Effects of haloperidol and reduced haloperidol on binding to sigma sites.

The s.c. administration of a single dose of 0.1 mg/kg of reduced haloperidol to guinea pigs produced a marked inhibition of the binding of [3H]dextromethorphan and [3H]3-(3-hydroxyphenyl)-N-(n-propyl)piperidine ([3H](+)-3-PPP) to brain. The inhibition was still evident 10 days later, and it was accompanied by residual brain levels of reduced haloperidol, and much lower levels of haloperidol. Scatchard and computer-assisted analysis demonstrated that the inhibition was due to a reduction in the number of binding sites without changes in the affinity. In the rat, haloperidol and reduced haloperidol also produced a rapid inhibition of binding to sigma sites. Interestingly, the brain of the reduced haloperidol-treated rats contained both haloperidol and reduced haloperidol, but the levels of reduced haloperidol in the haloperidol-treated rats were undetectable. However, the inhibition observed was of comparable magnitude, indicating that the haloperidol remaining in the brain is also inhibitory. In vitro experiments showed that the inhibition produced by haloperidol and reduced haloperidol was apparently competitive, but when brain membranes were preincubated with either drug, the inhibition was noncompetitive. By contrast, the inhibition produced by dextromethorphan was always competitive. Moreover, the inhibition produced by haloperidol and reduced haloperidol could not be reversed by washing. This investigation strongly suggests that the inhibition observed after the administration of haloperidol or reduced haloperidol is not a classic agonist-induced receptor down-regulation. The results indicated that the inhibition produced is a complex phenomenon, and suggest the formation of a slowly reversible or irreversible complex with reduced haloperidol or haloperidol.