The interaction between an active phorbol ester, 4-beta-phobol-12,13-dibutyrate (PDBu), and muscarinic cholinergic receptor (MAChR) agonists on the electrically evoked neurotransmitter release was studied in the striatal and prefrontal cortex (PFC) of the rabbit. MAChR agonists (carbachol and oxotremorine), physostigmine and PDBu enhanced dopamine (DA) release from striatum and prefrontal cortex. Pretreatment with PDBu antagonized the increase in DA release produced by MAChR agonists (M1 receptors). Pretreatment with MAChR agonists and physostigmine also inhibited the action of PDBu on DA release. The inhibition of ACh release from the striatum induced by MAChR agonists (M2 receptors) and by apomorphine (D2-DA receptors) was antagonized by PDBu. MAChR agonists, however, did not antagonize the effects of the D2 agonist on ACh release. In the prefrontal cortex, PDBu produced greater facilitation of DA release than in the striatum, and MAChR agonists were less effective in inhibiting the effects of PDBu on DA release. This study suggests that the facilitation of DA release induced by the MAChR agonists and that induced by PDBu occur via a similar mechanism: stimulation of protein kinase C. PDBu induces a broad-spectrum loss of responsiveness to M1-MAChR and M2-MAChR and to D2-DA release-modulatory receptors, which is probably due to massive protein kinase C stimulation, signaling cell overstimulation. MAChR agonists, on the other hand, would stimulate the protein kinase C in close proximity to the M1 ACh receptor, facilitating DA release but failing to induce broad-spectrum desensitization.