Phorbol esters and D2-dopamine receptors.
4-beta-Phorbol-12,13-dibutyrate (PDBu), a powerful activator of protein kinase C (PKC), enhanced dopamine (DA) release evoked by electrical stimulation (1 Hz, 2 min) from the striatum and the prefrontal cortex of the rabbit. However, acetylcholine (ACh) release from the striatum (1 Hz, 2 min), was only enhanced slightly by PDBu. The increase in DA release induced by PDBu was reduced markedly at higher frequencies of stimulation. Sulpiride (10 microM) alone, a D2 DA-receptor antagonist, or combined with nomifensine (3 microM), a neuronal-uptake inhibitor, did not prevent PDBu-induced facilitation of DA release from prefrontal cortex or striatum. The D2 DA agonists (LY-171555, bromocriptine and apomorphine) inhibited in a concentration-dependent manner the stimulation-evoked overflow of DA and ACh from the striatum, and of DA from the prefrontal cortex. Pretreatment with PDBu antagonized the inhibitory effect of the three agonists on DA and ACh release. A reduction both in Emax and IC50 was observed in PDBu-treated slices. Removal of endogenous DA by pretreatment with reserpine and alpha-methyl-p-tyrosine, failed to prevent PDBu-induced antagonism of apomorphine effects on ACh release, indicating that the antagonism of agonist effects was not due to higher synaptic levels of endogenous DA. The inactive enantiomer of PDBu, 4-alpha-12,13-dibutyrate did not enhance DA release and failed to modify the effects of D2 agonists on DA release.(ABSTRACT TRUNCATED AT 250 WORDS)
Cubeddu
L X
LX
Division of Clinical Pharmacology, School of Medicine, University of Carolina, Chapel Hill, North Carolina.
Lovenberg
T W
TW
Hoffman
I S
IS
Talmaciu
R K
RK
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology*; D011493:Protein Kinase C / Q000502:physiology; D011817:Rabbits; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2
D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D000109:Acetylcholine; D004298:Dopamine