The effects of subchronic (10 days) treatment with two antischizophrenic drugs, fluphenazine and sulpiride, on rat brain dopamine and muscarinic receptor sites were studied at various time points after withdrawal from the drug treatments. Striatal D-2 dopamine receptors and cortical muscarinic receptors were characterized with the radioligands 3H-spiperone and 3H-quinuclidinyl benzilate (3H-QNB), respectively. 2. Neither drug treatment affected significantly the number or affinity of cortical muscarinic receptors during the withdrawal time of 18 days. 3. The number of D-2 receptors in striatum was not altered after 4 or 8 fluphenazine-free days, but after 18 days fluphenazine caused an increase of 55% in the density of D-2 receptors. Sulpiride caused a slight increase in Bmax of striatal D-2 receptors after 4 and 8 withdrawal days but the maximum increase of 29% was observed after 18 withdrawal days. 4. Fluphenazine treatment caused an increase in the apparent dissociation constant 4 days after the termination of the treatment suggesting that residual neuroleptic levels may have been retained after this dose regimen, since the Kd returned near control levels as the withdrawal time passed. Sulpiride, however, caused a moderate increase in Kd throughout the withdrawal time. 5. In conclusion, these results suggest that even a rather short treatment with fluphenazine or sulpiride, a classical and an atypical neuroleptic, respectively, can induce pronounced changes in striatal dopamine receptor characteristics after a drug washout period of almost three weeks. Thus, possible delayed actions of classical as well as novel neuroleptic drugs on neurotransmitter function should be considered in studies examining the neuroleptic withdrawal effects.
