Carbachol-phorbol ester interactions at muscarinic receptors modulating dopamine release from rabbit striatal slices

Both 4-beta-12,13-dibutyrate phorbol-ester (PDBu) (EC50% = 82 +/- 12 nM) and carbachol (EC50% = 2.3 +/- 0.3.5 microM) enhanced dopamine (DA) release from rabbit striatal slices. No additivity was observed when slices were treated simultaneously with 0.1 microM PDBu and 10 microM carbachol. Pretreatment with PDBu (0.01-0.1 microM) abolished carbachol-induced facilitation of DA release. Pretreatment with carbachol (3-100 microM) antagonized the enhancement in DA release produced by PDBu. The effect of carbachol was blocked by atropine (0.1 microM) and not by hexamethonium (10 microM). The effect of PDBu was not modified by the acetylcholine receptor (AChR) antagonists. If muscarinic (MAChR) MAChR were blocked by atropine (0.1 microM), pretreatment with carbachol failed to antagonize PDBu-induced facilitation of DA release. This is the first report to indicate that activation of M1-MAChR by an agonist prevents the effects of an active phorbol-ester. We suggest that activation of M1-MAChR enhances DA release possibly through activation of PKC.