TY - JOUR T1 - Striatal Muscarinic Receptors Promote Activity Dependence of Dopamine Transmission via Distinct Receptor Subtypes on Cholinergic Interneurons in Ventral versus Dorsal Striatum JF - The Journal of Neuroscience JO - J. Neurosci. SP - 3398 LP - 3408 DO - 10.1523/JNEUROSCI.5620-09.2010 VL - 30 IS - 9 AU - Sarah Threlfell AU - Michael A. Clements AU - Tansi Khodai AU - Ilse S. Pienaar AU - Richard Exley AU - Jürgen Wess AU - Stephanie J. Cragg Y1 - 2010/03/03 UR - http://www.jneurosci.org/content/30/9/3398.abstract N2 - 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 M2- 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 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 M2/M4-mAChRs to the control of DA release in CPu versus NAc suggests targets to influence DA/ACh function differentially between striatal domains. ER -