On the mechanism of neuroleptic induced increase in striatal dopamine release: brain dialysis provides direct evidence for mediation by autoreceptors localized on nerve terminals.
The influence of sulpiride on the in vivo release of dopamine and DOPAC from the rat striatum was investigated by microdialysis. Racemic sulpiride was administered systemically (i.p.) to control rats and to rats in which a striatum was pretreated by kainic acid. In addition various concentrations (10(-8) to 10(-5) M) of the two enantiomers of sulpiride were infused into the striatum and the effects on the release of dopamine were recorded. Infusion as well as systemic administration of sulpiride caused a maximal increase in the release of dopamine of about 180-190% of basal values. A similar increase was seen in kainic acid-pretreated rats. The rises in dopamine seen after systemic administration or infusion of sulpiride were not additive, suggesting that similar mechanisms were involved. DOPAC dialysate levels also increased during infusion of the neuroleptic but the rise was significantly less when sulpiride was administered i.p. to kainic acid pretreated rats. It is concluded that the rise in dopamine release seen after neuroleptics is mediated by autoreceptors localized on nerve terminals. This implies that the well-known increase in electrical activity of dopaminergic neurons during neuroleptic treatment, is not responsible for the increased release of the transmitter.
Westerink
B H
BH
Department of Medicinal Chemistry, State University Groningen, The Netherlands.
de Vries
J B
JB
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism*; D017448:Receptors, Dopamine D2; D013237:Stereoisomerism; D013469:Sulpiride / Q000494:pharmacology*
D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D013469:Sulpiride; D004298:Dopamine