Methamphetamine-induced alteration in the physical state of rat caudate tyrosine hydroxylase

Abstract

Methamphetamine was found to induce a shift of a portion of rat striate (and not midbrain) tyrosine hydroxylase activity from the 11,000 g supernatant to the “synaptosomal” and “mitochondrial” particulate fractions with no change in total measurable enzyme activity, although the particulate enzyme demonstrated a greater affinity for the synthetic cofactor, 6,7-dimethyl-5,6,7,8-tetrahydropterin (DMPH 4). The magnitude of this shift appeared dose-related up to 5 mg/kg. It demonstrated a shortest latency of 10 min and a longest duration of 8 hr. It could not be produced in vitro by homogenizing the striate area in varying concentrations of methamphetamine or catecholamines. The effect could not be abolished by pretreatment with cycloheximide or intraventricular colchicine. It could not be induced by the administration of imipramine, footshock, electroconvulsive shock, or behaviorally activating intraventricularly-infused norepinephrine (NE). However, this change could be produced by the administration of α-methyltyrosine and reserpine. The ressrpine-induced change differed in that in addition to the shift of activity from the soluble to the particulate fraction, there was an increase in total measurable enzyme activity as well. It was suggested that a drug-induced reduction in intraneuronal catecholamines may be the common stimulus for the observed relative increase in rat caudate particulate tyrosine hydroxylase. The particulate state of caudate tyrosine hydroxylase generally resisted narrow clearance homogenization, hypotonic shock and sonication but varied in a complex way with varying ion concentrations (especially Ca 2 and Mg 2) in vitro. Varying membrane binding of soluble tyrosine hydroxylase via the manipulation in vitro of divalent cations led to apparent decreases in the specific activity of tyrosine hydroxylase. However, other recent studies in our laboratory have demonstrated that membrane binding of tyrosine soluble hydroxylase activates the enzyme allosterically for DMPH 4 binding as well as for the competitive inhibition of the affinity of this cofactor site by dopamine (DA) and norepinephrine (NE). It is within this context that the amphetamine-induced alteration in physical state of tyrosine hydroxylase assumes potential regulatory significance.