Extrastriatal dopamine D2 receptors: distribution, pharmacological characterization and region-specific regulation by clozapine.
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 (Kd = 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Janowsky
A
A
Department of Psychiatry and Pharmacology, Oregon Health Sciences University, Portland.
Neve
K A
KA
Kinzie
J M
JM
Taylor
B
B
de Paulis
T
T
Belknap
J K
JK
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D001549:Benzamides / Q000138:chemical synthesis / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003024:Clozapine / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism*; D017448:Receptors, Dopamine D2; D013134:Spiperone / Q000378:metabolism
D001549:Benzamides; D011759:Pyrrolidines; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; C063525:epidepride; D013134:Spiperone; D000661:Amphetamine; D003024:Clozapine; D006220:Haloperidol