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Lee A Phebus - One of the best experts on this subject based on the ideXlab platform.
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comparison of rat dopamine d2 Receptor occupancy for a series of antipsychotic drugs measured using radiolabeled or nonlabeled raclopride tracer
Life Sciences, 2006Co-Authors: Vanessa N Barth, Eyassu Chernet, Laura J Martin, Anne B Need, Karen S Rash, Michelle Morin, Lee A PhebusAbstract:Abstract 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 ED50 values determined, remarkably similar data were obtained. Occupancy ED50 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.
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use of lc ms to assess Brain tracer distribution in preclinical in vivo Receptor occupancy studies dopamine d2 serotonin 2a and nk 1 Receptors as examples
Life Sciences, 2005Co-Authors: Eyassu Chernet, Vanessa N Barth, Laura J Martin, Anne B Need, Karen S Rash, Lee A PhebusAbstract:Abstract High performance liquid chromatography combined with either single quad or triple quad mass spectral detectors (LC/MS) was used to measure the Brain distribution of Receptor occupancy tracers targeting dopamine D2, serotonin 5-HT2A and neurokinin NK-1 Receptors using the ligands raclopride, MDL-100907 and GR205171, respectively. All three non-radiolabeled tracer molecules were easily detectable in discrete rat Brain areas after intravenous doses of 3, 3 and 30 μg/kg, respectively. These levels showed a differential Brain distribution caused by differences in Receptor density, as demonstrated by the observation that pretreatment with compounds that occupy these Receptors reduced this differential distribution in a dose-dependent manner. Intravenous, subcutaneous and oral dose–occupancy curves were generated for haloperidol at the dopamine D2 Receptor as were oral curves for the antipsychotic drugs olanzapine and clozapine. In vivo dose–occupancy curves were also generated for orally administered clozapine, olanzapine and haloperidol at the cortical 5-HT2A binding site. In vivo occupancy at the striatal neurokinin NK-1 binding site by various doses of orally administered MK-869 was also measured. Our results demonstrate the utility of LC/MS to quantify tracer distribution in preclinical Brain Receptor occupancy studies.
Arielle Shanahan - One of the best experts on this subject based on the ideXlab platform.
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stimulus gated cocaine sensitization interoceptive drug cue control of cocaine locomotor sensitization
Pharmacology Biochemistry and Behavior, 2005Co-Authors: Robert J. Carey, Ernest N Damianopoulos, Gail Depalma, Arielle ShanahanAbstract:Abstract Repeated cocaine treatments typically generate sensitization effects which are environment specific. In this study, we investigated whether drug treatments with highly selective Receptor specificity can also function as contextual cues to control the expression of cocaine sensitization effects. Two experiments were conducted in which separate groups of rats ( N = 10) received ten paired or unpaired cocaine (10.0 mg/kg) treatments. In the experiments, autoReceptor preferring low doses of either the 5-HT 1A agonist, 8-OHDPAT (8OH) (0.05 mg/kg) or the D 1 /D 2 agonist apomorphine (APO) (0.05 mg/kg) were administered 20 min prior to cocaine administration and test environment placement (paired treatment). Under these conditions, the drug cues generated by the 8OH/APO treatments were associated with the cocaine stimulant effect in the test environment. The unpaired treatment groups received the same drug treatments but the cocaine was administered after testing, in the homecage. Consequently, for these groups, the 8OH/APO drug cues generated by the drug treatments would not become associated with the cocaine stimulant effect in the test environment. Critically, both 8OH and APO pretreatments elicited equivalent unconditioned response effects which were opposite to the cocaine unconditioned response effects; that is, behavioral inhibition vs. behavioral stimulation. Initially, the 8OH and APO pretreatments prevented the locomotor stimulant effects of cocaine; but, these inhibitory effects were reversed in the paired groups with repeated cocaine treatments, consistent with the emergence of cocaine sensitization effects. In the unpaired 8OH and APO pretreatment groups, behavioral suppression persisted throughout the treatment protocol. Subsequently, paired and unpaired groups were compared in four conditioning/sensitization tests. The conditioning tests included: a saline/saline test; and a 8OH/saline test (Experiment 1); and, a saline/saline test and a APO/saline test (Experiment 2). There were no paired/unpaired group differences in these conditioning tests. The sensitization tests included: a saline/cocaine test; and a 8OH/cocaine test (Experiment 1); and, a saline/cocaine test and a APO/cocaine test (Experiment 2). There were no paired/unpaired group differences in the saline/cocaine test for sensitization but paired/unpaired group differences were found in both the 8OH/cocaine and APO/cocaine sensitization tests. In these tests the paired but not the unpaired groups exhibited cocaine locomotor sensitization effects. Critically when, in an additional test, the pretreatments in the cocaine tests were reversed (i.e., 8OH paired group received APO and APO paired group received 8OH prior to cocaine), then there was no evidence for cocaine sensitization. Since the 8OH/APO pretreatments had equivalent inhibitory response effects, it was the stimulus properties of these drugs which controlled the expression of the cocaine locomotor sensitization effects. These findings support the critical role of associative processes in the stimulus-gating of psychostimulant drug sensitization. Importantly, this report incorporates a new methodology in which context can be specified in terms of highly specific Brain Receptor targets rather than in terms of global environmental situational cues.
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stimulus gated cocaine sensitization interoceptive drug cue control of cocaine locomotor sensitization
Pharmacology Biochemistry and Behavior, 2005Co-Authors: Robert J. Carey, Ernest N Damianopoulos, Gail Depalma, Arielle ShanahanAbstract:Abstract Repeated cocaine treatments typically generate sensitization effects which are environment specific. In this study, we investigated whether drug treatments with highly selective Receptor specificity can also function as contextual cues to control the expression of cocaine sensitization effects. Two experiments were conducted in which separate groups of rats ( N = 10) received ten paired or unpaired cocaine (10.0 mg/kg) treatments. In the experiments, autoReceptor preferring low doses of either the 5-HT 1A agonist, 8-OHDPAT (8OH) (0.05 mg/kg) or the D 1 /D 2 agonist apomorphine (APO) (0.05 mg/kg) were administered 20 min prior to cocaine administration and test environment placement (paired treatment). Under these conditions, the drug cues generated by the 8OH/APO treatments were associated with the cocaine stimulant effect in the test environment. The unpaired treatment groups received the same drug treatments but the cocaine was administered after testing, in the homecage. Consequently, for these groups, the 8OH/APO drug cues generated by the drug treatments would not become associated with the cocaine stimulant effect in the test environment. Critically, both 8OH and APO pretreatments elicited equivalent unconditioned response effects which were opposite to the cocaine unconditioned response effects; that is, behavioral inhibition vs. behavioral stimulation. Initially, the 8OH and APO pretreatments prevented the locomotor stimulant effects of cocaine; but, these inhibitory effects were reversed in the paired groups with repeated cocaine treatments, consistent with the emergence of cocaine sensitization effects. In the unpaired 8OH and APO pretreatment groups, behavioral suppression persisted throughout the treatment protocol. Subsequently, paired and unpaired groups were compared in four conditioning/sensitization tests. The conditioning tests included: a saline/saline test; and a 8OH/saline test (Experiment 1); and, a saline/saline test and a APO/saline test (Experiment 2). There were no paired/unpaired group differences in these conditioning tests. The sensitization tests included: a saline/cocaine test; and a 8OH/cocaine test (Experiment 1); and, a saline/cocaine test and a APO/cocaine test (Experiment 2). There were no paired/unpaired group differences in the saline/cocaine test for sensitization but paired/unpaired group differences were found in both the 8OH/cocaine and APO/cocaine sensitization tests. In these tests the paired but not the unpaired groups exhibited cocaine locomotor sensitization effects. Critically when, in an additional test, the pretreatments in the cocaine tests were reversed (i.e., 8OH paired group received APO and APO paired group received 8OH prior to cocaine), then there was no evidence for cocaine sensitization. Since the 8OH/APO pretreatments had equivalent inhibitory response effects, it was the stimulus properties of these drugs which controlled the expression of the cocaine locomotor sensitization effects. These findings support the critical role of associative processes in the stimulus-gating of psychostimulant drug sensitization. Importantly, this report incorporates a new methodology in which context can be specified in terms of highly specific Brain Receptor targets rather than in terms of global environmental situational cues.
Bennett L Leventhal - One of the best experts on this subject based on the ideXlab platform.
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primary structure of the human platelet serotonin 5 ht2a Receptor identity with frontal cortex serotonin 5 ht2a Receptor
Journal of Neurochemistry, 2002Co-Authors: Edwin H Cook, Kathlyn E Fletcher, Mark S Wainwright, Nancy Marks, Shuya Y Yan, Bennett L LeventhalAbstract:: Previous radioligand binding studies have demonstrated human platelet serotonin2A (5-HT2A) Receptor binding sites. Pharmacological similarities between platelet and frontal cortex 5-HT2A Receptor binding parameters have been demonstrated. However, it is not clear whether the platelet 5-HT2A Receptor primary structure is identical to that of the Brain Receptor. Three overlapping cDNAs were obtained to span completely the coding region of the 5-HT2A Receptor. These clones were sequenced with external and internal primers. The nucleotide sequence of human platelet 5-HT2A cDNA was identical to that reported for the human frontal cortex 5-HT2A Receptor, except for nucleotide 102 (T C), which has been reported to represent a normal DNA polymorphism that does not alter the amino acid sequence. This finding may have implications in the study of neuropsychiatric disorders for which altered platelet 5-HT2A Receptor binding has been demonstrated.
Ernest N Damianopoulos - One of the best experts on this subject based on the ideXlab platform.
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stimulus gated cocaine sensitization interoceptive drug cue control of cocaine locomotor sensitization
Pharmacology Biochemistry and Behavior, 2005Co-Authors: Robert J. Carey, Ernest N Damianopoulos, Gail Depalma, Arielle ShanahanAbstract:Abstract Repeated cocaine treatments typically generate sensitization effects which are environment specific. In this study, we investigated whether drug treatments with highly selective Receptor specificity can also function as contextual cues to control the expression of cocaine sensitization effects. Two experiments were conducted in which separate groups of rats ( N = 10) received ten paired or unpaired cocaine (10.0 mg/kg) treatments. In the experiments, autoReceptor preferring low doses of either the 5-HT 1A agonist, 8-OHDPAT (8OH) (0.05 mg/kg) or the D 1 /D 2 agonist apomorphine (APO) (0.05 mg/kg) were administered 20 min prior to cocaine administration and test environment placement (paired treatment). Under these conditions, the drug cues generated by the 8OH/APO treatments were associated with the cocaine stimulant effect in the test environment. The unpaired treatment groups received the same drug treatments but the cocaine was administered after testing, in the homecage. Consequently, for these groups, the 8OH/APO drug cues generated by the drug treatments would not become associated with the cocaine stimulant effect in the test environment. Critically, both 8OH and APO pretreatments elicited equivalent unconditioned response effects which were opposite to the cocaine unconditioned response effects; that is, behavioral inhibition vs. behavioral stimulation. Initially, the 8OH and APO pretreatments prevented the locomotor stimulant effects of cocaine; but, these inhibitory effects were reversed in the paired groups with repeated cocaine treatments, consistent with the emergence of cocaine sensitization effects. In the unpaired 8OH and APO pretreatment groups, behavioral suppression persisted throughout the treatment protocol. Subsequently, paired and unpaired groups were compared in four conditioning/sensitization tests. The conditioning tests included: a saline/saline test; and a 8OH/saline test (Experiment 1); and, a saline/saline test and a APO/saline test (Experiment 2). There were no paired/unpaired group differences in these conditioning tests. The sensitization tests included: a saline/cocaine test; and a 8OH/cocaine test (Experiment 1); and, a saline/cocaine test and a APO/cocaine test (Experiment 2). There were no paired/unpaired group differences in the saline/cocaine test for sensitization but paired/unpaired group differences were found in both the 8OH/cocaine and APO/cocaine sensitization tests. In these tests the paired but not the unpaired groups exhibited cocaine locomotor sensitization effects. Critically when, in an additional test, the pretreatments in the cocaine tests were reversed (i.e., 8OH paired group received APO and APO paired group received 8OH prior to cocaine), then there was no evidence for cocaine sensitization. Since the 8OH/APO pretreatments had equivalent inhibitory response effects, it was the stimulus properties of these drugs which controlled the expression of the cocaine locomotor sensitization effects. These findings support the critical role of associative processes in the stimulus-gating of psychostimulant drug sensitization. Importantly, this report incorporates a new methodology in which context can be specified in terms of highly specific Brain Receptor targets rather than in terms of global environmental situational cues.
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stimulus gated cocaine sensitization interoceptive drug cue control of cocaine locomotor sensitization
Pharmacology Biochemistry and Behavior, 2005Co-Authors: Robert J. Carey, Ernest N Damianopoulos, Gail Depalma, Arielle ShanahanAbstract:Abstract Repeated cocaine treatments typically generate sensitization effects which are environment specific. In this study, we investigated whether drug treatments with highly selective Receptor specificity can also function as contextual cues to control the expression of cocaine sensitization effects. Two experiments were conducted in which separate groups of rats ( N = 10) received ten paired or unpaired cocaine (10.0 mg/kg) treatments. In the experiments, autoReceptor preferring low doses of either the 5-HT 1A agonist, 8-OHDPAT (8OH) (0.05 mg/kg) or the D 1 /D 2 agonist apomorphine (APO) (0.05 mg/kg) were administered 20 min prior to cocaine administration and test environment placement (paired treatment). Under these conditions, the drug cues generated by the 8OH/APO treatments were associated with the cocaine stimulant effect in the test environment. The unpaired treatment groups received the same drug treatments but the cocaine was administered after testing, in the homecage. Consequently, for these groups, the 8OH/APO drug cues generated by the drug treatments would not become associated with the cocaine stimulant effect in the test environment. Critically, both 8OH and APO pretreatments elicited equivalent unconditioned response effects which were opposite to the cocaine unconditioned response effects; that is, behavioral inhibition vs. behavioral stimulation. Initially, the 8OH and APO pretreatments prevented the locomotor stimulant effects of cocaine; but, these inhibitory effects were reversed in the paired groups with repeated cocaine treatments, consistent with the emergence of cocaine sensitization effects. In the unpaired 8OH and APO pretreatment groups, behavioral suppression persisted throughout the treatment protocol. Subsequently, paired and unpaired groups were compared in four conditioning/sensitization tests. The conditioning tests included: a saline/saline test; and a 8OH/saline test (Experiment 1); and, a saline/saline test and a APO/saline test (Experiment 2). There were no paired/unpaired group differences in these conditioning tests. The sensitization tests included: a saline/cocaine test; and a 8OH/cocaine test (Experiment 1); and, a saline/cocaine test and a APO/cocaine test (Experiment 2). There were no paired/unpaired group differences in the saline/cocaine test for sensitization but paired/unpaired group differences were found in both the 8OH/cocaine and APO/cocaine sensitization tests. In these tests the paired but not the unpaired groups exhibited cocaine locomotor sensitization effects. Critically when, in an additional test, the pretreatments in the cocaine tests were reversed (i.e., 8OH paired group received APO and APO paired group received 8OH prior to cocaine), then there was no evidence for cocaine sensitization. Since the 8OH/APO pretreatments had equivalent inhibitory response effects, it was the stimulus properties of these drugs which controlled the expression of the cocaine locomotor sensitization effects. These findings support the critical role of associative processes in the stimulus-gating of psychostimulant drug sensitization. Importantly, this report incorporates a new methodology in which context can be specified in terms of highly specific Brain Receptor targets rather than in terms of global environmental situational cues.
Pablo Rusjan - One of the best experts on this subject based on the ideXlab platform.
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exploring occupancy of the histamine h3 Receptor by pitolisant in humans using positron emission tomography
British Journal of Pharmacology, 2020Co-Authors: Pablo Rusjan, Pamela Sabioni, Patricia Di Ciano, Esmaeil Mansouri, Isabelle Boileau, Alexia Laveille, Marc CapetAbstract:Background and purpose BF2.649 (pitolisant, Wakix®) is a novel histamine H3 Receptor inverse agonist/antagonist recently approved for the treatment of narcolepsy disorder. The objective of the study was to investigate in vivo occupancy of H3 Receptors by BF2.649 using PET Brain imaging with the H3 Receptor antagonist radioligand [11 C]GSK189254. Experimental approach Six healthy adult participants were scanned with [11 C]GSK189254. Participants underwent a total of two PET scans on separate days, 3 h after oral administration of placebo or after pitolisant hydrochloride (40 mg). [11 C]GSK189254 regional total distribution volumes were estimated in nine Brain regions of interest with the two tissue-compartment model with arterial input function using a common VND across the regions. Brain Receptor occupancies were calculated with the Lassen plot. Key results Pitolisant, at the dose administered, provided high (84 ± 7%; mean ± SD) occupancy of H3 Receptors. The drug was well-tolerated, and participants experienced few adverse events. Conclusion and implications The administration of pitolisant (40 mg) produces a high occupancy of H3 Receptors and may be a new tool for the treatment of a variety of CNS disorders that are associated with mechanisms involving H3 Receptors.