TY - JOUR
T1 - Quantitative autoradiography of ligands for dopamine receptors and transporters in brain of Göttingen minipig
T2 - comparison with results in vivo
AU - Minuzzi, Luciano
AU - Olsen, Aage Kristian
AU - Bender, Dirk
AU - Arnfred, Sidse
AU - Grant, Rebecca
AU - Danielsen, Erik H
AU - Cumming, Paul
N1 - Copyright 2005 Wiley-Liss, Inc.
PY - 2006/3/15
Y1 - 2006/3/15
N2 - The pig has been used as animal model for positron emission tomography (PET) studies of dopamine (DA) receptors and pharmacological perturbations of DA neurotransmission. However, the binding properties of DA receptors and transporters in pig brain have not been characterized in vitro. Therefore, the saturation binding parameters of [3H]SCH 23390 for DA D1 receptors and [3H]raclopride for DA D2/3 receptors were measured by quantitative autoradiography in cryostat sections from brain of groups of 8 week old and adult female Göttingen minipigs. The magnitudes of Bmax and Kd for these ligands were similar in young and old pigs, and were close to those reported for rat and human brain. Furthermore, gradients in the concentrations of D1 and D2/3 sites in striatum measured in vitro agreed with earlier findings in PET studies. However, the dopamine transporter (DAT) ligand [3H]GBR12935 did not bind in pig brain cryostat sections. Whereas the tropane derivative [125I]RTI-55 labeled serotonin transporters (serotonin transporter (SERT)) in pig brain, use of the same ligand under conditions specific for DAT, revealed a pattern of binding similar to that observed for SERT conditions. Parallel studies revealed the presence of DAT in rat and ferret brain. The distribution volume (Vd) of the selective DAT ligand [11C]NS2214 ([11C]Brasofensine) was mapped in groups of normal and MPTP-lesioned Göttingen miniature pigs. The in vivo pattern of Vd matched the distribution of SERT in vitro, and did not differ between the normal pigs and the lesioned animals with documented 60% DA depletions. However, the pattern of specific binding of the selective noradrenaline transporter ligand (S,S)-[11C]MeNER in a single Landrace pig showed that, of the three monoamine transporters, only DAT could not be detected in pig brain. We conclude that the pig is a suitable model for PET studies of DA D1 and D2/3 binding sites, which are fully developed on the eighth postnatal week. However, well-characterized piperazine and tropane radioligands failed to recognize DAT in pig brain; the two tropane radioligands lacked pharmacological specificity for DAT and SERT in pig brain in vitro and in vivo.
AB - The pig has been used as animal model for positron emission tomography (PET) studies of dopamine (DA) receptors and pharmacological perturbations of DA neurotransmission. However, the binding properties of DA receptors and transporters in pig brain have not been characterized in vitro. Therefore, the saturation binding parameters of [3H]SCH 23390 for DA D1 receptors and [3H]raclopride for DA D2/3 receptors were measured by quantitative autoradiography in cryostat sections from brain of groups of 8 week old and adult female Göttingen minipigs. The magnitudes of Bmax and Kd for these ligands were similar in young and old pigs, and were close to those reported for rat and human brain. Furthermore, gradients in the concentrations of D1 and D2/3 sites in striatum measured in vitro agreed with earlier findings in PET studies. However, the dopamine transporter (DAT) ligand [3H]GBR12935 did not bind in pig brain cryostat sections. Whereas the tropane derivative [125I]RTI-55 labeled serotonin transporters (serotonin transporter (SERT)) in pig brain, use of the same ligand under conditions specific for DAT, revealed a pattern of binding similar to that observed for SERT conditions. Parallel studies revealed the presence of DAT in rat and ferret brain. The distribution volume (Vd) of the selective DAT ligand [11C]NS2214 ([11C]Brasofensine) was mapped in groups of normal and MPTP-lesioned Göttingen miniature pigs. The in vivo pattern of Vd matched the distribution of SERT in vitro, and did not differ between the normal pigs and the lesioned animals with documented 60% DA depletions. However, the pattern of specific binding of the selective noradrenaline transporter ligand (S,S)-[11C]MeNER in a single Landrace pig showed that, of the three monoamine transporters, only DAT could not be detected in pig brain. We conclude that the pig is a suitable model for PET studies of DA D1 and D2/3 binding sites, which are fully developed on the eighth postnatal week. However, well-characterized piperazine and tropane radioligands failed to recognize DAT in pig brain; the two tropane radioligands lacked pharmacological specificity for DAT and SERT in pig brain in vitro and in vivo.
KW - Age Factors
KW - Animals
KW - Autoradiography
KW - Binding, Competitive
KW - Brain/diagnostic imaging
KW - Cocaine/analogs & derivatives
KW - Dopamine Antagonists/pharmacokinetics
KW - Dopamine Plasma Membrane Transport Proteins/metabolism
KW - Female
KW - Ferrets
KW - Humans
KW - In Vitro Techniques
KW - Ligands
KW - Piperazines/pharmacokinetics
KW - Positron-Emission Tomography
KW - Raclopride/pharmacokinetics
KW - Radiopharmaceuticals/pharmacokinetics
KW - Rats
KW - Receptors, Dopamine/metabolism
KW - Swine
KW - Swine, Miniature/physiology
U2 - 10.1002/syn.20234
DO - 10.1002/syn.20234
M3 - Journal article
C2 - 16385509
SN - 0887-4476
VL - 59
SP - 211
EP - 219
JO - Synapse
JF - Synapse
IS - 4
ER -