A quantitative study of dopamine control in the rat striatum

The control of dopamine release by negative feedback via dopaminergic autoreceptors has been well established. Using previously derived mathematical equations, we have incorporated this feedback component into a mass-action binding model in which the rate of ligand release is a function of the quantity that is bound. A consequence of this model is that competitive antagonists augment release, whereas competing agonists reduce such release. In order to obtain values of the parameters needed in the feedback equations, in vivo microdialysis was used to deliver drugs locally to the rat striatum and to monitor the resulting changes in extracellular dopamine levels. The dopamine agonists apomorphine and quinpirole and the antagonists haloperidol and sulpiride were individually infused into the rat striatum via the microdialysis probe, and the effect of each on extracellular dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic levels was recorded. The data obtained from the microdialysis experiments were used to construct dopamine's control curve, a new quantitative concept that describes the feedback control of the dopaminergic system. Once known, the ligand's control curve has predictive value that may be useful in the design of efficient drug tests. Alterations of dopamine's control curve, which may occur with aging, drug addiction and pathological states, can now be studied and may provide new insights for potential therapeutic strategies.