Dose response for amphetamine-induced changes in dopamine levels in push-pull perfusates of rat striatum

Levels of dopamine were determined in push-pull perfusates of striatum in chloral hydrate-anesthetized rats as a function of increasing systemic doses of amphetamine over the range 0.5-5.0 mg/kg. In the absence of amphetamine administration, basal dopamine levels remained stable for at least 6 h. Perfusate levels of dopamine responded in a quantitatively predictable fashion to increasing doses of amphetamine: (1) the maximal increase in perfusate levels of dopamine after amphetamine, relative to predrug levels, was directly proportional to the dose of the drug up to 3 mg/kg (fivefold after 0.5 mg/kg to 30-fold after 3 mg/kg); (2) the duration over which perfusate levels of dopamine were significantly elevated, with respect to preamphetamine levels, was proportional to the dose of amphetamine up to 5 mg/kg; and (3) each successively higher dose of amphetamine significantly increased the perfusate level of dopamine over that observed at the next lower dose up to 3 mg/kg amphetamine. However, maximal levels of dopamine in striatal perfusates were achieved following 3 mg/kg amphetamine and were not increased further at higher doses of the drug. The data suggest that, at higher doses of amphetamine, extraneuronal metabolism of dopamine may be of sufficient capacity to limit increases in synaptic levels of dopamine. The absence of further increases in perfusate levels of dopamine as the dose of amphetamine is increased beyond 3 mg/kg is discussed in terms of potential relevance to mechanisms of amphetamine-induced stereotyped behaviors.