A PET study on dopamine and serotonin receptor binding in the primate brain : challenges with antipsychotic drugs and amphetamine
Author: Chou, Yuan-Hwa
Date: 2001-02-23
Location: Föreläsningssalen vid Institutionen för klinisk neurovetenskap, sektionen för psykiatri, Karolinska sjukhuset
Time: 9.00
Department: Institutionen för klinisk neurovetenskap / Department of Clinical Neuroscience
Abstract
The brain imaging technique positron emission tomography (PET) has been applied to study dopamine and serotonin neurotransmission. In schizophrenia research, an important observation is that patients with schizophrenia, when compared with controls, have higher amphetamine induced dopamine release in the striatum. PET studies on non-human primates provide a model for examination of pharmacological principles before initiation of studies in man. The first aim of the thesis project was to develop methods for measurement of endogenous dopamine levels not only in the striatum but also in the extrastriatal dopamine systems that are of central interest in schizophrenia research.
The new radioligand [11C]NNC 112 was developed to measure D1-like dopamine receptor binding in cortical regions. The concentration of dopamine was changed in both directions using amphetamine and reserpine in cynomolgus monkeys. On the contrary to D2/D3 dopamine receptors, the results indicate that D1-like dopamine receptor binding is not sensitive to the dopamine concentration. [11C]FLB 457 is a recently developed high affinity radioligand for extrastriatal D2/D3, dopamine receptors. After administration of amphetamine, the regional binding of [11C]FLB 457 decreased by 2 to 16% in three monkeys. The reductions of [11C]FLB 457 binding were similar to those reported for [11C]raclopride binding in the striatum and support that [11C]FLB 457 binding is sensitive to the endogenous dopamine concentration.
Clozapine, the prototype atypical antipsychotic, is effective for patients that do not respond to conventional antipsychotic drugs. The second aim of the thesis was to examine possible mechanisms underlying the atypical properties of clozapine in three studies.
The previously reported low striatal D2/D3 dopamine receptor occupancy in clozapine treated patients has been suggested to represent a ceiling effect. The striatal D2/D3 dopamine receptor occupancy in three monkeys was 87-89% at a dose corresponding to five times the maximal recommended human dose. The results indicate that clozapine saturates striatal D2/D3 dopamine receptors at high doses and do not support the hypothesis of a ceiling effect.
The occupancy of frontal cortical D1-like dopamine receptors was determined since those receptors have been suggested to mediate antipsychotic effect. The frontal cortical D1-like dopamine receptor occupancy at clinically relevant doses was 54 to 83% and reached 12-25% higher levels than in the striatum. The observations support a suggested role of D1-like dopamine receptors in the treatment of schizophrenia and may reflect a regional difference in the distribution of the two D1-like dopamine receptor subtypes (D1), and D5).
In the last study, serotonin 5-HT1A receptor occupancy of clozapine ranged from 23 to 49% at clinically relevant doses and 39 to 5 M after a higher dose of clozapine in six monkeys. The occupancy of 5-HT1A receptors was on the same level as the D2/D3 dopamine receptor occupancy reported in clozapine treated patients. The results support that the 5-HT1A receptor is a candidate target for the atypical drug actions of clozapine.
The new radioligand [11C]NNC 112 was developed to measure D1-like dopamine receptor binding in cortical regions. The concentration of dopamine was changed in both directions using amphetamine and reserpine in cynomolgus monkeys. On the contrary to D2/D3 dopamine receptors, the results indicate that D1-like dopamine receptor binding is not sensitive to the dopamine concentration. [11C]FLB 457 is a recently developed high affinity radioligand for extrastriatal D2/D3, dopamine receptors. After administration of amphetamine, the regional binding of [11C]FLB 457 decreased by 2 to 16% in three monkeys. The reductions of [11C]FLB 457 binding were similar to those reported for [11C]raclopride binding in the striatum and support that [11C]FLB 457 binding is sensitive to the endogenous dopamine concentration.
Clozapine, the prototype atypical antipsychotic, is effective for patients that do not respond to conventional antipsychotic drugs. The second aim of the thesis was to examine possible mechanisms underlying the atypical properties of clozapine in three studies.
The previously reported low striatal D2/D3 dopamine receptor occupancy in clozapine treated patients has been suggested to represent a ceiling effect. The striatal D2/D3 dopamine receptor occupancy in three monkeys was 87-89% at a dose corresponding to five times the maximal recommended human dose. The results indicate that clozapine saturates striatal D2/D3 dopamine receptors at high doses and do not support the hypothesis of a ceiling effect.
The occupancy of frontal cortical D1-like dopamine receptors was determined since those receptors have been suggested to mediate antipsychotic effect. The frontal cortical D1-like dopamine receptor occupancy at clinically relevant doses was 54 to 83% and reached 12-25% higher levels than in the striatum. The observations support a suggested role of D1-like dopamine receptors in the treatment of schizophrenia and may reflect a regional difference in the distribution of the two D1-like dopamine receptor subtypes (D1), and D5).
In the last study, serotonin 5-HT1A receptor occupancy of clozapine ranged from 23 to 49% at clinically relevant doses and 39 to 5 M after a higher dose of clozapine in six monkeys. The occupancy of 5-HT1A receptors was on the same level as the D2/D3 dopamine receptor occupancy reported in clozapine treated patients. The results support that the 5-HT1A receptor is a candidate target for the atypical drug actions of clozapine.
List of papers:
I. Halldin C, Foged C, Chou YH, Karlsson P, Swahn CG, Sandell J, Sedvall G, Farde L (1998). "Carbon-11-NNC 112: a radioligand for PET examination of striatal and neocortical D1-dopamine receptors. " J Nucl Med 39(12): 2061-8
Pubmed
II. Chou YH, Karlsson P, Halldin C, Olsson H, Farde L (1999). "A PET study of D(1)-like dopamine receptor ligand binding during altered endogenous dopamine levels in the primate brain" Psychopharmacology 146(2): 220-7
Pubmed
III. Chou YH, Halldin C, Farde L (2000). "Effect of amphetamine on extrastriatal D2 dopamine receptor binding in the primate brain: a PET study. " Synapse 38(2): 138-43
Pubmed
IV. Nyberg S, Chou YH, Halldin C (2001). "Saturation of striatal D2 dopamine receptors by clozapine." International Journal of Neuropsychopharmacology (Submitted)
V. Chou YH, Farde L, Karlsson P, Olsson H, Sandell J (2001). "Clozapine binds preferentially to frontal cortical D1-like dopamine receptors in the primate brain." (Manuscript)
VI. Chou YH, Farde L, Halldin C (2001). "Occupancy of 5-HT 1A receptors clozapine in the monkey brain: A pet study." Neuropsychopharmacology (Submitted)
I. Halldin C, Foged C, Chou YH, Karlsson P, Swahn CG, Sandell J, Sedvall G, Farde L (1998). "Carbon-11-NNC 112: a radioligand for PET examination of striatal and neocortical D1-dopamine receptors. " J Nucl Med 39(12): 2061-8
Pubmed
II. Chou YH, Karlsson P, Halldin C, Olsson H, Farde L (1999). "A PET study of D(1)-like dopamine receptor ligand binding during altered endogenous dopamine levels in the primate brain" Psychopharmacology 146(2): 220-7
Pubmed
III. Chou YH, Halldin C, Farde L (2000). "Effect of amphetamine on extrastriatal D2 dopamine receptor binding in the primate brain: a PET study. " Synapse 38(2): 138-43
Pubmed
IV. Nyberg S, Chou YH, Halldin C (2001). "Saturation of striatal D2 dopamine receptors by clozapine." International Journal of Neuropsychopharmacology (Submitted)
V. Chou YH, Farde L, Karlsson P, Olsson H, Sandell J (2001). "Clozapine binds preferentially to frontal cortical D1-like dopamine receptors in the primate brain." (Manuscript)
VI. Chou YH, Farde L, Halldin C (2001). "Occupancy of 5-HT 1A receptors clozapine in the monkey brain: A pet study." Neuropsychopharmacology (Submitted)
Issue date: 2001-02-02
Publication year: 2001
ISBN: 91-628-4639-6
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