Protein kinase C and dopamine transport--1. Effects of amphetamine in vivo.

Rats, injected with small doses of amphetamine (0.03-0.1 mg/kg, i.p.), showed an increase in the soluble and a decrease in the activity of the particulate protein kinase C (PKC) in the striatum, while large doses of amphetamine (0.3-1.0 mg/kg) had the opposite effect of decreasing the soluble and increasing the particulate activity of PKC. These effects were manifested as a change in the Km for calcium, without an alteration in the Vmax. They were attenuated by pretreatment with benztropine, a dopamine (DA) uptake blocker and by alpha-methyl-p-tyrosine (alpha-MT), a DA synthesis inhibitor. The effects of 0.1 mg/kg amphetamine were insensitive to pretreatment with reserpine but were attenuated by the DA antagonists, SCH 23390 or sulpiride. These results suggest that the changes in activity of PKC induced by a small dose of amphetamine were mediated by an activation of DA autoreceptors, through an increase in the biophase concentration of DA at the synapse. In contrast, the effects of 1.0 mg/kg amphetamine on activity of PKC were attenuated by reserpine and by the DA agonists, LY 171555 or SKF 38393. They were, furthermore, potentiated by simultaneous treatment with sulpiride, which indicates that the two drugs act by different mechanisms. These results suggest that larger doses of amphetamine altered the activity of PKC at the DA transport site.