Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2013 Dec;15(4):431-43.
doi: 10.31887/DCNS.2013.15.4/enestler.

Cellular basis of memory for addiction

Affiliations
Review

Cellular basis of memory for addiction

Eric J Nestler. Dialogues Clin Neurosci. 2013 Dec.

Abstract

DESPITE THE IMPORTANCE OF NUMEROUS PSYCHOSOCIAL FACTORS, AT ITS CORE, DRUG ADDICTION INVOLVES A BIOLOGICAL PROCESS: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. Here, we review the types of molecular and cellular adaptations that occur in specific brain regions to mediate addiction-associated behavioral abnormalities. These include alterations in gene expression achieved in part via epigenetic mechanisms, plasticity in the neurophysiological functioning of neurons and synapses, and associated plasticity in neuronal and synaptic morphology mediated in part by altered neurotrophic factor signaling. Each of these types of drug-induced modifications can be viewed as a form of "cellular or molecular memory." Moreover, it is striking that most addiction-related forms of plasticity are very similar to the types of plasticity that have been associated with more classic forms of "behavioral memory," perhaps reflecting the finite repertoire of adaptive mechanisms available to neurons when faced with environmental challenges. Finally, addiction-related molecular and cellular adaptations involve most of the same brain regions that mediate more classic forms of memory, consistent with the view that abnormal memories are important drivers of addiction syndromes. The goal of these studies which aim to explicate the molecular and cellular basis of drug addiction is to eventually develop biologically based diagnostic tests, as well as more effective treatments for addiction disorders.

Lo central de la drogadicción, a pesar de la importancia de los numerosos factores psicosociales, es que implica un proceso biológico. Un estado de adicción se define por la capacidad que tiene la exposición repetida a una droga de abuso para inducir cambios en un cerebro vulnerable, el impulse a la búsqueda compulsiva y la obtención de drogas, y la pérdida de control sobre el uso de éstas. En este artículo se examinan los tipos de adaptaciones moleculares y celulares que ocurren en regiones especificas del cerebro y que median alteraciones conductuales asociadas con la adicción. Estas adaptaciones incluyen alteraciones en la expresión génica, producidas en parte por mecanismos epigenéticos, en la plasticidad del funcionamiento neurofisiológico de neuronas y sinapsis, y en la plasticidad asociada con la morfología neuronal y sináptica mediada en parte por las señales alteradas del factor neurotrófico, Cada uno de estos tipos de modificaciones inducidos por drogas se puede considerar como una forma de “memoria celular o molecular”. Sin embargo, llama la atención que la mayoría de las formas de plasticidad relacionadas con la adicción son muy similares a los tipos de plasticidad que se han asociado con las formas más clásicas de “memoria conductual”, lo que refleja tal vez el repertorio limitado de los mecanismos de adaptación de que disponen las neuronas cuando se enfrentan con las exigencias del medioambiente. Por último, las adaptaciones moleculares y celulares relacionadas con las adicciones incluyen la mayor parte de las mismas regiones del cerebro que median las formas más clásicas de la memoria, lo que resulta consistente con la opinión de que las memorias anormales son importantes impulsoras de los síndromes adictivos. El propósito de estos estudios que buscan explicar las bases moleculares y celulares de la adicción a drogas es, eventualmente, poder desarrollar pruebas diagnósticas con bases biológicas, como también contar con terapias más efectivas para los trastornos adictivos.

Malgré l'importance de nombreux facteurs psychosociaux, l'addiction à une drogue repose essentiellement sur un processus biologique: l'état de dépendance se définit par la faculté d'une exposition répétée à une consommation de drogue à provoquer des modifications dans un cerveau vulnérable conduisant à leur recherche et à leur prise compulsive et à la perte du contrôle de leur utilisation. Nous analysons ici les types d'adaptation moléculaire et cellulaire qui interviennent dans des régions cérébrales particulières à l'origine des anomalies du comportement addictif: ce sont des altérations de l'expression génique dues en partie à des mécanismes épigénétiques, à la plasticité du fonctionnement neurophysiologique des neurones et des synapses et l'association d'une plasticité au niveau de la morphologie neuronale et synaptique due en partie à une modification de la transmission du signal des facteurs neurotrophiques. Chacun de ces types de modifications induites par les drogues peut être vu comme une forme de «mémoire cellulaire ou moléculaire». De plus, il est frappant de voir que la plupart des formes de plasticité liées à l'addiction sont très semblables aux types de plasticité associés aux formes plus classiques de «mémoire comportementale» reflétant peut-être le caractère limité du répertoire des mécanismes adaptatifs disponibles pour les neurones lorsqu'ils font face aux défis environnementaux. Finalement, les adaptations moléculaires et cellulaires liées à l'addiction concernent la plupart des mêmes régions cérébrales impliquées dans les formes plus classiques de mémoire, ce qui conforte l'idée que des souvenirs anormaux sont d'importants vecteurs de syndromes de dépendance. Le but de ces études, qui expliquent les bases moléculaires et cellulaires de la dépendance à une drogue, est finalement de développer des tests diagnostiques biologiques, ainsi que des traitements plus efficaces pour les troubles addictifs.

Keywords: CREB; dendritic spines; epigenetics; gene transcription; nucleus accumbens; synaptic plasticity; ventral tegmental area; whole cell plasticity; ΔFosB.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.. Mechanisms of transcriptional and epigenetic regulation by drugs of abuse. In eukaryotic cells, DNA is organized by wrapping around histone octomers to form nucleosomes, which are then further organized and condensed to form chromosomes (left part). Only by temporarily unraveling compacted chromatin can the DNA of a specific gene be made accessible to the transcriptional machinery. Drugs of abuse act through synaptic targets such as reuptake mechanisms, ion channels, and neurotransmitter (NT) receptors to alter intracellular signaling cascades (right part). This leads to the activation or inhibition of transcription factors (TFs) and of many other nuclear targets, including chromatin-regulatory proteins (shown by thick arrows); the detailed mechanisms involved in the synaptic regulation of chromatin-regulatory proteins remain poorly understood. These processes ultimately result in the induction or repression of particular genes, including those for noncoding RNAs such as microRNAs; altered expression of some of these genes can in turn further regulate gene transcription. It is proposed that some of these drug-induced changes at the chromatin level are extremely stable and thereby underlie the long-lasting behaviours that define addiction. CREB, cyclic AMP-responsive element binding protein; DNMTs, DNA methyltransferases; HATs, histone acetyltransferases; HDACs, histone deacetylases; HDMs, histone demethylases; HMTs, histone methyltransferases; MEF2, myocyte-specific enhancer factor 2; NF-kB, nuclear factor-KB; pol II, RNA polymerase II. Reproduced from ref 44: Robison AJ, Nestler EJ. Transcriptional and epigenetic mechanisms of addiction. Nat Rev Neurosci. 2011 ;12:623-637. Copyright © Nature Publishing Group 2011
Figure 2.
Figure 2.. Model of addiction-related synaptic and structural plasticity in nucleus accumbens (NAc). Chronic exposure to cocaine results in a time-dependent and transient reorganization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartic acid (NMDA) glutamate receptors at NAc medium spiny neuron (MSN) synapses, as well as structural changes in the spine head of NAc MSNs that correlate with distinct forms of synaptic plasticity. For example, chronic cocaine induces surface expression of NMDA receptors, silent synapse formation and long-term depression (LTD) at early withdrawal time points. During more prolonged withdrawal (wd), these synaptic changes reverse with the result being increased expression of surface AMPA receptors, a consolidation of the synapse into a mushroom-shaped spine and long-term potentiation (LTP). These effects rapidly revert back again upon exposure to a challenge dose of cocaine leading to restructuring of the spine into thin spines and a depression of synaptic strength. Reproduced from ref 82: Russo SJ, Dietz DM, Dumitriu D, Morrison JH, Malenka RC, Nestler EJ. The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens. Trends Neurosci. 2010;33:267-276. Copyright © Elsevier 2010
Figure 3.
Figure 3.. Molecular mechanisms underlying cocaine induction of dendritic spines on nucleus accumbens (NAc) medium spiny neurons. A) shows cocaine-induced increases in dendritic spine number that can be blocked by viral overexpression of G9a or JunD (an antagonist of AP1 -mediated transcription), or mimicked by viral overexpression of FosB. B) Regulation of AMPA receptor (AMPAR) trafficking and of the actin cytoskeleton (left), as well as regulation of the transcription of glutamate receptors and actin regulatory proteins (eg, as mediated via ΔFosB, right) have been shown to play important roles in mediating cocaine's regulation of NAc dendritic spine density. UMK, LIM domain kinase; RAC, Ras-related C3 botulinum toxin substrate. Reproduced from ref 44: Robison AJ, Nestler EJ. Transcriptional and epigenetic mechanisms of addiction. Nat Rev Neurosci. 2011;12:623-637. Copyright © Nature Publishing Group 2011
Figure 4.
Figure 4.. Working model of chronic morphine-induced adaptations in ventral tegmental area (VTA) dopamine neurons. Chronic morphine decreases VTA dopamine (DA) soma size yet increases neuronal excitability, while dopamine transmission to the nucleus accumbens is decreased. The net effect of morphine is a less responsive reward pathway, ie, reward tolerance. Downregulation of IRS2-AKT signaling in VTA mediates the effects of chronic morphine on soma size and electrical excitability; the effect on excitability is mediated via decreased γ-aminobutyric acid (GABA)A currents and suppression of K' channel expression. Morphine-induced downregulation of mTORC2 activity in VTA is crucial for these morphine-induced morphological and physiological adaptations as well as for reward tolerance. In contrast to mT0RC2, chronic morphine increases mTORCI activity, which does not influence these morphine-induced adaptations. BDNF, brain-derived neurotrophic factor; IRS, insulin receptor substance; mTORC, mTOR complex; AKT, protein kinase B Reproduced from ref 77: Mazei-Robison MS, Koo JW, Friedman AK, et al. Role for mTOR signaling and neuronal activity in morphine-induced adaptations in ventral tegmental area dopamine neurons. Neuron.2011 ;72:977-990. Copyright © Cell Press 2011

Similar articles

Cited by

References

    1. Hyman SE., Malenka RC., Nestler EJ. Neural mechanisms of addiction: the role of reward-related learning and memory. Annu Rev Neurosci. 2006;29:565–598. - PubMed
    1. Wang JC., Kapoor M., Goate AM. The genetics of substance dependence. Annu Rev Genomics Hum Genet. 2012;13:241–261. - PMC - PubMed
    1. Kandel DB., Yamaguchi K., Klein LC. Testing the gateway hypothesis. Addiction. 2006;101:470–472. - PubMed
    1. Kalivas PW., O'Brien C. Drug addiction as a pathology of staged neuroplasticity. Neuropsychopharmacology. 2008;33:166–180. - PubMed
    1. Nestler EJ. Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci. 2001;2:119–128. - PubMed

Publication types

MeSH terms