TY - JOUR
T1 - Extrastriatal dopamine D2 receptors
T2 - Distribution, pharmacological characterization and region-specific regulation by clozapine
AU - Janowsky, A.
AU - Neve, K. A.
AU - Kinzie, J. M.
AU - Taylor, B.
AU - De Paulis, T.
AU - Belknap, J. K.
PY - 1992
Y1 - 1992
N2 - The distribution of dopamine D2 receptors in the rat brain was determined by quantitative autoradiography of the binding of [125I]epidepride and the effects of chronic drug administration on regulation of receptors in striatal and extrastriatal brain regions were characterized. [125I]Epidepride (2200 Ci/mmol) bound with high affinity to coronal tissue sections from the rat brain (K(d) = 78 pM), and specific binding was detected in a number of discrete layers, nuclei or regions of the hippocampus, thalamus, cerebellum and other extrastriatal sites. Pharmacological analysis of radioligand binding to hippocampal and cerebellar membranes indicated binding to dopamine D2 receptors, and approximately 10% of the binding appeared to represent low affinity idazoxan-displaceable binding to alpha-2 adrenoceptors. The binding to extrastriatal regions resembled previously reported radioligand binding to dopamine D2 receptors in striatal and cortical membranes. Chronic (14 day) administration of two dopamine D2 receptor antagonists, either the typical neuroleptic haloperidol (1.5 mg/kg i.p.) or the atypical neuroleptic clozapine (30 mg/kg i.p.), caused a significant increase in the density of [125I]epidepride binding sites in the medial prefrontal cortex and parietal cortex. Only haloperidol caused a significant increase in the density of [3H]spiperone and [125I]epidepride binding sites in the striatum and a slight increase in [125I]epidepride binding sites in the hippocampus. Similar administration of amphetamine (5 mg/kg i.p.) had no significant effect on the density of dopamine D2 receptors in any brain region examined. In addition, no drug-induced changes in the characteristics of dopamine D2 receptors in discrete areas of the cerebellum were observed. The data indicate that clozapine exerts a regionally specific effect on dopamine D2 receptors, and these changes may play a role in its therapeutic profile. In addition, [125I]epidepride appears to be relatively selective, and one of the most potent radioactive ligands available for characterizing changes in the regulation of dopamine D2 receptors in brain regions that contain a very low density of binding sites.
AB - The distribution of dopamine D2 receptors in the rat brain was determined by quantitative autoradiography of the binding of [125I]epidepride and the effects of chronic drug administration on regulation of receptors in striatal and extrastriatal brain regions were characterized. [125I]Epidepride (2200 Ci/mmol) bound with high affinity to coronal tissue sections from the rat brain (K(d) = 78 pM), and specific binding was detected in a number of discrete layers, nuclei or regions of the hippocampus, thalamus, cerebellum and other extrastriatal sites. Pharmacological analysis of radioligand binding to hippocampal and cerebellar membranes indicated binding to dopamine D2 receptors, and approximately 10% of the binding appeared to represent low affinity idazoxan-displaceable binding to alpha-2 adrenoceptors. The binding to extrastriatal regions resembled previously reported radioligand binding to dopamine D2 receptors in striatal and cortical membranes. Chronic (14 day) administration of two dopamine D2 receptor antagonists, either the typical neuroleptic haloperidol (1.5 mg/kg i.p.) or the atypical neuroleptic clozapine (30 mg/kg i.p.), caused a significant increase in the density of [125I]epidepride binding sites in the medial prefrontal cortex and parietal cortex. Only haloperidol caused a significant increase in the density of [3H]spiperone and [125I]epidepride binding sites in the striatum and a slight increase in [125I]epidepride binding sites in the hippocampus. Similar administration of amphetamine (5 mg/kg i.p.) had no significant effect on the density of dopamine D2 receptors in any brain region examined. In addition, no drug-induced changes in the characteristics of dopamine D2 receptors in discrete areas of the cerebellum were observed. The data indicate that clozapine exerts a regionally specific effect on dopamine D2 receptors, and these changes may play a role in its therapeutic profile. In addition, [125I]epidepride appears to be relatively selective, and one of the most potent radioactive ligands available for characterizing changes in the regulation of dopamine D2 receptors in brain regions that contain a very low density of binding sites.
UR - http://www.scopus.com/inward/record.url?scp=0026653139&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0026653139&partnerID=8YFLogxK
M3 - Article
C2 - 1534844
AN - SCOPUS:0026653139
SN - 0022-3565
VL - 261
SP - 1282
EP - 1290
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 3
ER -