| Description |
Acute administration of haloperidol to rats causes a marked decrease in the Km of neostriatal tyrosine hydroxylase for the pteridine cofactor, 6MPH(,4), with no change in Vmax. This effect is dependent on the pH of the assay mixture. It occurs at pH 6.5 but not at pH 6.0, the pH optimum for TH. With phosphorylating conditions at pH 6.5, the haloperidol-induced activation is no longer observed, and the kinetics of TH are the same as those from control rats. At pH values of 6.0, 6.3 and 6.5, a significant decrease in Vmax occurs, with increasing pH, while no significant change in Km for the cofactor is observed for TH from control rats. However, when phosphorylating conditions are employed, a marked increase in Km for the cofactor is observed while only a slight decrease in Vmax is seen, with increasing pH, for the control enzyme at the three pH values tested. The kinetic characteristics of neostriatal tyrosine hydroxylase (TH) activity were then determined after rats were given large, repeated doses of methamphetamine. The Vmax of the enzyme was markedly decreased after methamphetamine, but no change in the Km for pteridine cofactors nor for the substrate, tyrosine, was detected. The decrease in Vmax with methamphetaminee was independent of the phosphorylated state of the enzyme. The effect of propranolol in blocking the methamphetamine-induced depression of tryptophan hydroxylase was then investigated. Acute administration of methamphetamine produced a marked decrease in tryptophan hydroxylase activity in all serotonergic nerve terminal regions of rat brain examined. This decrease was antagonized in a regionally selective manner by propranolol. Almost complete blockade occurred in regions that are commonly implicated in schizophrenia, mesolimbic areas, neostriatum, and hypothalamus; whereas in other regions examined, only partial or no blockade occurred. In contrast, haloperidol did not produce a similar antagonism. The results are discussed in the context of the efficacy of large doses of propranolol in some schizophrenic patients. |
