Characterization of haloperidol-mediated effects on rat striatal tyrosine hydroxylase

Abstract

The dependence on pH of rat striatal tyrosine hydroxylase (TH) was studied both in the presence and absence of phosphorylating conditions. In the absence of phosphorylating conditions the K m of TH for the cofactor 6MPH 4 increased with increasing pH (5.8–6.3) and changes in V max reflected the pH optimum of the enzyme. In the presence of phosphorylating conditions little change in either V max or K m was noted over this pH range. Rats treated acutely with haloperidol (1.0mg/kg, i.p.) demonstrated a decrease in K m which was more marked at pH 6.30 than at pH 5.85. Subacute treatment with haloperidol (1.0 mg/kg/day, i.p.) for 10 days significantly increased the K m of TH for cofactor in striata examined 23 hr after the last injection and decreased the K m 1 hr after the last injection. Rats receiving subacute treatment with haloperidol (1.0 mg/kg/day, i.p.) for 10 days followed by a drug-free interval of 1, 8 or 15 days demonstrated a significantly reduced K m for cofactor 1 hr after challenge with an eleventh injection when the drug-free interval was short and there was no change in K m when the drug-free interval extended to 2 weeks. In similarly treated animals, which did not receive an acute challenge with haloperidol, the K m of TH for 6MPH 4 was elevated 23 hr after the last of 10 injections and continued to rise when the drug-free interval extended to 1 week. Thereafter, the K m decreased towards that seen in control, untreated animals. The present data suggest that short-term treatment with haloperidol changes the affinity of TH for cofactor and that these drug effects are more prominent at pH 6.0–6.6 than at the pH optimum for native striatal TH (pH 5.8–6.0). Furthermore, an apparent tolerance to the effects of haloperidol develops 2 weeks following the cessation of 10 days of treatment with haloperidol. The combined effects of pH and the schedule of drug administration on striatal TH activity are likely to explain the differences in some apparently inconsistent reports in the literature.