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, 15 (4), 431-43

Cellular Basis of Memory for Addiction


Cellular Basis of Memory for Addiction

Eric J Nestler. Dialogues Clin Neurosci.


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.

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


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

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