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Addiction and the brain: The neurobiology of compulsion and its persistence

Abstract

People take addictive drugs to elevate mood, but with repeated use these drugs produce serious unwanted effects, which can include tolerance to some drug effects, sensitization to others, and an adapted state — dependence — which sets the stage for withdrawal symptoms when drug use stops. The most serious consequence of repetitive drug taking, however, is addiction: a persistent state in which compulsive drug use escapes control, even when serious negative consequences ensue. Addiction is characterized by a long-lasting risk of relapse, which is often initiated by exposure to drug-related cues. Substantial progress has been made in understanding the molecular and cellular mechanisms of tolerance, dependence and withdrawal, but as yet we understand little of the neural substrates of compulsive drug use and its remarkable persistence. Here we review evidence for the possibility that compulsion and its persistence are based on a pathological usurpation of molecular mechanisms that are normally involved in memory.

Key Points

  • Many drugs of abuse produce tolerance, sensitization, dependence and addiction. Of these effects, addiction (compulsive drug use despite adverse consequences) has been the hardest to study. It is proposed that compulsion and its persistence arise from a pathological usurpation of the molecular mechanisms that are normally involved in memory.

  • Tolerance, sensitization and dependence (leading to withdrawal symptoms when drug use is discontinued) do not, by themselves, explain addiction or late relapses to drug use long after withdrawal has ended. Relapses can be triggered by cues that were previously associated with drug use.

  • The rewarding properties of drugs of abuse seem to be mediated by the midbrain dopaminergic system, which also mediates the rewarding effects of positive natural stimuli such as food. Midbrain dopamine neurons receive highly processed information from the cortex and other regions, and project to the nucleus accumbens and dorsal striatum. Here, dopaminergic signals can interact with excitatory transmitters carried by projections from the cortex, hippocampus and amygdala.

  • Drug-induced synaptic plasticity in the nucleus accumbens and dorsal striatum could contribute to addiction. Long-term potentiation and long-term depression can be elicited at excitatory synapses in the nucleus accumbens and dorsal striatum, although their mechanisms differ. Both forms of plasticity can also be induced in midbrain dopaminergic regions.

  • Treatment with cocaine can induce changes in synaptic weight in the midbrain and nucleus accumbens, and can increase spine density in the nucleus accumbens and prefrontal cortex.

  • Drug-induced synaptic plasticity probably results from a complicated cascade of molecular events in many cells and circuits. Proteins that are thought to be involved include ΔFosB, the cyclin-dependent kinase Cdk5, and the cyclic-AMP-response-element-binding protein (CREB), which is involved in the expression of genes that are upregulated in response to drugs of abuse (both transiently and in the long term).

  • Better models of compulsive drug use despite negative consequences are needed to clarify the molecular and cellular events that lead to addiction.

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Correspondence to Steven E. Hyman.

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Glossary

ASYMMETRICAL SYNAPSES

Synaptic contacts in which the postsynaptic thickening is wider than the presynaptic one. They are thought to comprise largely excitatory connections. Symmetrical synapses, in contrast, are characterized by pre- and postsynaptic thickenings of roughly similar widths and are thought to be inhibitory.

CONDITIONED PLACE PREFERENCE

The development in an experimental animal of a preference for a location that is repeatedly paired with a rewarding stimulus (for example, cocaine).

IMMEDIATE-EARLY GENES

Genes that are induced rapidly and transiently without a need for new protein synthesis. Many immediate-early genes, such as Fos, control the transcription of other genes, and thereby provide the early stages in the control of the production of specific proteins.

DYSPHORIA

A negative or aversive emotional state that is usually associated with anxiety and depression.

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Figure 1: Dopamine–glutamate interactions in the striatum.
Figure 2: Signalling to the nucleus stimulated by dopamine and glutamate.