Associate editor: T.C. Napier
Ion channels and intracellular signaling proteins as potential targets for novel therapeutics for addictive and depressive disorders

https://doi.org/10.1016/j.pharmthera.2005.06.020Get rights and content

Abstract

Modern neuroscience is placing increased emphasis on understanding how the activity of ion channels and intracellular molecules in the central nervous system affect behavior. An improved understanding of the brain and the biological bases of conditions such as addictive and depressive disorders is important because it should ultimately enable the design of innovative treatments for these conditions. The development of rational therapies that are based on knowledge of what is different about the addicted or depressed brain would be an important advance. Here, we describe how multidisciplinary studies that combine numerous approaches (behavioral analysis, physiology, molecular biology, and genetic engineering) have begun to provide important advances that have helped to establish causal relationships between the pathophysiology of these conditions and behavior. This type of work has identified classes of molecules on the outside of cells (receptors and ion channels) that receive signals from other cells and initiate cellular events that have short-term effects on the neurons. It has also identified other classes of molecules that are inside of cells (signal transduction molecules) that can have immediate effects on cell function (e.g., ion channel phosphorylation), as well longer term effects (alterations in protein expression) that affect the ways in which neurons function within circuits. Innovative treatments that block, negate, or even reverse the extracellular or intracellular neuroadaptations resulting from exposure to drugs of abuse or stress might be more effective than current therapies because they directly target the molecular processes that cause maladaptive behaviors.

Section snippets

General introduction

Modern neuroscience is placing increased emphasis on understanding how molecules in the brain affect behavior. An improved understanding of the brain and the biological bases of conditions such as addictive and depressive disorders is important because it should ultimately enable the design of innovative treatments for these conditions. The development of rational therapies that are based on knowledge of what is different about the addicted or depressed brain would be an important advance,

Ion channels as therapeutic targets for substance abuse

Ion channels are the basic, essential effectors that allow neurons to modulate the various aspects of their short- and long-term excitability. They are classified and named sodium, potassium, calcium, and chloride channels based on the main type of ion to which they are permeable (Hille, 2001). Ion channels present a high degree of functional specificity depending on many factors, such as voltage dependence, conductance properties, ligand specificity, and subunit composition. This specificity

Intracellular signaling molecules

Alterations in ion channel function affect intracellular signal transduction systems. Events on the cell surface (e.g., stimulation of glutamate receptors or G-protein-coupled receptors) can directly or indirectly affect ion flux through ionotropic receptors or channels (Fig. 1). Increased Ca2+ influx is one of several events that can trigger intracellular signaling cascades that result in alterations in the activity of transcription factors and, in turn, gene transcription. Localized within

Summary and conclusions

Neurology and psychiatry are entering a new phase in which basic research is beginning to identify molecules that are involved in causing aberrant behaviors. A better understanding of the molecular adaptations that lead to the development or expression of addictive or depressive-like behaviors should soon lead to significant improvements in the diagnosis and treatment of a variety of debilitating conditions in humans. It has become clear that key aspects of conditions such as addiction or mood

Acknowledgments

We apologize to authors whose work could not be cited due to space limitations. We thank Anjlee Mahajan for proofreading. Our research is supported by the State of California for medical research on alcohol and substance abuse through the University of California, San Francisco (AB), DA12736 (to WC), and MH63266 (to WC).

References (95)

  • S. Finkbeiner et al.

    CREB: a major mediator of neuronal neurotrophin responses

    Neuron

    (1997)
  • N.S. Foulkes et al.

    CREM gene: use of alternative DNA-binding domains generates multiple antagonists of cAMP-induced transcription

    Cell

    (1991)
  • R. Karler et al.

    Calcium channel blockers and behavioral sensitization

    Life Sci

    (1991)
  • A.E. Kelley

    Memory and addiction: shared neural circuitry and molecular mechanisms

    Neuron

    (2004)
  • K.S. Kim et al.

    Both the basal and inducible transcription of the tyrosine hydroxylase gene are dependent upon a cAMP response element

    J Biol Chem

    (1993)
  • G.F. Koob et al.

    Neuroscience of addiction

    Neuron

    (1998)
  • S.D. Mague et al.

    Early developmental exposure to methylphenidate reduces cocaine-induced potentiation of brain stimulation reward in rats

    Biol Psychiatry

    (2005)
  • M. Mayford et al.

    Genetic approaches to memory storage

    Trends Genet

    (1999)
  • E.J. Nestler

    Historical review: molecular and cellular mechanisms of opiate and cocaine addiction

    Trends Pharmacol Sci

    (2004)
  • E.J. Nestler et al.

    Preclinical models: status of basic research in depression

    Biol Psychiatry

    (2002)
  • J. O'Donnell et al.

    Antidepressant effects of inhibitors of cAMP phosphodiesterase (PDE4)

    Trends Pharm Sci

    (2004)
  • B.P. Ramos et al.

    Dysregulation of protein kinase a signaling in the aged prefrontal cortex: new strategy for treating age-related cognitive decline

    Neuron

    (2003)
  • M. Sheng et al.

    Membrane depolarization and calcium induce c-fos transcription via phosphorylation of transcription factor CREB

    Neuron

    (1990)
  • T.S. Shippenberg et al.

    Sensitization to the behavioral effects of cocaine: modulation by dynorphin and kappa-opioid receptor agonists

    Pharmacol Biochem Behav

    (1997)
  • R.Z. Terwilliger et al.

    A general role for adaptations in G-proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function

    Brain Res

    (1991)
  • S.M. Turgeon et al.

    Enhanced CREB phosphorylation and changes in c-Fos and FRA expression in striatum accompany amphetamine sensitization

    Brain Res

    (1997)
  • M.C. Wang et al.

    L-type voltage-gated calcium channels: understanding function through structure

    FEBS Lett

    (2004)
  • J.C. Yin et al.

    CREB and the formation of long-term memory

    Curr Opin Neurobiol

    (1996)
  • Q. Zhang et al.

    L-type Ca(2+) channel blockers inhibit the development but not the expression of sensitization to morphine in mice

    Eur J Pharmacol

    (2003)
  • D.L. Alkon

    Regenerative changes of voltage-dependent Ca2+ and K+ currents encode a learned stimulus association

    J Physiol (Paris)

    (1982)
  • S.L. Andersen et al.

    Altered responsiveness to cocaine in rats exposed to methylphenidate during development

    Nat Neurosci

    (2002)
  • A. Barco et al.

    CREB, memory enhancement and the treatment of memory disorders: promises, pitfalls and prospects

    Expert Opin Ther Targets

    (2003)
  • M. Barrios et al.

    Differential effects of L-type calcium channel blockers and stimulants on naloxone-precipitated withdrawal in mice acutely dependent on morphine

    Psychopharmacology (Berl)

    (1991)
  • M. Barrot et al.

    CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli

    Proc Natl Acad Sci U S A

    (2002)
  • Y.A. Blednov et al.

    Potassium channels as targets for ethanol: studies of G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2) null mutant mice

    J Pharmacol Exp Ther

    (2001)
  • C.T. Bond et al.

    Small-conductance calcium-activated potassium channels

    Ann NY Acad Sci

    (1999)
  • W.A. Carlezon et al.

    Unmet expectations: the brain minds

    Nat Med

    (2003)
  • W.A. Carlezon et al.

    Sensitization to morphine induced by viral-mediated gene transfer

    Science

    (1997)
  • W.A. Carlezon et al.

    Regulation of cocaine reward by CREB

    Science

    (1998)
  • W.A. Carlezon et al.

    Viral-mediated gene transfer as a tool for neuropsychiatric research

    Crit Rev Neurobiol

    (2000)
  • H. Cha-Molstad et al.

    Cell-type-specific binding of the transcription factor CREB to the cAMP-response element

    Proc Natl Acad Sci U S A

    (2004)
  • E.H. Chartoff et al.

    Dopamine-dependent increases in phosphorylation of cAMP response element binding protein (CREB) during precipitated morphine withdrawal in primary cultures of rat striatum

    J Neurochem

    (2003)
  • X. Chen et al.

    Altered gating of opiate receptor-modulated K+ channels on amygdala neurons of morphine-dependent rats

    Proc Natl Acad Sci U S A

    (2000)
  • A.C. Conti et al.

    cAMP response element-binding protein is essential for the upregulation of brain-derived neurotrophic factor transcription, but not the behavioral or endocrine responses to antidepressant drugs

    J Neurosci

    (2002)
  • P.K. Dash et al.

    cAMP response element-binding protein is activated by Ca2+/calmodulin—as well as cAMP-dependent protein kinase

    Proc Natl Acad Sci U S A

    (1991)
  • G. Di Chiara et al.

    Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats

    Proc Natl Acad Sci U S A

    (1988)
  • Y. Dong et al.

    Cocaine-induced plasticity of intrinsic membrane properties in prefrontal cortex pyramidal neurons: adaptations in potassium currents

    J Neurosci

    (2005)
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