DIFFERENTIAL-EFFECTS OF MUSCARINIC RECEPTOR AGONISTS AND PHORBOL ESTER ON MUSCARINIC AND D2-DOPAMINE RELEASE-MODULATORY RECEPTORS

The interaction between an active phorbol ester, 4-beta-phobol-12,13-d ibutyrate (PDBu), and muscarinic cholinergic receptor (MAChR) agonists on the electrically evoked neurotr ansmitter release was studied in t he 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 P DBu antagonized the increase in DA release produced by MAChR agonists (M1 receptors). Pretreatment with MAChR agonists and physostigmine als o inhibited the action of PDBu on DA release. The inhibition of ACh re lease from the striatum induced by MAChR agonists (M2 receptors) and b y apomorphine (D2-DA receptors) was antagonized by PDBu. MAChR agonist s, however, did not antagonize the effects of the D2 agonist on ACh re lease. In the prefrontal cortex, PDBu produced greater facilitation of DA release than in the striatum, and MAChR agonists were less effecti ve in inhibiting the effects of PDBu on DA release. This study suggest s that the facilitation of DA release induced by the MAChR agonists an d that induced by PDBu occur via a similar mechanism: stimulation of p rotein kinase C. PDBU induces a broad-spectrum loss of responsiveness to M1-MAChR and M2-MAChR and to D2-DA release-modulatory receptors, wh ich is probably due to massive protein kinase C stimulation, signaling cell overstimulation, MAChR agonists, on the other hand, would stimul ate the protein kinase C in close proximity to the M1 ACh receptor, fa cilitating DA release but failing to induce broad-spectrum desensitiza tion.