Blockade of dopamine autoreceptors by haloperidol and the apparent dynamics of potassium-stimulated endogenous release of dopamine from and reuptake into striatal suspensions in the rat.
A study was made to determine what effects the blockade of dopamine (DA) autoreceptors has on the dynamics of depolarization-stimulated release of DA from suspensions of the striatum. A rotating disk electrode voltammetric technique and a first order kinetic model were used to measure and quantify time-resolved depolarization-induced release of DA from and reuptake into the same striatal suspension. Multiphasic dose-response relationships between the magnitudes, rates and apparent rate constants of release of DA and the concentration of the autoreceptor antagonist, haloperidol, were observed. At small concentrations of haloperidol, less than or equal to 0.1 microM, the magnitude of release of DA and apparent release rate constants were increased, however, the duration of release, the initial rate of release and the rate constants of reuptake of DA were unaffected. At larger concentrations of haloperidol, greater than 1.0 microM, release of DA was prolonged and reuptake was decreased. The rate constants for release of DA correlated with the magnitude of release of DA at all of the concentrations of haloperidol studied. The concentrations of haloperidol in tissue were estimated and then correlated with functionally significant systemic doses of haloperidol by direct comparison to published data, relating total concentrations of haloperidol in tissue with systemic doses and their behavioral effects. At these doses, haloperidol was found to increase the release rate constant and magnitude of release of DA, without altering the duration of release or the timing of reuptake. Thus, at presumed functionally significant doses, autoreceptor antagonism resulted in a modulation of the amplitude of release of DA only.
McElvain
J S
JS
Department of Biochemistry, Washington State University, Pullman 99164-4630.
Schenk
J O
JO
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008433:Mathematics; D011188:Potassium / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
D011954:Receptors, Dopamine; D006220:Haloperidol; D011188:Potassium; D004298:Dopamine