title: 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 several mAChR subtypes on various neurons. We investigated whether mAChR regulation of DA signaling varies with presynaptic activity and identified the mAChRs responsible in sensorimotor- versus limbic-associated striatum. We detected 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 of DA release 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 M(4)-mAChRs (not M(5)) prevented mAChR control of DA, indicating that M(2)- and M(4)-mAChRs are required. In nucleus accumbens (NAc) core or shell, mAChR function was prevented in M(4)-knock-outs, but not M(2)- or M(5)-knock-outs. These data indicate that striatal mAChRs, by inhibiting ACh release from cholinergic interneurons and thus modifying nAChR activity, offer variable control of DA release probability that promotes how DA release reflects activation of dopaminergic axons. Furthermore, different coupling of striatal M(2)/M(4)-mAChRs to the control of DA release in CPu versus NAc suggests targets to influence DA/ACh function differentially between striatal domains.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Threlfell
authors.forename: Michael A
authors.initials: MA
authors.lastname: Clements
authors.forename: Tansi
authors.initials: T
authors.lastname: Khodai
authors.forename: Ilse S
authors.initials: IS
authors.lastname: Pienaar
authors.forename: Richard
authors.initials: R
authors.lastname: Exley
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wess
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Cragg
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001479:Basal Ganglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D004594:Electrophysiology; D007395:Interneurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000494:pharmacology; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D043585:Receptor, Muscarinic M2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D043588:Receptor, Muscarinic M4 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D018721:Muscarinic Agonists; D043585:Receptor, Muscarinic M2; D043588:Receptor, Muscarinic M4; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D000109:Acetylcholine; D004298:Dopamine