P.3.d.013 Energetic metabolism, leptin are altered in rats submitted to chronic administration of olanzapine (original) (raw)
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The role of D1–D2 receptor hetero-dimerization in the mechanism of action of clozapine
European Neuropsychopharmacology, 2008
Clozapine is effective although still not perfect drug used to treat schizophrenia. The precise mechanism of its action is not known. Here we show that there are two binding sites for clozapine at the dopamine D 1 and D 2 receptors, and the affinity of D 1 R strongly depended on whether the receptor was present alone or together with D 2 R (or its genetic variant D 2 Ser311Cys) in the cell membrane, pointing to the role of receptor hetero-dimerization in the observed phenomenon. The use of fluorescence resonance energy transfer (FRET) technology, observed via fluorescence lifetime microscopy of the single cell, indicated that low concentration of clozapine (10 − 9 M), sufficient to saturate the high affinity site, uncoupled the D 1 R-D 2 R hetero-dimers. Therefore it has been concluded that clozapine might antagonize the effect of concomitant stimulation of both dopamine receptors, which has been shown previously to enhance the formation of heterodimers and to stimulate the calcium signaling pathway.
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2006
Most antipsychotics were thought to induce antipsychotic action at an excess of 70% striatal dopamine D 2 receptor occupancy, while the clinical dose of clozapine was reported to show less than 60% occupancy. High-dose clozapine could occupy as high as 80% of striatal dopamine D 2 receptor in monkey PET studies. Although the time course of dopamine D 2 receptor occupancy is an important property of antipsychotics, that by clozapine has not been investigated in a clinical setting. We measured the time course of extrastriatal dopamine D 2 receptor occupancy with different doses of clozapine and evaluated whether the measured occupancies fitted the binding theory. Three consecutive PET scans with [ 11 C]FLB 457 were performed for two patients with schizophrenia, chronically taking 600 mg/day and 200 mg/ day of clozapine, respectively. Series of occupancies were also measured in combination with fluvoxamine or paroxetine in one patient. Dopamine D 2 receptor occupancies were also simulated using individual clozapine plasma data and previously determined in vivo ED 50 value. The occupancy of one patient with high plasma concentration (1207 ng/ml at peak time) was around 75% at peak and around 60% after 26 h. Another patient with medium plasma concentration (649 ng/ml at peak time) showed less than 50% occupancy at peak, decreasing to 15% after 25 h. The measured occupancy values fitted well with the simulated occupancy values. At high plasma concentration, clozapine can induce high extrastriatal dopamine D 2 receptor occupancy in the human brain, and this finding fitted well with the theoretical estimation. D Abbreviations: PET, positron emission tomography; SSRI, selective serotonin reuptake inhibitor.
American Journal of Psychiatry, 2004
Objective: Clozapine, the prototype of atypical antipsychotics, remains unique in its efficacy in the treatment of refractory schizophrenia. Its affinity for dopamine D 4 receptors, serotonin 5-HT 2A receptor antagonism, effects on the noradrenergic system, and its relatively moderate occupancy of D 2 receptors are unlikely to be the critical mechanism underlying its efficacy. In an attempt to elucidate the molecular/synaptic mechanism underlying clozapine's distinctiveness in refractory schizophrenia, the authors studied the in vivo D 1 and D 2 receptor profile of clozapine compared with other atypical antipsychotics. Method: Positron emission tomography with the radioligands [ 11 C]SCH23390 and [ 11 C]raclopride was used to investigate D 1 and D 2 receptor occupancy in vivo in 25 schizophrenia patients receiving atypical antipsychotic treatment with clozapine, olanzapine, quetiapine, or risperidone. Results: Mean striatal D 1 occupancies ranged from 55% with clozapine to 12% with quetiapine (rank order: clozapine > olanzapine > risperidone > quetiapine). The striatal D 2 occupancy ranged from 81% with risperidone to 30% with quetiapine (rank order: risperidone > olanzapine > clozapine > quetiapine). The ratio of striatal D 1 /D 2 occupancy was significantly higher for clozapine (0.88) relative to olanzapine (0.54), quetiapine (0.41), or risperidone (0.31).
Pharmacological reports : PR
The tight correlation between the clinical potency and the D2R blocking action of antipsychotic medications suggests that dopamine hyperactivity plays a significant role in psychosis. Clozapine, one of the most effective antipsychotic drugs, has been shown to display moderate affinity for various neurotransmitter receptors, including the dopamine D1 and D2 receptors; however, the exact mechanism of action of clozapine has not yet been fully elucidated. Here, we describe our working hypothesis pointing to the role of dopamine D1-D2 receptor hetero-dimerization as a mechanism of action of clozapine. It has been widely assumed that D1 and D2 receptors are segregated to separate neuronal populations; however, other data suggest that D1 and D2 receptors are co-expressed by a moderate to substantial proportion of striatal neurons, as well as in the medial prefrontal cortex. Our recent studies indicate that concomitant stimulation of both D1 and D2 dopamine receptors induces an increase in...
Psychiatry and Clinical Neurosciences, 1993
In vivo occupancy of dopamine-D,, D2 and serotonin-5-HT2 receptors by haloperidol 10 mg/kg and clozapine 20 mg/kg were studied. Rats were injected intravenously with ['HI -YM-09151-2, [%I] -SCH23390, or r H ] -ketanserin 10 min after the administration of the tested drugs. Fifteen to 240 min akter the ligand injection, the receptor occupancy rates of the drugs in the striatum and frontal cortex were calculated. Clozapine demonstrated the higher 5-HT2 and lower D, occupancies in the respective regions. A dose-response analysis of D, and 5-HT,, receptor occupancy by the drugs consolidated the higher 5-HT, binding affinity of clozapine in comparison with haloperidol. The present methodology may serve as an accurate tool to evaluate the peculiarity of various antipsychotics.
Life Sciences, 2006
Preclinical brain receptor occupancy measures have heretofore been conducted by quantifying the brain distribution of a radiolabeled tracer ligand using either scintillation spectroscopy or tomographic imaging. For smaller animals like rodents, the majority of studies employ tissue dissection and scintillation spectroscopy. These measurements can also be accomplished using liquid chromatography coupled to mass spectral detection to measure the brain distribution of tracer molecules, obviating the need for radioligands. In order to validate mass spectroscopy-based receptor occupancy methods, we examined dopamine D2 receptor dose-occupancy curves for a number of antipsychotic drugs in parallel experiments using either mass spectroscopy or radioligand-based approaches. Oral dose-occupancy curves were generated for 8 antipsychotic compounds in parallel experiments using either radiolabeled or unlabeled raclopride tracer. When curves generated by these two methods were compared and ED 50 values determined, remarkably similar data were obtained. Occupancy ED 50 values were (mg/kg): chlorpromazine, 5.1 and 2.7; clozapine, 41 and 40; haloperidol, 0.2 and 0.3; olanzapine, 2.1 and 2.2; risperidone, 0.1 and 0.4; spiperone, 0.5 and 0.4; thioridazine 9.2 and 9.5; and ziprasidone 1.4 and 2.1 (unlabeled and radiolabeled raclopride tracer, respectively). The observation that in vivo application of both techniques led to comparable data adds to the validation state of the mass spectroscopy-based approach to receptor occupancy assays.
Nuclear Medicine and Biology, 1995
CIA-69024, (+)-1-(2-bromo-4,5-dimethoxybenzyl)-7-hydroxy-6-methoxy-2-["C]methyl-l,2,3,4-tetrahydroisoquinoline, is a specific and selective dopamine Dl radiotracer. The in viuo biodistribution of this novel radioligand in mice showed a high uptake in the striatum (6.7%ID/g) at 5 min, followed by clearance with a half-life of 16.1 min. As a measure of specificity, the striatal/cerebellar ratio reached a maximum of 7.4 at 30 min post-injection. Radioactivity in the striatum was reduced to the level of the cerebellum by pre-adminstration of the Dl antagonist SCH 23390 (1 mg/kg). Pretreatment of mice with spiperone (D2), 7-hydroxydipropylaminotetralin (7-OH-DPAT) (D3), clozapine (D4), ketanserin (5-HT2/5-HT2C), mazindol (monoamine reuptake), prazosin (x,), and haloperidol (D2/(r) had no inhibitory effect on ["CIA-69024 uptake in the striatum. The dextrorotatory enantiomer of the dopamine antagonist butaclamol inhibited striatal uptake, while the less active isomer ( -)-butaclamol did not. ["CIA-69024 binding was inhibited by unlabeled A-69024 in a dose dependent manner (ED,, = 0.3 mg/kg) in the striatum while no change occurred in the cerebellum. ["CIA-69024 warrants further investigation as a PET ligand for examination of central dopamine Dl receptors in humans.
Modulation of the clozapine structure increases its selectivity for the dopamine D4 receptor
European Journal of Pharmacology, 1995
Clozapine has a more marked affinity for the recently cloned dopamine D 4 receptor than for the dopamine D 2 receptor. In the search for a selective ligand for the dopamine D 4 receptor, useful as a pharmacological tool or as a potent atypical antipsychotic, a pyridobenzodiazepine derivative bioisoster of clozapine, JL 18, 8-methyl-6-(4-methyl-l-piperazinyl)-llHpyrido[2,3-b][1,4]benzodiazepine, was found to be the most dopamine D4-selective ligand belonging to the diarylazepine class. Indeed, JL 18 binds to the dopamine D 4 receptor with affinity up to 25 times superior to that for the dopamine D 2 receptor and presents reduced affinities for other receptors.
In vivo binding to dopamine receptors: a correlate of potential antipsychotic activity
European Journal of Pharmacology, 1992
Antagonists of dopamine receptors (especially those of the D e subtype) have long been recognized as effective antipsychotics. SCH 39166, a dopamine D I selective antagonist, is now also being evaluated for its clinical antipsychotic properties. The studies described herein determine the binding affinity of a variety of dopamine receptor antagonists (both dopamine D I and D e selective compounds) for the dopamine D 1 and D z receptors, in vivo, and correlate this affinity with their behavioral activity in the rat conditioned avoidance response (CAR) test. The in viw) binding affinities of the D i selective compounds at the dopaminc D 1 site exhibited a high correlation (r = 0.97) with their activities in the rat CAR test. Likewise, D 2 selective compounds' inhibition of in vivo binding to dopaminc D 2 receptors correlated with their behavioral potencies (r = 0.98). Conversely, any binding of selective agents to their non-targeted receptor did not correlate with their behavioral activity.