A Subpopulation of Neuronal M₄Muscarinic Acetylcholine Receptors Plays a Critical Role in Modulating Dopamine-Dependent Behaviors

<jats:p>Acetylcholine (ACh) regulates many key functions of the CNS by activating cell surface receptors referred to as muscarinic ACh receptors (M<jats:sub>1</jats:sub>–M<jats:sub>5</jats:sub>mAChRs). Like other mAChR subtypes, the M<jats:sub>4</jats:sub>mAChR is widely expressed in different regions of the forebrain. Interestingly, M<jats:sub>4</jats:sub>mAChRs are coexpressed with D<jats:sub>1</jats:sub>dopamine receptors in a specific subset of striatal projection neurons. To investigate the physiological relevance of this M<jats:sub>4</jats:sub>mAChR subpopulation in modulating dopamine-dependent behaviors, we used Cre/loxP technology to generate mutant mice that lack M<jats:sub>4</jats:sub>mAChRs only in D<jats:sub>1</jats:sub>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 D<jats:sub>1</jats:sub>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 M<jats:sub>4</jats:sub>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.</jats:p>