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  • Review Article
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Molecular basis of long-term plasticity underlying addiction

Nature Reviews Neuroscience volume 2, pages 119–128 (2001)Cite this article

A Correction to this article was published on 01 March 2001

Key Points

  • Addiction — the loss of control over drug use — involves stable brain changes that are responsible for the long-lasting nature of the behavioural abnormalities. Although drugs of abuse comprise chemically divergent molecules, their actions in the brain converge in some common points. In particular, all of them lead to the activation of the mesolimbic dopamine system — a main reward system of the brain. One likely mechanism of addiction is that repeated stimulation of the mesolimbic dopamine system leads to marked alterations in reinforcement mechanisms and motivational state.

  • Different molecular modifications have been put forward to explain the long-lasting nature of addiction. For example, transcriptional modifications are thought to be crucial for the development of addictive states. The two main transcriptional regulators known to change upon repeated drug exposure are CREB and ΔFosB.

  • Increased transcription of the CREB gene accompanies the upregulation of the cAMP pathway known to occur in certain brain regions after repeated drug intake. Upregulation of the cAMP pathway and CREB might mediate a homeostatic adaptation that diminishes further drug responsiveness. However, as the increased levels of CREB have a relatively short life, additional mechanisms are thought to underlie longer-lasting manifestations of addiction.

  • The levels of ΔFosB, another transcriptional regulator, are also increased after administration of drugs of abuse. As the half-life of this molecule is very long, it provides a molecular mechanism of addiction based in the stability of the protein by which drug-induced changes in gene expression can persist long after drug intake stops.

  • Other mechanisms independent of transcription might contribute to the long-term plastic changes underlying addiction. For instance, reduced protein degradation and the regulation of receptor sensitivity are two modifications known to occur after drug administration. Similarly, structural changes in the neurons of the mesolimbic dopamine system and their targets, such as increased spine density in the nucleus accumbens, are known to accompany repeated drug exposure.

  • There are many parallels between the molecular changes underlying addiction and those related to other forms of brain plasticity such as learning and memory. From a behavioural perspective, certain features of addiction, such as the ability of drug-associated cues to induce relapse, have been described as forms of memory. Also, activation of the cAMP pathway and of CREB-mediated transcription has been observed in forms of synaptic plasticity believed to constitute cellular correlates of memory. As a result, the key future challenges in the addiction and the memory fields are equivalent to a large extent.

Abstract

Studies of human addicts and behavioural studies in rodent models of addiction indicate that key behavioural abnormalities associated with addiction are extremely long lived. So, chronic drug exposure causes stable changes in the brain at the molecular and cellular levels that underlie these behavioural abnormalities. There has been considerable progress in identifying the mechanisms that contribute to long-lived neural and behavioural plasticity related to addiction, including drug-induced changes in gene transcription, in RNA and protein processing, and in synaptic structure. Although the specific changes identified so far are not sufficiently long lasting to account for the nearly permanent changes in behaviour associated with addiction, recent work has pointed to the types of mechanism that could be involved.

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Figure 1: Key neural circuits of addiction.
Figure 2: Regulation of CREB by drugs of abuse.
Figure 3: Regulation of ΔFosB by drugs of abuse.
Figure 4: Regulation of post-transcriptional mechanisms by drugs of abuse.
Figure 5: Regulation of dendritic structure by drugs of abuse.

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Acknowledgements

This work was supported by grants from the National Institute on Drug Abuse.

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Authors and Affiliations

  1. Department of Psychiatry and Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, 5,323 Harry Hines Boulevard, Dallas, 75390-9070 , Texas, USA

    Eric J. Nestler

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DATABASE LINKS

CREB

ΔFosB

CBP

PKA

Ca2+/calmodulin-dependent protein kinase IV

c-Fos

FosB

Fra-1

Fra-2

GluR2

Egr1–3

GDNF

Cdk5

ENCYCLOPEDIA OF LIFE SCIENCES

Drugs and the synapse

Cocaine and amphetamines

Glossary

LIMBIC SYSTEM

A collection of cortical and subcortical structures important for processing memory and emotional information. Prominent structures include the hippocampus and amygdala.

CANNABINOIDS

Derivatives of 2-(2-2-isopropyl-5-methylphenyl)-5-pentyl-resorcinol, a molecule found in the plant Cannabis sativa. Cannabinoids are responsible for the psychoactive effects of marijuana.

PHENCYCLIDINE

A potent psychoactive drug also known as angel dust, which has anaesthetic and analgesic actions. It blocks the NMDA receptor channel.

MEDIUM SPINY NEURONS

The main cell population of the ventral and dorsal striatum; these GABA-mediated projection neurons form the two main outputs of these structures, called the direct and indirect pathways.

TOLERANCE

Reduced drug responsiveness with repeated exposure to a constant drug dose.

DEPENDENCE

Altered physiological state that develops to compensate for persistent drug exposure and that gives rise to a withdrawal syndrome after cessation of drug exposure.

DYSPHORIA

Negative or aversive emotional state usually associated with anxiety and depression.

SENSITIZATION

Enhanced drug responsiveness with repeated exposure to a constant dose.

RAS PROTEINS

A group of small G proteins involved in growth, differentiation and cellular signalling that require the binding of GTP to enter into their active state.

LOCUS COERULEUS

Nucleus of the brainstem. The main supplier of noradrenaline to the brain

TYROSINE HYDROXYLASE

The rate-limiting enzyme in the biosynthesis of noradrenaline, dopamine and other catecholamines.

WITHDRAWAL SYNDROME

A collection of signs and symptoms that appear after sudden cessation of drug intake. Depending on the drug, they can include mild shakiness, sweating, anxiety and even hallucinations.

DOMINANT-NEGATIVE

A mutant molecule that forms heteromeric complexes with the wild type to yield a non-functional complex.

ZINC FINGER

Protein module in which cysteine or cysteine–histidine residues coordinate a zinc ion. Zinc fingers are often used in DNA recognition and also in protein–protein interactions.

GLUCOCORTICOIDS

Hormones produced by the adrenal cortex, which are involved in carbohydrate and protein metabolism, but also affect brain function. Cortisol (human) and corticosterone (rodent) are prime examples.

PROTEASOME

Protein complex responsible for degrading intracellular proteins that have been tagged for destruction by the addition of ubiquitin.

ARRESTINS

Inhibitory proteins that bind to phosphorylated receptors, blocking their interaction with G proteins and terminating signalling. For example, β-arrestin binds to phosphorylated β-adrenergic receptors and inhibits their ability to activate Gs.

DYNAMIN

Protein involved in the formation of microtubule bundles and in membrane transport.

CYCLIN-DEPENDENT KINASE 5

A member of a family of cyclin-dependent kinases, Cdk5 is enriched in brain, requires another protein termed p35 for its activation and is implicated in the regulation of neural growth and survival.

LONG-TERM POTENTIATION

A long-lasting increase in the efficacy of synaptic transmission commonly elicited by high-frequency neuron stimulation.

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Nestler, E. Molecular basis of long-term plasticity underlying addiction . Nat Rev Neurosci 2, 119–128 (2001). https://doi.org/10.1038/35053570

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