Antipsychotics with inverse agonist activity at the dopamine D3 receptor.
In NG 108-15 cells expressing the recombinant human D3 receptor, dopamine agonists enhance [3H]thymidine incorporation and decrease cAMP accumulation. In these cells, but not in wild type cells, haloperidol, fluphenazine, and various other antipsychotics inhibited basal [3H]thymidine incorporation in a concentration-dependent manner. In contrast, other dopamine antagonists such as nafadotride or (+)AJ 76, two D3-preferring antagonists, were without effect. The concentration-response curve of haloperidol was shifted to the right in presence of nafadotride, with a potency compatible with its nanomolar apparent affinity as neutral antagonist. Pertussis toxin treatment abolished or markedly reduced the responses to haloperidol or fluphenazine. In contrast, no significant enhancement of cAMP accumulation could be observed, under the influence of haloperidol or eticlopride. These data indicate that some dopamine antagonists behave as inverse agonists, and thus appear to inhibit an agonist-independent activity of the D3 receptor on [3H]thymidine incorporation pathway, but not on the cAMP pathway.
Griffon
N
N
Unité de Neurobiologie et Pharmacologie de l'INSERM, Centre Paul Broca, Paris, France.
Pilon
C
C
Sautel
F
F
Schwartz
J C
JC
Sokoloff
P
P
D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D016466:CHO Cells; D002118:Calcium / Q000502:physiology; D003024:Clozapine / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D000242:Cyclic AMP / Q000502:physiology; D004261:DNA Replication / Q000187:drug effects; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005475:Flupenthixol / Q000494:pharmacology; D005910:Glioma / Q000473:pathology; D006220:Haloperidol / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D006822:Hybrid Cells / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology; D009447:Neuroblastoma / Q000473:pathology; D037342:Pertussis Toxin; D010640:Phenothiazines / Q000494:pharmacology; D010868:Pimozide / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D019257:Quinpirole / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D050637:Receptors, Dopamine D3; D011994:Recombinant Proteins / Q000819:agonists; D018967:Risperidone / Q000494:pharmacology; D012457:Salicylamides / Q000494:pharmacology; D015290:Second Messenger Systems / Q000502:physiology; D013469:Sulpiride / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D014150:Antipsychotic Agents; C493593:DRD3 protein, human; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D009281:Naphthalenes; D010640:Phenothiazines; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D011994:Recombinant Proteins; D012457:Salicylamides; D013764:Tetrahydronaphthalenes; D010566:Virulence Factors, Bordetella; D005576:Colforsin; D010868:Pimozide; D019257:Quinpirole; D013469:Sulpiride; C051171:5-methoxy-1-methyl-2-(n-propylamino)tetralin; D000242:Cyclic AMP; D037342:Pertussis Toxin; D005475:Flupenthixol; D003024:Clozapine; D006220:Haloperidol; C097285:nafadotride; D018967:Risperidone; D002118:Calcium