Striatal muscarinic receptors promote activity dependence of dopamine transmission via distinct receptor subtypes on cholinergic interneurons in ventral versus dorsal striatum

Abstract

Striatal dopamine (DA) and acetylcholine (ACh) regulate motivated behaviors and striatal plasticity. Interactions between these neurotransmitters may be important, through synchronous changes in parent neuron activities and reciprocal presynaptic regulation of release. How DA signaling is regulated by striatal muscarinic receptors (mAChRs) is unresolved; contradictory reports indicate suppression or facilitation, implicating severalmAChRsubtypes on various neurons.Weinvestigated whethermAChRregulation ofDAsignaling varies with presynaptic activity and identified the mAChRs responsible in sensorimotor- versus limbic-associated striatum.Wedetected DA in real time at carbon fiber microelectrodes in mouse striatal slices. Broad-spectrum mAChR agonists [oxotremorine-M, APET (arecaidine propargyl ester tosylate)] decreased DA release evoked by low-frequency stimuli (1-10 Hz, four pulses) but increased the sensitivity ofDArelease to presynaptic activity, even enhancing release by high frequencies (e.g., >25 Hz for four pulses). These bidirectional effects depended on ACh input to striatal nicotinic receptors (nAChRs) on DA axons but not GABA or glutamate input. In caudate-putamen (CPu), knock-out of M 2- or M4-mAChRs (not M5 ) prevented mAChR control of DA, indicating that M2- and M4-mAChRs are required. In nucleus accumbens (NAc) core or shell, mAChR function was prevented in M4-knock-outs, but not M2- or M5-knock- outs. These data indicate that striatal mAChRs, by inhibitingAChrelease from cholinergic interneurons and thus modifyingnAChRactivity, offer variable control of DA release probability that promotes how DA release reflects activation of dopaminergic axons. Furthermore, different coupling of striatal M 2/M4-mAChRs to the control of DA release in CPu versus NAc suggests targets to influence DA/ACh function differentially between striatal domains. Copyright © 2010 the authors.