceptor antagonism is the sole mechanism underlying the inhibitory effect of risperidone on the DRN cells. 5. The inhibitory effect of risperidone on 5-HT cell firing in the DRN was significantly attenuated in rats pretreated with the 5-HT depletor PCPA (p-chlorophenylalanine; 300 mg kg-1, i.p., day-1 for 3 consecutive days) in comparison with drug naive animals. 6. Administration of risperidone (2.0 mg kg-1, s.c.) significantly enhanced 5-HT output in the DRN. 7. Consequently, the reduction in 5-HT cell firing by risperidone appears to be related to increased availability of 5-HT in the somatodendritic region of the neurones leading to an enhanced 5-HT1A autoreceptor activation and, in turn, to inhibition of firing, and is probably only to a minor extent caused by its alpha 1-adrenoceptor antagonistic action.
Adrenergic alpha-Antagonists↗
The agonist activities of the putative antipsychotic agents, L-745,870 and U-101958 in HEK293 cells expressing the human dopamine D4.4 receptor.
1. Dopamine D4 receptor antagonists are being developed by several pharmaceutical companies as putative novel antipsychotics, possibly with low propensity to side-effects. Two such compounds, L-745,870 and U-101958 have been recently introduced. 2. The radioligand binding and functional activities of L-745,870 and U-101958 were investigated in human embryonic kidney (HEK)293 cells expressing the human recombinant dopamine D4.4 receptor (HEK293/D4 cells). [3H]-spiperone binding experiments were performed and inhibition of forskolin-stimulated cyclic AMP accumulation was used as the functional response. 3. [3H]-spiperone was found to label a homogeneous and saturable population of specific binding sites in HEK293/D4 cell homogenates (Bmax 505+/-90 fmol mg(-1) protein, pK(D) 9.5+/-0.1, n=3). Inhibition of specific [3H]-spiperone binding was observed with spiperone (pKi 9.6+/-0.1, n=3), clozapine (pKi 7.4+/-0.1, n=4), L-745,870 (pKi 8.5+/-0.1, n=3) and U-101958 (pKi 8.9+/-0.1, n=3). By contrast, raclopride was very weak (pKi < 5, n=3). 4. Dopamine inhibited forskolin-stimulated cyclic AMP accumulation in HEK293/D4 cells in a concentration-dependent fashion (Emax 71+/-2% inhibition of forskolin-stimulated levels, pEC50 8.7+/-0.1, n=10). This effect was mimicked by the dopamine D2-like receptor agonists, quinpirole and 7-hydroxy-2-dipropylaminotetralin (7-OH-DPAT). 5. L-745,870 and U-101958 also inhibited forskolin-stimulated cyclic AMP accumulation in HEK293/D4 cells in a concentration-dependent way. L-745,870 was less efficacious than dopamine (71% the efficacy of dopamine), whereas U-101958 behaved as a full agonist compared to dopamine. Potencies (pEC50) values of L-745,870 and U-101958 were 9.0+/-0.2 (n=4) and 8.7+/-0.3 (n=3), consistent with pKi values determined in radioligand binding studies. 6. Dopamine, L-745,870 and U-101958 (up to 1 microM) were devoid of effect on forskolin-stimulated cyclic AMP accumulation in control, non-transfected HEK293 cells. 7. The agonist effects of dopamine, L-745,870 and U-101958 in HEK293/D4 cells could be antagonized by spiperone (pK(B) 8.2-8.8) and clozapine (pK(B) 7.1), but not by raclopride (pK(B) < 5). None of these antagonists had any significant agonist activity at concentrations up to 10 microM. 8. These results show that the putative dopamine D4 receptor antagonists, L-745,870 and U-101958 are not devoid of intrinsic activity at human recombinant dopamine D4.4 receptors. Therefore, they may not represent the most appropriate drugs for testing the benefit of D4 receptor antagonism in schizophrenic patients, if agonism should translate in vivo.
Aminopyridines↗
Measurement of methylphenidate-induced change in extrastriatal dopamine concentration using [11C]FLB 457 PET.
[(11)C]FLB 457 is a very high-affinity radiotracer that allows the measurement of dopamine D(2/3) receptor availability in regions of the brain where densities are very low, such as the cerebral cortex. It is not known if [(11)C]FLB 457 binding is sensitive to the concentration of endogenous dopamine in humans in a manner analogous to [(11)C]raclopride and [(123)I]IBZM in the striatum. To test this possibility, extrastriatal [(11)C]FLB 457 binding was measured at baseline and after the oral administration of 40 to 60 mg of the psychostimulant methylphenidate (MP) in 12 healthy volunteers using positron emission tomography (PET) in a balanced-order, double-blind design. The dynamic PET data were quantified using a two-tissue compartment model with a metabolite-corrected arterial plasma input function. Two volunteers were excluded because of excessive head movement. In the remainder, MP caused significant reductions in the volume of distribution (VD) in temporal and frontal cortical regions and thalamus, suggesting that [(11)C]FLB 457 binding is sensitive to endogenous dopamine concentration. Moreover, the change in [(11)C]FLB 457 binding after MP correlated with the dose of MP (in mg/kg body weight) in all regions assessed. We conclude that MP in doses within the therapeutic range for the treatment of attention deficit hyperactivity disorder causes increases in dopamine concentrations in extrastriatal regions and that [(11)C]FLB 457 PET may be a useful tool for the assessment of change in dopamine concentration in these areas in humans.
Adult↗
Quantification of PET studies with the very high-affinity dopamine D2/D3 receptor ligand [11C]FLB 457: re-evaluation of the validity of using a cerebellar reference region.
The very high-affinity position emission tomography (PET) radioligand [(11)C]FLB 457 was developed in order to study extrastriatal tissues, where the density of dopamine D(2)/D(3) receptors is one to two orders of magnitude lower than in the striatum. The present study investigated the validity of using the cerebellum as a reference region. Ten healthy volunteers underwent a 90-min dynamic PET study after the bolus injection of [(11)C]FLB 457. The total volume of distribution (VD(t)) was estimated for the thalamus, hippocampus, frontal cortex, and cerebellum using a two-tissue compartmental model with a metabolite-corrected arterial plasma input function. VD(t) was sensitive to co-injected stable FLB 457 in all regions, including the cerebellum. Ex vivo saturation studies were also conducted in 17 rats where the dose of stable ligand was varied over five orders of magnitude. Specific binding was estimated to account for more than half of the rat cerebellar uptake of [(11)C]FLB 457, questioning the latter as an estimate of nonspecific binding in human PET studies. To check whether the cerebellum is a reference region, the binding potential (BP) was calculated either from the VD(t) ratio or using the simplified reference tissue model (SRTM). A non-negligible density of D(2)/D(3) receptors in the cerebellum was shown to lead to underestimation of BP as well as erroneous estimation of differential occupancies. Binging potential estimates from the SRTM were found to be sensitive to changes in cerebral blood flow, providing further evidence for caution in the use of the cerebellum as a reference region in measures of [(11)C]FLB 457 binding.
Adult↗
The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers.
Positron emission tomography (PET) studies have revealed significant interindividual variation in dopamine D2 receptor density in vivo in human striatum. Low D2 receptor binding in vivo has been found to associate with alcohol/substance dependence. It has been suggested that the A1 allele of human D2 receptor gene might be associated to a specific type of alcoholism and possibly to a reduced D2 receptor density in vitro. We have determined D2 dopamine receptor-binding density (Bmax), affinity (Kd) and availability (Bmax/Kd) in 54 healthy Finnish volunteers using PET and [11C]raclopride in order to determine whether the A1 allele is associated with a 'baseline' difference in D2 receptor characteristics in vivo. A statistically significant reduction in D2 receptor availability reflecting an alteration in receptor density was observed in the A1/A2 genotype group compared to the A2/A2 group. There was no difference in apparent Kd between the two groups. In conclusion, the association between the A1 allele and low D2 receptor availability in healthy subjects indicates that the A1 allele of the TaqIA polymorphism might be in linkage disequilibrium with a mutation in the promoter/regulatory gene element that affects dopamine D2 receptor expression. This study provides an in vivo neurobiological correlate to the A1 allele in healthy volunteers.
Adult↗
D4 dopamine receptor-mediated phospholipid methylation and its implications for mental illnesses such as schizophrenia.
Previous studies have shown D2-like dopamine receptor involvement in the regulation of phospholipid methylation (PLM), while others have documented impaired methionine and folate metabolism in schizophrenia. Utilizing [14C]formate labeling in cultured neuroblastoma cell lines, we now show that D4 dopamine receptors (D4R) mediate the stimulatory effect of dopamine (DA) on PLM. The effect of DA was potently blocked by highly D4R-selective antagonists and stimulated by the D4R-selective agonist CP-226269. DA-stimulated PLM was dependent upon the activity of methionine cycle enzymes, but DA failed to increase PLM in [3H]methionine labeling studies, indicating that a methionine residue in the D4R might be involved in mediating PLM. A direct role for MET313, located on transmembrane helix No. 6 immediately adjacent to phospholipid headgroups, was further suggested from adenosylation, site-directed mutagenesis and GTP-binding results. A comparison of PLM in lymphocytes from schizophrenia patients vs control samples showed a four-fold lower activity in the schizophrenia group. These findings reveal a novel mechanism by which the D4R can regulate membrane composition. Abnormalities in D4R-mediated PLM may be important in psychiatric illnesses such as schizophrenia.
Amino Acid Sequence↗