Nicotinic and muscarinic cholinergic receptors coexist on GABAergic nerve endings in the mouse striatum and interact in modulating GABA release

Muscarinic cholinergic receptors (mAChRs) and nicotinic cholinergic receptors (nAChRs) regulating GABA release from striatal nerve endings were studied by monitoring release of previously accumulated [3H]GABA or endogenous GABA from superfused mouse striatal synaptosomes. Oxotremorine inhibited the release of [3H]GABA elicited by depolarization with 4-aminopyridine (4-AP), an effect antagonized by atropine. Agonists at nAChRs, including the α4β2∗ subunit-selective RJR2403, provoked the release of [3H]GABA as well as of the endogenous transmitter; these effects also were prevented by oxotremorine and pilocarpine suggesting coexpression of functional mAChRs and α4β2∗ nAChRs on GABAergic nerve endings. The inhibitory effects of oxotremorine on the release of [3H]GABA evoked by 4-AP or by RJR2403 were: (i) prevented by the M2/M4 mAChR antagonist himbacine; (ii) insensitive to the M2 antagonist AFDX116; (iii) blocked by the selective M4 mAChR antagonists MT3, thus indicating the involvement of receptors of the M4 subtype. In conclusion, in the corpus striatum, acetylcholine released from cholinergic interneurons can activate α4β2∗ nAChRs mediating release of GABA; this evoked release can be negatively modulated by M4 mAChRs coexpressed on the same GABAergic terminals.