Nicotinic modulation of serotonergic activity in the dorsal raphe nucleus

Abstract Cholinergic signaling mediated by nicotinic receptors has been associated to a large number of physiological and behavioral processes such as learning, memory, attention, food-intake and mood disorders. Although it is well established that many nicotinic actions are mediated through an increase in serotonin (5-HT) release, the physiological mechanisms by which nicotine produces these effects are still unclear. The dorsal raphe nucleus (DRN) contains the major amount of 5-HT neurons projecting to different parts of the brain. DRN also contains nicotinic acetylcholine receptors (nAChRs) located at somatic and presynaptic elements. Nicotine produces both inhibitory and excitatory effects on different subpopulations of 5-HT DRN neurons. In this review, we describe the presynaptic and postsynaptic mechanisms by which nicotine increases the excitability of DRN neurons as well as the subtypes of nAChRs involved. We also describe the inhibitory effects of nicotine and the role of 5-HT1A receptors in this effect. These nicotinic actions modulate the activity of different neuronal subpopulations in the DRN, changing the 5-HT tone in the brain areas where these groups of neurons project. Some of the physiological implications of nicotine-induced 5-HT release are discussed.

[1]  P. Adams,et al.  Characterization of human recombinant neuronal nicotinic acetylcholine receptor subunit combinations alpha2beta4, alpha3beta4 and alpha4beta4 stably expressed in HEK293 cells. , 1998, The Journal of pharmacology and experimental therapeutics.

[2]  R. Drucker-Colín,et al.  Nicotine stimulation of dorsal raphe neurons: effects on laterodorsal and pedunculopontine neurons , 2001, European Neuropsychopharmacology.

[3]  D. Bertrand,et al.  Nicotinic acetylcholine receptors: from structure to brain function. , 2003, Reviews of physiology, biochemistry and pharmacology.

[4]  Federico Minneci,et al.  Persistent decrease in synaptic efficacy induced by nicotine at Schaffer collateral–CA1 synapses in the immature rat hippocampus , 2004, The Journal of physiology.

[5]  D Colquhoun,et al.  Activation of ion channels in the frog end‐plate by high concentrations of acetylcholine. , 1988, The Journal of physiology.

[6]  K. Chu,et al.  Nicotine and gastrointestinal disorders: its role in ulceration and cancer development. , 2013, Current pharmaceutical design.

[7]  R. R. Hutchinson,et al.  Effects of nicotine on avoidance, conditioned suppression and aggression response measures in animal and man. , 1973 .

[8]  R. Drucker-Colín,et al.  A novel effect of nicotine on mood and sleep in major depression , 1998, Neuroreport.

[9]  F. Joseph McClernon,et al.  Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization , 2006, Psychopharmacology.

[10]  J. Williams,et al.  GABA- and glutamate-mediated synaptic potentials in rat dorsal raphe neurons in vitro. , 1989, Journal of neurophysiology.

[11]  R. Salín-Pascual,et al.  Changes in sleep after acute and repeated administration of nicotine in the rat , 1999, Psychopharmacology.

[12]  R. Bitner,et al.  Alpha-7 nicotinic receptor expression by two distinct cell types in the dorsal raphe nucleus and locus coeruleus of rat , 2002, Brain Research.

[13]  I. Lucki,et al.  The spectrum of behaviors influenced by serotonin , 1998, Biological Psychiatry.

[14]  J. Brioni,et al.  Nicotinic receptor agonists exhibit anxiolytic-like effects on the elevated plus-maze test. , 1993, European journal of pharmacology.

[15]  C. Gotti,et al.  Neuronal nicotinic receptors: from structure to pathology , 2004, Progress in Neurobiology.

[16]  S. File,et al.  Nicotinic–serotonergic interactions in brain and behaviour , 2002, Pharmacology Biochemistry and Behavior.

[17]  Trevor Sharp,et al.  A review of central 5-HT receptors and their function , 1999, Neuropharmacology.

[18]  C. Spielberger,et al.  Effects of smoking/nicotine on anxiety, heart rate, and lateralization of EEG during a stressful movie. , 1989, Psychophysiology.

[19]  R. Gray,et al.  Hippocampal synaptic transmission enhanced by low concentrations of nicotine , 1996, Nature.

[20]  H. Mansvelder,et al.  Long-Term Potentiation of Excitatory Inputs to Brain Reward Areas by Nicotine , 2000, Neuron.

[21]  Jie Wu,et al.  Naturally-expressed nicotinic acetylcholine receptor subtypes. , 2011, Biochemical pharmacology.

[22]  G. Aghajanian,et al.  Electrophysiological and pharmacological characterization of serotonergic dorsal raphe neurons recorded extracellularly and intracellularly in rat brain slices , 1983, Brain Research.

[23]  P. Adams,et al.  Characterization of Human Recombinant Neuronal Nicotinic Acetylcholine Receptor Subunit Combinations a 2 b 4 , a 3 b 4 and a 4 b 4 Stably Expressed in HEK 293 Cells , 1998 .

[24]  E. V. Bockstaele,et al.  Topography of serotonin neurons in the dorsal raphe nucleus that send axon collaterals to the rat prefrontal cortex and nucleus accumbens , 1993, Brain Research.

[25]  J. Changeux,et al.  Brain nicotinic receptors: structure and regulation, role in learning and reinforcement 1 Published on the World Wide Web on 24 October 1997. 1 , 1998, Brain Research Reviews.

[26]  L. Role,et al.  Nicotine enhancement of fast excitatory synaptic transmission in CNS by presynaptic receptors. , 1995, Science.

[27]  Nicotinic excitation of serotonergic projections from dorsal raphe to the nucleus accumbens. , 2011, Journal of neurophysiology.

[28]  D. Bertrand,et al.  Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system. , 2007, Annual review of pharmacology and toxicology.

[29]  J. Changeux,et al.  Calcium mobilization elicited by two types of nicotinic acetylcholine receptors in mouse substantia nigra pars compacta , 2000, The European journal of neuroscience.

[30]  A. Churg,et al.  Pulmonary hypertension in chronic obstructive pulmonary disease: current theories of pathogenesis and their implications for treatment , 2005, Thorax.

[31]  J. Abrams,et al.  Anatomic and Functional Topography of the Dorsal Raphe Nucleus , 2004, Annals of the New York Academy of Sciences.

[32]  Wim Timens,et al.  The pathology of chronic obstructive pulmonary disease. , 2009, Annual review of pathology.

[33]  D. Brunzell,et al.  Effect of nicotine and nicotinic receptors on anxiety and depression , 2002, Neuroreport.

[34]  D. Krieger.  Brain peptides: what, where, and why? , 1983, Science.

[35]  L. Role,et al.  Physiological diversity of nicotinic acetylcholine receptors expressed by vertebrate neurons. , 1995, Annual review of physiology.

[36]  R. Wurtman,et al.  Effects of systemic nicotine on serotonin release in rat brain , 1993, Brain Research.

[37]  D. Gilbert,et al.  Paradoxical tranquilizing and emotion-reducing effects of nicotine. , 1979, Psychological bulletin.

[38]  H. Steinbusch,et al.  Identification of serotonin and non-serotonin-containing neurons of the mid-brain raphe projecting to the entorhinal area and the hippocampal formation. A combined immunohistochemical and fluorescent retrograde tracing study in the rat brain , 1982, Neuroscience.

[39]  Mark Ellisman,et al.  Synaptically Driven Calcium Transients via Nicotinic Receptors on Somatic Spines , 2001, The Journal of Neuroscience.

[40]  M. Jouvet,et al.  Afferent connections of the nucleus raphe dorsalis in the cat as visualized by the horseradish peroxidase technique , 1977, Brain Research.

[41]  N. Davidson,et al.  Regions of beta 2 and beta 4 responsible for differences between the steady state dose-response relationships of the alpha 3 beta 2 and alpha 3 beta 4 neuronal nicotinic receptors , 1995, The Journal of general physiology.

[42]  John T. Williams,et al.  Nicotine activates and desensitizes midbrain dopamine neurons , 1997, Nature.

[43]  E. Lambe,et al.  Nicotine Induces Glutamate Release from Thalamocortical Terminals in Prefrontal Cortex , 2003, Neuropsychopharmacology.

[44]  Pomerleau Of.  Nicotine as a psychoactive drug: anxiety and pain reduction. , 1986 .

[45]  S. Vijayaraghavan,et al.  Modulation of Presynaptic Store Calcium Induces Release of Glutamate and Postsynaptic Firing , 2003, Neuron.

[46]  T. Hattori,et al.  Dorsal raphe cells with collateral projections to the caudate-putamen and substantia nigra: A fluorescent retrograde double labeling study in the rat , 1980, Brain Research.

[47]  S. Rani,et al.  Cellular effects of swim stress in the dorsal raphe nucleus , 2007, Psychoneuroendocrinology.

[48]  L. Role,et al.  Nicotinic Receptors in the Development and Modulation of CNS Synapses , 1996, Neuron.

[49]  P. Panula,et al.  Histamine in the nervous system ofMacoma balthica (Bivalvia) , 1991, Agents and Actions.

[50]  K. Commons,et al.  Alpha 4 nicotinic acetylcholine receptor subunit links cholinergic to brainstem monoaminergic neurotransmission , 2003, Synapse.

[51]  E. Neher,et al.  Single acetylcholine-activated channels show burst-kinetics in presence of desensitizing concentrations of agonist , 1980, Nature.

[52]  J. Kew,et al.  Presynaptic α7- and β2-Containing Nicotinic Acetylcholine Receptors Modulate Excitatory Amino Acid Release from Rat Prefrontal Cortex Nerve Terminals via Distinct Cellular Mechanisms , 2008, Molecular Pharmacology.

[53]  S. Heinemann,et al.  The role of the beta 4‐subunit in determining the kinetic properties of rat neuronal nicotinic acetylcholine alpha 3‐receptors. , 1991, The Journal of physiology.

[54]  S. Hernández-López,et al.  Presynaptic α4β2 Nicotinic Acetylcholine Receptors Increase Glutamate Release and Serotonin Neuron Excitability in the Dorsal Raphe Nucleus , 2012, The Journal of Neuroscience.

[55]  S. Maier,et al.  Impaired escape performance and enhanced conditioned fear in rats following exposure to an uncontrollable stressor are mediated by glutamate and nitric oxide in the dorsal raphe nucleus , 2000, Behavioural Brain Research.

[56]  P. Skolnick,et al.  Glutamate and depression: clinical and preclinical studies. , 2003, Annals of the New York Academy of Sciences.

[57]  A. Lajtha,et al.  Nicotine-induced monoamine neurotransmitter changes in the brain of young rats , 2008, Brain Research Bulletin.

[58]  K. Commons,et al.  Shifting topographic activation and 5‐HT1A receptor‐mediated inhibition of dorsal raphe serotonin neurons produced by nicotine exposure and withdrawal , 2011, The European journal of neuroscience.

[59]  S. T. Kitai,et al.  The organization of divergent axonal projections from the midbrain raphe nuclei in the rat , 1986, The Journal of comparative neurology.

[60]  M. Prins,et al.  Influence of smoking on incidence and prevalence of peripheral arterial disease. , 2004, Journal of vascular surgery.

[61]  J. Changeux,et al.  Diversity and distribution of nicotinic acetylcholine receptors in the locus ceruleus neurons. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[62]  S. File,et al.  The dorsal raphé nucleus is a crucial structure mediating nicotine's anxiolytic effects and the development of tolerance and withdrawal responses , 2001, Psychopharmacology.

[63]  C. Montigny,et al.  Role of Somatodendritic 5‐HT Autoreceptors in Modulating 5‐HT Neurotransmission a , 1998, Annals of the New York Academy of Sciences.

[64]  B. Jacobs,et al.  Structure and function of the brain serotonin system. , 1992, Physiological reviews.

[65]  E. V. Bockstaele,et al.  Collateralized dorsal raphe nucleus projections: A mechanism for the integration of diverse functions during stress , 2011, Journal of Chemical Neuroanatomy.

[66]  T. Liljefors,et al.  Neuronal nicotinic acetylcholine receptors: structural revelations, target identifications, and therapeutic inspirations. , 2005, Journal of medicinal chemistry.

[67]  B. Waterhouse,et al.  Glutamatergic afferent projections to the dorsal raphe nucleus of the rat , 2003, Brain Research.

[68]  G. Aghajanian,et al.  Habenular and other midbrain raphe afferents demonstrated by a modified retrograde tracing technique , 1977, Brain Research.

[69]  W. Dement,et al.  Electrophysiological and behavioral effects of electrical stimulation of the raphe nuclei in cats. , 1973, Physiology & behavior.

[70]  K. Cunningham,et al.  Habenula lesions decrease the responsiveness of dorsal raphe serotonin neurons to cocaine , 1994, Pharmacology Biochemistry and Behavior.

[71]  J. Gillin,et al.  Dose‐Dependent Effects of Transdermal Nicotine on Early Morning Awakening and Rapid Eye Movement Sleep Time in Nonsmoking Normal Volunteers , 1994, Journal of clinical psychopharmacology.

[72]  S. Maier,et al.  Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus , 2005, Nature Neuroscience.

[73]  Michele Zoli,et al.  Molecular and Physiological Diversity of Nicotinic Acetylcholine Receptors in the Midbrain Dopaminergic Nuclei , 2001, The Journal of Neuroscience.

[74]  S. Vijayaraghavan,et al.  Action Potential-Independent and Nicotinic Receptor-Mediated Concerted Release of Multiple Quanta at Hippocampal CA3–Mossy Fiber Synapses , 2008, The Journal of Neuroscience.

[75]  A. Fox,et al.  Whole‐cell recordings of inwardly rectifying K+ currents activated by 5‐HT1A receptors on dorsal raphe neurones of the adult rat. , 1993, The Journal of physiology.

[76]  J P Changeux,et al.  The functional architecture of the acetylcholine nicotinic receptor explored by affinity labelling and site-directed mutagenesis , 1992, Quarterly Reviews of Biophysics.

[77]  Mechanisms of nicotine actions on dorsal raphe serotoninergic neurons. , 2002, European journal of pharmacology.

[78]  G Chouvet,et al.  Role and Origin of the GABAergic Innervation of Dorsal Raphe Serotonergic Neurons , 2000, The Journal of Neuroscience.

[79]  S. Wonnacott,et al.  Presynaptic nicotinic ACh receptors , 1997, Trends in Neurosciences.

[80]  D. Donnelly-roberts,et al.  Reduced nicotinic receptor-mediated antinociception following in vivo antisense knock-down in rat , 2000, Brain Research.

[81]  S. Wonnacott,et al.  Intracellular Ca2+ signals evoked by stimulation of nicotinic acetylcholine receptors in SH‐SY5Y cells: contribution of voltage‐operated Ca2+ channels and Ca2+ stores , 2002, Journal of neurochemistry.

[82]  R. McCarley,et al.  Presynaptic Nicotinic Receptors Facilitate Monoaminergic Transmission , 1998, The Journal of Neuroscience.

[83]  J. Bargas,et al.  Serotoninergic dorsal raphe neurons possess functional postsynaptic nicotinic acetylcholine receptors , 2008, Synapse.

[84]  N. Hymowitz.  Smoking and cancer: a review of public health and clinical implications. , 2011, Journal of the National Medical Association.

[85]  M. Sarter,et al.  Collateral innervation of the medial and lateral prefrontal cortex by amygdaloid, thalamic, and brain‐stem neurons , 1984, The Journal of comparative neurology.

[86]  J. Patrick,et al.  Both alpha- and beta-subunits contribute to the agonist sensitivity of neuronal nicotinic acetylcholine receptors , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[87]  Dagoberto Tapia,et al.  Control of the subthalamic innervation of substantia nigra pars reticulata by D1 and D2 dopamine receptors. , 2006, Journal of neurophysiology.

[88]  J. McIntosh,et al.  Determinants of specificity for alpha-conotoxin MII on alpha3beta2 neuronal nicotinic receptors. , 1997, Molecular pharmacology.

[89]  J. Patrick,et al.  Molecular cloning, functional properties, and distribution of rat brain alpha 7: a nicotinic cation channel highly permeable to calcium , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[90]  R. Drucker-Colín,et al.  Effects of nicotine and mecamylamine on rat dorsal raphe neurons. , 1998, European journal of pharmacology.

[91]  Jun Noguchi,et al.  Nicotinic cholinergic synaptic mechanisms in the ventral tegmental area contribute to nicotine addiction. , 2004, Learning & memory.

[92]  K. Commons.  Alpha4 containing nicotinic receptors are positioned to mediate postsynaptic effects on 5-HT neurons in the rat dorsal raphe nucleus , 2008, Neuroscience.

[93]  M. Soiza-Reilly,et al.  Glutamatergic drive of the dorsal raphe nucleus , 2011, Journal of Chemical Neuroanatomy.

[94]  L. Heimer,et al.  Double and triple labeling of neurons with fluorescent substances; The study of collateral pathways in the ascending raphe system , 1980, Neuroscience Letters.

[95]  L. Butcher,et al.  Cholinergic systems in the rat brain: IV. descending projections of the pontomesencephalic tegmentum , 1989, Brain Research Bulletin.

[96]  John A. Dani,et al.  Differential Desensitization and Distribution of Nicotinic Acetylcholine Receptor Subtypes in Midbrain Dopamine Areas , 2003, The Journal of Neuroscience.

[97]  A. Lajtha,et al.  Nicotine-Induced Changes in Neurotransmitter Levels in Brain Areas Associated with Cognitive Function , 2004, Neurochemical Research.

[98]  A. Leone.  Smoking and hypertension: independent or additive effects to determining vascular damage? , 2011, Current vascular pharmacology.

[99]  P. Whiting,et al.  Pharmacological properties of immuno-isolated neuronal nicotinic receptors , 1986, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[100]  L. Wiklund,et al.  Possible excitatory amino acid afferents to nucleus raphe dorsalis of the rat investigated with retrograde wheat germ agglutinin and d-[3H]aspartate tracing , 1985, Brain Research.

[101]  R. Lukas,et al.  nicotinic acetylcholine receptors in rat midbrain dopamine neurons , 2004 .

[102]  J. Lindstrom,et al.  Nicotine acts as a pharmacological chaperone to up-regulate human alpha4beta2 acetylcholine receptors. , 2005, Molecular pharmacology.

[103]  M. McNamee,et al.  Desensitization of the nicotinic acetylcholine receptor: Molecular mechanisms and effect of modulators , 1989, Cellular and Molecular Neurobiology.

[104]  J. Changeux,et al.  Identification of Four Classes of Brain Nicotinic Receptors Using β2 Mutant Mice , 1998, The Journal of Neuroscience.

[105]  T Baldwinson,et al.  Physiological roles of neuronal nicotinic receptor subtypes: new insights on the nicotinic modulation of neurotransmitter release, synaptic transmission and plasticity. , 2003, Current topics in medicinal chemistry.