Abstract
Cholinergic neurons in laterodorsal (LDT) and pedunculopontine (PPT) tegmental nuclei respond to novel, arousing stimuli, then directly activate dopamine neurons, and increase dopamine outputs as measured by either in vivo microdialysis or by electrochemistry (described here). These mesopontine cholinergic neurons also directly activate superior colliculus and thalamic systems important for attention to novel stimuli, and for reward-seeking behaviors. M5 muscarinic receptors that activate dopamine neurons and reward-seeking behaviors have been studied using pharmacology, knockout mice, oligonucleotide knockdown, and with electrochemistry and Herpes simplex viral gene transfections (HSV-M5) protocols described here. Protocols for using HSV-M5 genes, and designed M4D and M3D muscarinic receptor genes in behaving mice and for dopamine electrochemistry are presented, along with consequences for drug and gene therapy.
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References
Bonner TI, Young AC, Brann MR, Buckley NJ (1988) Cloning and expression of the human and rat m5 muscarinic acetylcholine receptor genes. Neuron 1:403–410
Yeomans JS (2012) Muscarinic receptors in brain stem and mesopontine cholinergic arousal functions. Handb Exp Pharmacol 208:243–259
Yasuda RP, Ciesla W, Flores LR, Wall SJ, Li M, Satkus SA, Weisstein JS, Spagnola BV, Wolfe BB (1993) Development of antisera selective for m4 and m5 muscarinic cholinergic receptors: distribution of m4 and m5 receptors in rat brain. Mol Pharmacol 43:149–157
Levey AI (1993) Immunological localization of m1-m5 muscarinic acetylcholine receptors in peripheral tissues and brain. Life Sci 52:441–448
Vilaro MT, Palacios JM, Mengod G (1990) Localization of m5 muscarinic receptor mRNA in rat brain examined by in situ hybridization histochemistry. Neurosci Lett 114:154–159
Weiner DM, Brann MR (1989) The distribution of a dopamine D2 receptor mRNA in rat brain. FEBS Lett 253:207–213
Takeuchi J, Fulton J, Jia ZP, Abramov-Newerly W, Jamot L, Sud M, Coward D, Ralph M, Roder J, Yeomans J (2002) Increased drinking in mutant mice with truncated M5 muscarinic receptor genes. Pharmacol Biochem Behav 72:117–123
Yamada M, Lamping KG, Duttaroy A, Zhang W, Cui Y, Bymaster FP, McKinzie DL, Felder CC, Deng CX, Faraci FM, Wess J (2001) Cholinergic dilation of cerebral blood vessels is abolished in M(5) muscarinic acetylcholine receptor knockout mice. Proc Natl Acad Sci U S A 98:14096–14101
Redgrave P, Horrell RI (1976) Potentiation of central reward by localised perfusion of acetylcholine and 5-hydroxytryptamine. Nature 262:305–307
Bauco P, Wise RA (1994) Potentiation of lateral hypothalamic and midline mesencephalic brain stimulation reinforcement by nicotine: examination of repeated treatment. J Pharmacol Exp Ther 271:294–301
Yeomans JS, Kofman O, McFarlane V (1985) Cholinergic involvement in lateral hypothalamic rewarding brain stimulation. Brain Res 329:19–26
Blaha CD, Allen LF, Das S, Inglis WL, Latimer MP, Vincent SR, Winn P (1996) Modulation of dopamine efflux in the nucleus accumbens after cholinergic stimulation of the ventral tegmental area in intact, pedunculopontine tegmental nucleus-lesioned, and laterodorsal tegmental nucleus-lesioned rats. J Neurosci 16:714–722
Yeomans JS, Baptista M (1997) Both nicotinic and muscarinic receptors in ventral tegmental area contribute to brain-stimulation reward. Pharmacol Biochem Behav 57:915–921
Yeomans JS, Takeuchi J, Baptista M, Flynn DD, Lepik K, Nobrega J, Fulton J, Ralph MR (2000) Brain-stimulation reward thresholds raised by an antisense oligonucleotide for the m5 muscarinic receptor infused near dopamine cells. J Neurosci 20:8861–8867
Sharf R, McKelvey J, Ranaldi R (2006) Blockade of muscarinic acetylcholine receptors in the ventral tegmental area prevents acquisition of food-rewarded operant responding in rats. Psychopharmacology (Berl) 186:113–121
Rezayof A, Nazari-Serenjeh F, Zarrindast MR, Sepehri H, Delphi L (2007) Morphine-induced place preference: involvement of cholinergic receptors of the ventral tegmental area. Eur J Pharmacol 562:92–102
Rada PV, Mark GP, Yeomans JS, Hoebel BG (2000) Acetylcholine release in ventral tegmental area by hypothalamic self-stimulation, eating, and drinking. Pharmacol Biochem Behav 65:375–379
Mesulam MM, Mufson EJ, Wainer BH, Levey AI (1983) Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1-Ch6). Neuroscience 10:1185–1201
Oakman SA, Faris PL, Kerr PE, Cozzari C, Hartman BK (1995) Distribution of pontomesencephalic cholinergic neurons projecting to substantia nigra differs significantly from those projecting to ventral tegmental area. J Neurosci 15:5859–5869
Oakman SA, Faris PL, Cozzari C, Hartman BK (1999) Characterization of the extent of pontomesencephalic cholinergic neurons’ projections to the thalamus: a comparison with projections to midbrain dopaminergic neurons. Neuroscience 94:529–547
Watabe-Uchida M, Zhu L, Ogawa SK, Vamanrao A, Uchida N (2012) Whole-brain mapping of direct inputs to midbrain dopamine neurons. Neuron 74:858–873
Wasserman DI, Wang HG, Rashid AJ, Josselyn SA, Yeomans JS (2013) Cholinergic control of morphine-induced locomotion in rostromedial tegmental nucleus versus ventral tegmental area sites. Eur J Neurosci 38:2774–2785
Isa T, Hall WC (2009) Exploring the superior colliculus in vitro. J Neurophysiol 102:2581–2593
Dean P, Redgrave P, Westby GW (1989) Event or emergency? two response systems in the mammalian superior colliculus. Trends Neurosci 12:137–147
Steriade M, Datta S, Paré D, Oakson G, Curró Dossi RC (1990) Neuronal activities in brain-stem cholinergic nuclei related to tonic activation processes in thalamocortical systems. J Neurosci 10:2541–2559
Paré D, Steriade M, Deschênes M, Bouhassira D (1990) Prolonged enhancement of anterior thalamic synaptic responsiveness by stimulation of a brain-stem cholinergic group. J Neurosci 10:20–33
McCormick DA (1992) Neurotransmitter actions in the thalamus and cerebral cortex and their role in neuromodulation of thalamocortical activity. Prog Neurobiol 39:337–388
Semba K, Fibiger HC (1992) Afferent connections of the laterodorsal and the pedunculopontine tegmental nuclei in the rat: a retro- and antero-grade transport and immunohistochemical study. J Comp Neurol 323:387–410
Manns ID, Alonso A, Jones BE (2000) Discharge properties of juxtacellularly labeled and immunohistochemically identified cholinergic basal forebrain neurons recorded in association with the electroencephalogram in anesthetized rats. J Neurosci 20:1505–1518
Dringenberg HC, Olmstead MC (2003) Integrated contributions of basal forebrain and thalamus to neocortical activation elicited by pedunculopontine tegmental stimulation in urethane-anesthetized rats. Neuroscience 119:839–853
Lepore M, Franklin KB (1996) N-methyl-D-aspartate lesions of the pedunculopontine nucleus block acquisition and impair maintenance of responding reinforced with brain stimulation. Neuroscience 71:147–155
Bechara A, van der Kooy D (1989) The tegmental pedunculopontine nucleus: a brain-stem output of the limbic system critical for the conditioned place preferences produced by morphine and amphetamine. J Neurosci 9:3400–3409
Leonard CS, Llinás R (1994) Serotonergic and cholinergic inhibition of mesopontine cholinergic neurons controlling REM sleep: an in vitro electrophysiological study. Neuroscience 59:309–330
Kohlmeier KA, Ishibashi M, Wess J, Bickford ME, Leonard CS (2012) Knockouts reveal overlapping functions of M(2) and M(4) muscarinic receptors and evidence for a local glutamatergic circuit within the laterodorsal tegmental nucleus. J Neurophysiol 108:2751–2766
Chapman CA, Yeomans JS, Blaha CD, Blackburn JR (1997) Increased striatal dopamine efflux follows scopolamine administered systemically or to the tegmental pedunculopontine nucleus. Neuroscience 76:177–186
Yeomans JS, Mathur A, Tampakeras M (1993) Rewarding brain stimulation: role of tegmental cholinergic neurons that activate dopamine neurons. Behav Neurosci 107:1077–1087
Mathur A, Shandarin A, LaViolette SR, Parker J, Yeomans JS (1997) Locomotion and stereotypy induced by scopolamine: contributions of muscarinic receptors near the pedunculopontine tegmental nucleus. Brain Res 775:144–155
Forster GL, Blaha CD (2000) Laterodorsal tegmental stimulation elicits dopamine efflux in the rat nucleus accumbens by activation of acetylcholine and glutamate receptors in the ventral tegmental area. Eur J Neurosci 12:3596–3604
Tzavara ET, Bymaster FP, Davis RJ, Wade MR, Perry KW, Wess J, McKinzie DL, Felder C, Nomikos GG (2004) M4 muscarinic receptors regulate the dynamics of cholinergic and dopaminergic neurotransmission: relevance to the pathophysiology and treatment of related CNS pathologies. FASEB J 18:1410–1412
Forster GL, Blaha CD (2003) Pedunculopontine tegmental stimulation evokes striatal dopamine efflux by activation of acetylcholine and glutamate receptors in the midbrain and pons of the rat. Eur J Neurosci 17:751–762
Forster GL, Yeomans JS, Takeuchi J, Blaha CD (2001) M5 muscarinic receptors are required for prolonged accumbal dopamine release after electrical stimulation of the pons in mice. J Neurosci 22:RC190
Steidl S, Miller AD, Blaha CD, Yeomans JS (2011) M5 muscarinic receptors mediate striatal dopamine activation by ventral tegmental morphine and pedunculopontine stimulation in mice. PLoS One 6:e27538
Ohno K, Hondo M, Sakurai T (2008) Cholinergic regulation of orexin/hypocretin neurons through M(3) muscarinic receptor in mice. J Pharmacol Sci 106:485–491
Michel FJ, Robillard JM, Trudeau LE (2004) Regulation of rat mesencephalic GABAergic neurones through muscarinic receptors. J Physiol 556:429–445
Blaha CD, Phillips AG (1996) A critical assessment of electrochemical procedures applied to the measurement of dopamine and its metabolites during drug-induced and species-typical behaviors. Behav Pharmacol 7:675–708
Kawagoe KT, Zimmerman JB, Wightman RM (1993) Principles of voltammetry and microelectrode surface states. J Neurosci Methods 48:225–240
Blaha CD, Lane RF (1983) Chemically modified electrode for in vivo monitoring of brain catecholamines. Brain Res Bull 10:861–864
Basile AS, Fedorova I, Zapata A, Liu X, Shippenberg T, Duttaroy A, Yamada M, Wess J (2002) Deletion of the M5 muscarinic acetylcholine receptor attenuates morphine reinforcement and withdrawal but not morphine analgesia. Proc Natl Acad Sci U S A 99:11452–11457
Fink-Jensen A, Fedorova I, Wortwein G, Woldbye DP, Rasmussen T, Thomsen M, Bolwig TG, Knitowski KM, McKinzie DL, Yamada M, Wess J, Basile A (2003) Role for M5 muscarinic acetylcholine receptors in cocaine addiction. J Neurosci Res 74:91–96
Steidl S, Yeomans JS (2009) M5 muscarinic receptor knockout mice show reduced morphine-induced locomotion but increased locomotion after cholinergic antagonism in the ventral tegmental area. J Pharmacol Exp Ther 328:263–275
Schmidt LS, Miller AD, Lester DB, Bay-Richter C, Schülein C, Frikke-Schmidt H, Wess J, Blaha CD, Woldbye DP, Fink-Jensen A, Wortwein G (2010) Increased amphetamine-induced locomotor activity, sensitization, and accumbal dopamine release in M5 muscarinic receptor knockout mice. Psychopharmacology (Berl) 207(4):547–558
Miller AD, Forster GL, Yeomans JS, Blaha CD (2005) Midbrain muscarinic receptors modulate morphine-induced accumbal and striatal dopamine efflux in the rat. Neuroscience 136:531–538
Forster GL, Falcon AJ, Miller AD, Heruc GA, Blaha CD (2002) Effects of laterodorsal tegmentum lesions on behavioral and dopamine responses evoked by morphine and d-amphetamine. Neuroscience 114:817–823
Jhou TC, Xu SP, Lee MR, Gallen CL, Ikemoto S (2012) Mapping of reinforcing and analgesic effects of the mu opioid agonist endomorphin-1 in the ventral midbrain of the rat. Psychopharmacology (Berl) 224:303–312
Wasserman DW, Tan JM, Kim J, Yeomans JS (2014) Muscarinic control of rostromedial tegmental nucleus GABA neurons and morphine-induced locomotion. Poster presented at Society for Neuroscience, Washington, D.C., 15–19 November 2014.
Rogan SC, Roth BL (2011) Remote control of neuronal signaling. Pharmacol Rev 63:291–315
Tzschentke TM (2001) Pharmacology and behavioral pharmacology of the mesocortical dopamine system. Prog Neurobiol 63:241–320
Neve RL, Geller AI (1995) A defective herpes simplex virus vector system for gene delivery into the brain: comparison with alternative gene delivery systems and usefulness for gene therapy. Clin Neurosci 3:262–267
Carlezon WA, Boundy VA, Haile CN, Lane SB, Kalb RG, Neve RL, Nestler EJ (1997) Sensitization to morphine induced by viral-mediated gene transfer. Science 277:812–814
Han JH, Kushner SA, Yiu AP, Hsiang HLL, Buch T, Waisman A, Bontempi B, Neve RL, Frankland PW, Josselyn SA (2009) Selective erasure of a fear memory. Science 323:1492–1496
Liu M, Thankachan S, Kaur S, Begum S, Blanco-Centurion C, Sakurai T, Yanagisawa M, Neve R, Shiromani PJ (2008) Orexin (hypocretin) gene transfer diminishes narcoleptic sleep behavior in mice. Eur J Neurosci 28:1382–1393
Franklin KBJ, Paxinos G (2007) The mouse brain stereotaxic coordinates, 3rd edn. Academic, San Diego, CA
Taniguchi H, He M, Wu P, Kim S, Paik R, Sugino K, Kvitsiani D, Fu Y, Lu J, Lin Y, Miyoshi G, Shima Y, Fishell G, Nelson SB, Huang ZJ (2011) A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex. Neuron 71:995–1013
Armbruster BN, Li X, Pausch MH, Herlitze S, Roth BL (2007) Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc Natl Acad Sci U S A 104:5163–5168
Wess J, Eglen RM, Gautam D (2007) Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development. Nat Rev Drug Discov 6:721–733
Acknowledgements
We thank our many collaborators and coauthors, including Gina Forster and Anthony Miller (electrochemistry), Haoran Wang, Sheena Josselyn, and Asim Rashid (HSV-M5), Jun Chul Kim and Bryan Roth (AAV-M3D and AAV-M4D), and Junichi Takeuchi, Zheng-ping Jia, John Roder, and Juergen Wess (knockouts).
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Steidl, S., Wasserman, D.I., Blaha, C.D., Yeomans, J. (2016). Muscarinic Receptor Gene Transfections and In Vivo Dopamine Electrochemistry: Muscarinic Receptor Control of Dopamine-Dependent Reward and Locomotion. In: Myslivecek, J., Jakubik, J. (eds) Muscarinic Receptor: From Structure to Animal Models. Neuromethods, vol 107. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-2858-3_14
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