Evaluation of Dopamine D-2 Receptor Occupancy by Clozapine, Risperidone, and Haloperidol In Vivo in the Rodent and Nonhuman Primate Brain Using 18F-Fallypride

Mukherjee, Jogeshwar; Christian, Bradley T.; Narayanan, Tanjore K.; Shi, Bingzhi; Mantil, Joseph

doi:10.1016/s0893-133x(01)00251-2

Cited by 72 publications

(64 citation statements)

References 38 publications

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“…In addition, the reported ED 50 values for risperidone to block behavioral effects of dopamine agonists are between 0.06 and 0.1 mg/kg (Janssen et al, 1988;Megens et al, 1994;Arnt, 1995). Similarly, olanzapine (Bymaster et al, 1996) and clozapine (Mukherjee et al, 2001) dose ranges in this study are known to produce rodent D 2 receptor occupancies comparable to D 2 occupancies demonstrated in humans receiving these compounds (Kapur et al, 1998(Kapur et al, , 1999.…”

Section: Antipsychotic Administration and Dosingmentioning

confidence: 55%

“…We have not excluded the possibility that risperidone dosing greater than 1.0 mg/kg may be required to produce significant elevations in cerebral cortical allopregnanolone. Exceeding 1.0 mg/kg risperidone dosing in rodents would likely have limited clinical relevance, however, since 1.0 mg/ kg dosing of this compound produces D 2 receptor occupancy greater than 90% (Mukherjee et al, 2001) and considerable sedation. In humans, striatal D 2 occupancy greater than 80% is associated with extrapyramidal side effects (Farde et al, 1992).…”

Section: Discussion Olanzapine and Clozapine Effects On Cerebral Cortmentioning

confidence: 99%

“…In designing these experiments, we targeted rodent dosing strategies relevant to antipsychotic dosing in human subjects (Mukherjee et al, 2001;Kapur et al, 1998Kapur et al, , 1999 and consistent with doses utilized in the existing rodent literature Kinkead et al, 2000;Atkins et al, 1999;Zhang et al, 2000). Therapeutic response is frequently associated with D 2 receptor occupancy of approximately 60-70% in humans, but D 2 occupancies greater than 80% are associated with increased extrapyramidal side effects.…”

Section: Antipsychotic Administration and Dosingmentioning

confidence: 99%

“…Therapeutic response is frequently associated with D 2 receptor occupancy of approximately 60-70% in humans, but D 2 occupancies greater than 80% are associated with increased extrapyramidal side effects. Both haloperidol and risperidone 0.1 mg/kg doses produce striatal D 2 receptor occupancies that exceed 80% in rodents (Mukherjee et al, 2001). In addition, the reported ED 50 values for risperidone to block behavioral effects of dopamine agonists are between 0.06 and 0.1 mg/kg (Janssen et al, 1988;Megens et al, 1994;Arnt, 1995).…”

Section: Antipsychotic Administration and Dosingmentioning

confidence: 99%

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Olanzapine and Clozapine Increase the GABAergic Neuroactive Steroid Allopregnanolone in Rodents

Marx

VanDoren

Duncan

et al. 2003

Neuropsychopharmacol

133

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The neuroactive steroid allopregnanolone is a potent g-aminobutyric acid type A (GABA A ) receptor modulator with anxiolytic and anticonvulsant effects. Olanzapine and clozapine also have anxiolytic-like effects in behavioral models. We therefore postulated that olanzapine and clozapine would elevate allopregnanolone levels, but risperidone and haloperidol would have minimal effects. Male rats received intraperitoneal olanzapine (2.5-10.0 mg/kg), clozapine (5.0-20.0 mg/kg), risperidone (0.1-1.0 mg/kg), haloperidol (0.1-1.0 mg/ kg), or vehicle. Cerebral cortical allopregnanolone and peripheral progesterone and corticosterone levels were determined. Adrenalectomized animals were also examined. Both olanzapine and clozapine increased cerebral cortical allopregnanolone levels, but neither risperidone nor haloperidol had significant effects. Olanzapine and clozapine also increased serum progesterone and corticosterone levels. Adrenalectomy prevented olanzapine-and clozapine-induced elevations in allopregnanolone. Allopregnanolone induction may contribute to olanzapine and clozapine anxiolytic, antidepressant, and mood-stabilizing actions. Alterations in this neuroactive steroid may result in the modulation of GABAergic and dopaminergic neurotransmission, potentially contributing to antipsychotic efficacy.

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Section: Antipsychotic Administration and Dosingmentioning

confidence: 55%

Section: Discussion Olanzapine and Clozapine Effects On Cerebral Cortmentioning

confidence: 99%

Section: Antipsychotic Administration and Dosingmentioning

confidence: 99%

Section: Antipsychotic Administration and Dosingmentioning

confidence: 99%

See 2 more Smart Citations

Olanzapine and Clozapine Increase the GABAergic Neuroactive Steroid Allopregnanolone in Rodents

Marx

VanDoren

Duncan

et al. 2003

Neuropsychopharmacol

133

View full text Add to dashboard Cite

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“…8), which weighs about 100 g. This is a very high level of brain uptake for a large molecule. For example, the brain uptake of fallypride, a lipid soluble small molecule dopamine receptor agonist, by the adult Rhesus monkey brain is 4% ID/100 g brain (Mukherjee et al, 2001). The brain uptake of the humanized HIRMAb is about 50% of the brain uptake of the chimeric HIRMAb by the Rhesus monkey brain (Coloma et al, 2000), which parallels the relative affinities of these antibodies for the HIR (Table V).…”

Section: Discussionmentioning

confidence: 93%

Humanization of anti‐human insulin receptor antibody for drug targeting across the human blood–brain barrier

Boado

Zhang

et al. 2006

Biotech & Bioengineering

187

138

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A murine monoclonal antibody (MAb) to the human insulin receptor (HIR) has been engineered for use as a brain drug delivery system for transport across the human blood-brain barrier (BBB). The HIRMAb was humanized by complementarity determining region (CDR) grafting on the framework regions (FR) of the human B43 IgG heavy chain and the human REI kappa light chain. A problem encountered in the humanization process was the poor secretion of the CDR-grafted HIRMAb by myeloma cells. This problem was solved by the production of human/mouse hybrids of the engineered heavy chain variable region (VH), which led to the replacement of five amino acids in the FR3 of the VH with original murine amino acids. No replacement of FR amino acids in the light chain variable region (VL) was required. The affinity of the humanized HIRMAb for the HIR was decreased 27% relative to the murine HIRMAb. The humanized HIRMAb avidly bound to the HIR of isolated human brain capillaries, which are used as an in vitro model system of the human BBB. The HIRMAb cross reacts with the HIR of Old World primates such as the Rhesus monkey. The humanized HIRMAb was radiolabeled with 125-iodine, and injected intravenously into an adult, anesthetized Rhesus monkey. Brain scanning showed the humanized HIRMAb was rapidly transported into all parts of the primate brain after intravenous administration. The humanized HIRMAb may be used as a brain drug and gene delivery system for the targeting of large molecule therapeutics across the BBB in humans.

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Positron emission tomography and its use to image the occupancy of drug binding sites

Gatley

Volkow

Fowler

et al. 2003

Drug Development Research

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The development of positron emission tomography (PET) and the ability to synthesize compounds labeled with the short-lived positron emitters 11 C and 18 F has made possible the imaging and quantification of drug binding sites in the human body. By conducting PET studies with an appropriate radioligand before and after treatment with a drug, the fraction of the total number of binding sites that is occupied by the drug (the "occupancy" of the site) can often be determined. To the extent that occupancy is a good indicator of pharmacological activity, such PET experiments can aid the development of drug dosage regimens. Some of the general issues involved in PET studies of drug occupancy are discussed. There have been many such studies involving antipsychotic drugs and dopamine D 2 receptor radioligands. Since neuroleptics have been extensively reviewed elsewhere, only the major findings are discussed here. Other binding sites (and drug classes) in the dopamine system to which this methodology has been applied include: the dopamine transporter (stimulant drugs) and monoamine oxidase A and B (antidepressant drugs). Occupancy studies are also possible for many drug targets beyond the dopamine system. Drug Dev.

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Evaluation of Dopamine D-2 Receptor Occupancy by Clozapine, Risperidone, and Haloperidol In Vivo in the Rodent and Nonhuman Primate Brain Using 18F-Fallypride

Abstract: We have used the high-affinity dopamine D-2 receptor radioligand, 18

Cited by 72 publications

References 38 publications

Olanzapine and Clozapine Increase the GABAergic Neuroactive Steroid Allopregnanolone in Rodents

Olanzapine and Clozapine Increase the GABAergic Neuroactive Steroid Allopregnanolone in Rodents

Humanization of anti‐human insulin receptor antibody for drug targeting across the human blood–brain barrier

Positron emission tomography and its use to image the occupancy of drug binding sites

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