Chronic neuroleptic treatment increases D-2 but not D-1 receptors in rat striatum.

In vitro binding of [3H]cis(Z)-flupentixol (FPT) to rat striatal membranes was evaluated as an assay for D-1 receptors. It was found that under the appropriate assay conditions [3H]FPT bound to a single saturable site which was most abundant in striatum and bound dopaminergic agonists in the potency order that these drugs demonstrate for adenylate cyclase. These data support previous work suggesting that [3H]FPT labels the D-1 receptor. Next, rats received haloperidol or fluphenazine for 54 days and striatal dopamine receptors were assayed 72 h later. The drug treatments increased the density of D-2 receptors as measured by [3H]spiperone binding by 40% and 25% respectively. However, no change was observed in D-1 receptor density. We conclude that effects of chronic neuroleptic treatment that depend upon increased dopamine receptor density are mediated via the D-2 receptor subtype.

[1]  P. Seeman,et al.  Antipsychotic drug doses and neuroleptic/dopamine receptors , 1976, Nature.

[2]  S H Snyder,et al.  Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs , 1976, Science.

[3]  M. Zigmond,et al.  High‐and Low‐Affinity States of Striatal D2 Receptors Are Not Affected by 6‐Hydroxydopamine or Chronic Haloperidol Treatment , 1984, Journal of neurochemistry.

[4]  J. Hyttel.  SCH 23390 - the first selective dopamine D-1 antagonist. , 1983, European journal of pharmacology.

[5]  J. Hyttel,et al.  Effects of neuroleptics on 3H-haloperidol and 3H-cis(Z)-flupenthixol binding and on adenylate cyclase activity in vitro. , 1978, Life sciences.

[6]  R. Lefkowitz,et al.  A quantitative analysis of beta-adrenergic receptor interactions: resolution of high and low affinity states of the receptor by computer modeling of ligand binding data. , 1980, Molecular pharmacology.

[7]  J. Kebabian,et al.  Multiple receptors for dopamine , 1979, Nature.

[8]  J. C. Stoof,et al.  Opposing roles for D-1 and D-2 dopamine receptors in efflux of cyclic AMP from rat neostriatum , 1981, Nature.

[9]  C. Marsden,et al.  Changes in apomorphine-induced stereotypy as a result of subacute neuroleptic treatment correlates with increased D-2 receptors, but not with increases in D-1 receptors. , 1983, Biochemical pharmacology.

[10]  N. Birdsall,et al.  The binding of agonists to brain muscarinic receptors. , 1978, Molecular pharmacology.

[11]  R. George,et al.  Subcellular localization of dopamine-sensitive adenylate cyclase and dopamine receptor binding activities. , 1978, Life sciences.

[12]  J. Kebabian,et al.  The Dopamine Receptor in the Intermediate Lobe of the Rat Pituitary Gland: Pharmacological Characterization , 1980 .

[13]  J. Glowinski,et al.  Characteristics of dopamine and β-adrenergic sensitive adenylate cyclases in the frontal cerebral cortex of the rat. Comparative effects of neuroleptics on frontal cortex and striatal dopamine sensitive adenylate cyclases , 1977, Brain Research.

[14]  J. Kebabian,et al.  Evidence that LY-141865 specifically stimulates the D-2 dopamine receptor , 1981, Nature.

[15]  F. Owen,et al.  Characteristics of 3H-cis-flupenthixol binding to calf brain membranes. , 1980, European journal of pharmacology.

[16]  C. Marsden,et al.  Alterations in different populations of striatal dopamine receptors produced by 18 months continuous administration of cis- or trans-flupenthixol to rats , 1984, Neuropharmacology.

[17]  R. Lefkowitz,et al.  The β-Adrenergic Receptor: Ligand Binding Studies Illuminate the Mechanism of Receptor-Adenylate Cyclase Coupling , 1983 .

[18]  H. Sarau,et al.  The central effects of a novel dopamine agonist. , 1978, European journal of pharmacology.

[19]  R. Baldessarini,et al.  Dopamine and the pathophysiology of dyskinesias induced by antipsychotic drugs. , 1980, Annual review of neuroscience.

[20]  C. Goetz,et al.  Tardive dyskinesia: review and update. , 1980, The American journal of psychiatry.