Biphasic effects of amphetamine on striatal dopamine dynamics

S(+)-Amphetamine (AMPH) was administered to rats over the dose range 0.15-10.0 mg/kg (1.74(3)mumoles/kg) at various times before sacrifice. 15 min before sacrifice rats received an intraventricular injection of 3H-tyrosine, and the accumulation of striatal 3H-dopamine (DA) was assessed as an index of striatal DA formation and utilization. 3H-DA formation exhibited a biphasic dose response to AMPH. At 16 and 31 min after AMPH administration, 3H-DA accumulation increased linearly in response to AMPH to a maximal rate of 200% of control values at 1.0 mg/kg, then declined to less than 50% of control values at AMPH doses of 5 and 10 mg/kg. As a function of time, low doses of AMPH (to 2.0 mg/kg)) only increased 3H-DA accumulation, whereas high doses of AMPH (greater than 2.5 mg/kg) only decreased 3H-DA accumulation. All doses of AMPH increased endogenous levels of striatal DA. The data are discussed in terms of compensatory adaptive mechanisms of the nigrostriatal dopaminergic pathway.