Cholinergic control of morphine-induced locomotion in rostromedial tegmental nucleus versus ventral tegmental area sites

• Published in: The European journal of neuroscience 2013-09, Vol.38 (5), p.2774-2785
• Main Authors: Wasserman, David I., Wang, Haoran G., Rashid, Asim J., Josselyn, Sheena A., Yeomans, John S.
• Format: Article
• Language: English
• Subjects: Acetylcholine - metabolism; Analgesics; Animals; Biological and medical sciences; dopamine; Dopaminergic Neurons - metabolism; Fundamental and applied biological sciences. Psychology; GABA; GABAergic Neurons - metabolism; Locomotion - drug effects; Male; Medical sciences; Mice; Mice, Knockout; Mice, Transgenic; Morphine - pharmacology; mouse; muscarinic; Neuropharmacology; opioid; Pedunculopontine Tegmental Nucleus - drug effects; Pedunculopontine Tegmental Nucleus - physiology; Pharmacology. Drug treatments; Receptor, Muscarinic M5 - genetics; Receptor, Muscarinic M5 - metabolism; Ventral Tegmental Area - drug effects; Ventral Tegmental Area - physiology; Vertebrates: nervous system and sense organs
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.12279

M5 muscarinic acetylcholine receptors expressed on ventral tegmental dopamine (DA) neurons are needed for opioid activation of DA outputs. Here, the M5 receptor gene was bilaterally transfected into neurons in the ventral tegmental area (VTA) or the adjacent rostromedial tegmental nucleus (RMTg) in mice by means of a Herpes simplex viral vector (HSV) to increase the effect of endogenous acetylcholine. Three days after HSV‐M5 gene infusion in VTA sites, morphine‐induced locomotion more than doubled at two doses, while saline‐induced locomotion was unaffected. When the HSV‐M5 gene was infused into the adjacent RMTg, morphine‐induced locomotion was strongly inhibited. The sharp boundary between these opposing effects was found where tyrosine hydroxylase (TH) and cholinesterase labelling decreases (−4.00 mm posterior to bregma). The same HSV‐M5 gene transfections in M5 knockout mice induced even stronger inhibitory behavioural effects in RMTg but more variability in VTA sites due to stereotypy. The VTA sites where HSV‐M5 increased morphine‐induced locomotion receive direct inputs from many RMTg GAD‐positive neurons, and from pontine ChAT‐positive neurons, as shown by cholera‐toxin B retrograde tracing. Therefore, morphine‐induced locomotion was decreased by M5 receptor gene expression in RMTg GABA neurons that directly inhibit VTA DA neurons. Conversely, enhancing M5 receptor gene expression on VTA DA neurons increased morphine‐induced locomotion via cholinergic inputs. M5‐HSV transfections of VTA dopamine and non‐dopamine neurons increased morphine‐induced locomotion in wild‐type and M5 knockout mice. M5‐HSV transfections of RMTg GABA neurons reduced morphine‐induced locomotion in the wild‐types and knockouts. Cholera‐toxin B retrograde tracing from VTA identified RMTg GABA neurons, and caudal PT and LDT cholinergic neurons as inputs.