TY - JOUR T1 - A Subpopulation of Neuronal M<sub>4</sub> Muscarinic Acetylcholine Receptors Plays a Critical Role in Modulating Dopamine-Dependent Behaviors JF - The Journal of Neuroscience JO - J. Neurosci. SP - 2396 LP - 2405 DO - 10.1523/JNEUROSCI.3843-09.2010 VL - 30 IS - 6 AU - Jongrye Jeon AU - Ditte Dencker AU - Gitta Wörtwein AU - David P. D. Woldbye AU - Yinghong Cui AU - Albert A. Davis AU - Allan I. Levey AU - Günther Schütz AU - Thomas N. Sager AU - Arne Mørk AU - Cuiling Li AU - Chu-Xia Deng AU - Anders Fink-Jensen AU - Jürgen Wess Y1 - 2010/02/10 UR - http://www.jneurosci.org/content/30/6/2396.abstract N2 - Acetylcholine (ACh) regulates many key functions of the CNS by activating cell surface receptors referred to as muscarinic ACh receptors (M1–M5 mAChRs). Like other mAChR subtypes, the M4 mAChR is widely expressed in different regions of the forebrain. Interestingly, M4 mAChRs are coexpressed with D1 dopamine receptors in a specific subset of striatal projection neurons. To investigate the physiological relevance of this M4 mAChR subpopulation in modulating dopamine-dependent behaviors, we used Cre/loxP technology to generate mutant mice that lack M4 mAChRs only in D1 dopamine receptor-expressing cells. The newly generated mutant mice displayed several striking behavioral phenotypes, including enhanced hyperlocomotor activity and increased behavioral sensitization following treatment with psychostimulants. These behavioral changes were accompanied by a lack of muscarinic inhibition of D1 dopamine receptor-mediated cAMP stimulation in the striatum and an increase in dopamine efflux in the nucleus accumbens. These novel findings demonstrate that a distinct subpopulation of neuronal M4 mAChRs plays a critical role in modulating several important dopamine-dependent behaviors. Since enhanced central dopaminergic neurotransmission is a hallmark of several severe disorders of the CNS, including schizophrenia and drug addiction, our findings have substantial clinical relevance. ER -