Synaptic plasticity and drug addiction

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Recent studies have suggested that the development of addictive behaviours shares common features with traditional learning models. Synaptic plasticity, a possible substrate for learning, has been demonstrated in neural reward circuits and might contribute to the learning of addictive behaviours. Changes in the strength of synaptic connections have been investigated in dopaminergic cells of the ventral tegmental area in response to several addictive drugs. Rapid and persistent forms of synaptic plasticity (specifically, long-lasting synaptic potentiation) have been demonstrated to accompany some of the behavioural effects of addictive drugs. We hypothesize that drug-induced synaptic plasticity might play a role in reward-related learning and addiction by modifying the fine tuning of dopaminergic cell firing.

Introduction

Understanding the principles and mechanisms that guide the learning and memory of reward-related information is a challenging but exciting goal in neurobiology. Drugs that are addictive in humans (including cocaine, amphetamine, morphine, nicotine and alcohol) have reward value; that is, they motivate actions to acquire them 1., 2.. In human drug addiction and in animal models of drug addiction, learning by ‘association’ establishes patterns of behaviour that lead to the drug 3., 4.. If a particular action, such as seeking out a drug dealer or (in laboratory animals) pressing a lever directly results in a drug reward, the association between the action and the reward is strengthened. This is known as operant or instrumental associative learning. In classical Pavlovian associative learning, a non-rewarding stimulus (or cue) is paired with a reward so that the cue becomes predictive of the reward, acquires reward value itself and motivates action. For example, human cocaine users watching a video of cocaine-related paraphernalia and behaviours experience drug craving [5]. In laboratory animals, sensory cues previously paired with a drug can themselves elicit drug-motivated behaviours. This is seen in the ‘place preference’ assay, where injections of a drug are paired with a distinctive sensory cage compartment; animals show a ‘preference’ to spend more time in the drug-paired compartment than in the vehicle-paired compartment.

The learning of drug-associated actions and drug-associated cues probably contributes to the progression from drug use to motivated drug-taking to the compulsive craving, seeking and taking of drugs that characterises drug addiction 3., 4., 6.. Drug-associated learning might be viewed as abnormal [4], as it serves no normal physiological role. Persistent neural adaptations in behaviour, physiology, pharmacology and gene expression might result from, and even contribute to, drug-associated learning. For example, sensitization (increased responsiveness) of neural circuits that assess the motivational value of drug rewards can enhance both instrumental and classical forms of learning [7]. In this review, we consider the possibility that synaptic plasticity, a proposed substrate of learning 8.••, 9., 10., occurs in neural reward circuits, and we review recent evidence that this synaptic plasticity can be induced or modified by addictive drugs.

Section snippets

Glutamate receptors as targets for addictive drugs

Traditionally, dopamine has received most attention as the key player in drug addiction 1., 2., 11.. However, another substantial body of literature supports a role for glutamate in learning and other adaptive processes in animal models of drug addiction 8.••, 12., 13., 14.. Glutamate receptors and glutamatergic transmission are modified during drug-associated learning, and pharmacological agents acting at glutamate receptors influence classical Pavlovian and instrumental associative learning 7.

Addictive drugs and synaptic plasticity in the ventral tegmental area

Mechanisms of learning in response to addictive drugs probably occur in neural circuits interacting with and influencing dopaminergic cells originating in the ventral tegmental area (VTA) and terminating in forebrain regions, including the nucleus accumbens of the ventral striatum. The traditionally viewed ‘core’ dopaminergic reward circuitry is highlighted in Figure 1. Brain regions that are now recognized to play a role in drug addiction by interacting with the dopaminergic projections are

Drug-induced synaptic plasticity and VTA dopaminergic cell activity

We have provided evidence that drug-induced synaptic plasticity occurs in VTA dopaminergic cells, and that both glutamate and dopamine are required for learning mechanisms in reward and addiction 1., 8.••, 12.. Glutamate controls many aspects of dopaminergic cell function, including midbrain dopaminergic cell firing and dopamine release 30., 31.. Therefore, what are the consequences of glutamatergic synaptic plasticity in the VTA for dopaminergic cell activity and dopamine release? VTA

Conclusions

Forms of synaptic plasticity sensitive to addictive drugs have been identified in the VTA. Addictive drugs administered in vivo cause a rapid and persistent potentiation of AMPAR-mediated synaptic responses. Changes in AMPAR subunit expression are reported, but how such changes relate to the functional plasticity and behavioural effects of drugs is unclear. Future studies aimed at measuring AMPAR subunit turnover in response to addictive drugs would be useful in determining, firstly, the nature

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank Drs Patricia Di Ciano and Tara Crowder for insightful discussions about glutamate receptors in reward-related learning and for reading and providing helpful comments on our manuscript, and Dr Carmen Canavier for helpful discussions about glutamate receptors and dopaminergic cell firing. We also thank Lisa Daitch for editing the manuscript.

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