title: Muscarinic control of rostromedial tegmental nucleus GABA neurons and morphine-induced locomotion.
abstract: Opioids induce rewarding and locomotor effects by inhibiting rostromedial tegmental GABA neurons that express μ-opioid and nociceptin receptors. These GABA neurons then strongly inhibit dopamine neurons. Opioid-induced reward, locomotion and dopamine release also depend on pedunculopontine and laterodorsal tegmental cholinergic and glutamate neurons, many of which project to and activate ventral tegmental area dopamine neurons. Here we show that laterodorsal tegmental and pedunculopontine cholinergic neurons project to both rostromedial tegmental nucleus and ventral tegmental area, and that M4 muscarinic receptors are co-localized with μ-opioid receptors associated with rostromedial tegmental GABA neurons. To inhibit or excite rostromedial tegmental GABA neurons, we utilized adeno-associated viral vectors and DREADDs to express designed muscarinic receptors (M4D or M3D respectively) in GAD2::Cre mice. In M4D-expressing mice, clozapine-N-oxide increased morphine-induced, but not vehicle-induced, locomotion. In M3D-expressing mice, clozapine-N-oxide blocked morphine-induced, but not vehicle-induced, locomotion. We propose that cholinergic inhibition of rostromedial tegmental GABA neurons via M4 muscarinic receptors facilitates opioid inhibition of the same neurons. This model explains how mesopontine cholinergic systems and muscarinic receptors in the rostromedial tegmental nucleus and ventral tegmental area are important for dopamine-dependent and dopamine-independent opioid-induced rewards and locomotion.
authors.affiliation: Department of Psychology, University of Toronto, Toronto, ON, Canada.|Department of Psychology, University of Guelph, Guelph, ON, N1G 2W1, Canada.
authors.forename: David I
authors.initials: DI
authors.lastname: Wasserman
authors.affiliation: Department of Psychology, University of Toronto, Toronto, ON, Canada.
authors.forename: Joel M J
authors.initials: JM
authors.lastname: Tan
authors.affiliation: Department of Psychology, University of Toronto, Toronto, ON, Canada.
authors.forename: Jun Chul
authors.initials: JC
authors.lastname: Kim
authors.affiliation: Department of Psychology, University of Toronto, Toronto, ON, Canada.
authors.forename: John S
authors.initials: JS
authors.lastname: Yeomans
mesh_terms: D000818:Animals; D059329:Cholinergic Neurons / Q000187:drug effects / Q000502:physiology; D003024:Clozapine / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D008124:Locomotion; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D018721:Muscarinic Agonists / Q000494:pharmacology; D043588:Receptor, Muscarinic M4 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D012201:Reward; D013681:Tegmentum Mesencephali / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology
chemical_list: D018756:GABA Antagonists; D018721:Muscarinic Agonists; D043588:Receptor, Muscarinic M4; D017450:Receptors, Opioid, mu; D009020:Morphine; D003024:Clozapine
keywords: cholinergic; designer receptors exclusively activated by designer drugs; mouse; opiate; tVTA