The role of drug efficacy in agonist-induced desensitization was studied in C-6 glioma cells transfected with the monkey dopamine D1A (mD1A) receptor. Dopamine pretreatment for 2 hr produced greater than 80% loss of responsiveness in the stimulation of cAMP accumulation that was blocked by the D1 antagonist SCH23390. A series of full and partial D1 agonists from structurally dissimilar classes were then examined. Three full agonists (dihydrexidine, SKF82958, A77636) desensitized the receptor to the same extent as dopamine, whereas two other full agonists (dinapsoline and A68930) and all the partial agonists tested (SKF38393, pergolide and d-lysergic acid diethylamide tartrate) produced only partial desensitization (i.e., 50% that of dopamine). Whereas partial agonists (i.e., SKF38393, pergolide and d-lysergic acid diethylamide tartrate) caused no alteration in ligand-accessible mD1A receptors, four of the full agonists (dopamine, dihydrexidine, dinapsoline, A68930) caused a 30 to 40% reduction in receptor number. One full agonist, A77636, caused nearly an 80% decrease in receptor number, despite the fact that the degree of functional desensitization was similar to the other full agonists. The desensitization of the D1 receptor was homologous, not affecting beta-2 adrenergic receptors endogenous to C-6 cells. Neither incubation with cAMP analogs, nor inhibition of protein kinase A, affected dopamine-induced desensitization, suggesting a cAMP-independent mechanism in this cell line. Together, these data suggest that functional desensitization of the mD1A receptor expressed in C-6 glioma cells is a cAMP-independent mechanism, cannot be predicted reliably from agonist efficacy for stimulating adenylate cyclase and can occur in the absence of changes in receptor number.