ReviewDopamine receptors in the learning, memory and drug reward circuitry
Introduction
The brain neurotransmitter dopamine (DA) has long been investigated as an important modulator of motivated behaviour for natural and drug rewards [1], [2], [3], [4], [5], [6], [7]. Pathological disturbances of the brain DA systems are implicated in a number of neurological and neuropsychiatric disorders, including Parkinson's disease, schizophrenia, drug addiction and attention-deficit hyperactivity disorder (ADHD) [2], [7], [8], [9], [10], [11]. However, the precise role of DA in pathological forms of motivated behaviour, including addiction, is still a matter of considerable debate and uncertainty.
Early theories suggested that DA mediates the hedonic or pleasurable effects of addictive drugs [12] but there is little evidence to support this [1], even though a wide variety of drugs commonly abused by humans share the ability to increase synaptic DA concentration in the nucleus accumbens (NAcb) [13], a key forebrain structure mediating the primary reinforcing and psycho-stimulant effects of drugs of abuse [14], [15], [16]. Other influential theories suggest a role for DA in transferring incentive salience to reward-related stimuli [1] and in overcoming effort-related response costs [17]. The focus of this review concerns the role of DA in synaptic plasticity and learning within the reward circuitry of the brain [4], [18], [19]. The concept that DA modulates reward-related synaptic plasticity and learning is substantiated by a wealth of evidence, including electrophysiological data showing DA activity to obey formal prediction error rules and thereby, potentially, to promote new learning [4]. In this article the hypothesis that drug addiction represents the final stage of a progressive series of disturbances in the brain's learning and memory systems [20], [21], [22] is discussed from the perspective of DA receptor function within the brain's reward systems.
Section snippets
Brain dopamine receptors
DA neurotransmission in the brain is mediated by two general classes of G-protein-coupled DA receptors, the DA D1 class and the DA D2 class, which are distinguishable by their opposite modulation of adenylyl cyclase [23], [24]. The DA D1-like receptor family include DA D1 receptors (or DA D1A) and a low-abundance DA D5 receptor (or DA D1B), which positively regulate adenylyl cyclase activity to increase intracellular cyclic AMP. The DA D2 class of receptors – DA D2, DA D3 and DA D4 receptors –
Definition
Drug addiction or substance dependence as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV (American Psychiatric Association) is a chronically relapsing brain disorder characterised by a loss of control over drug intake and a significant impairment in functioning. The main criteria used to define substance dependence include: recurrent use resulting in a failure to fulfil major obligations at work, school, or home; recurrent use in situations which are physically
Learning mechanisms in addiction
Drug addiction has been hypothesised to result from pathological neuroadaptations in the brain's normal learning and memory systems [20], [22], [72], [73]. The establishment of compulsive drug-seeking habits has been viewed as the endpoint of a series of complex transitions in Pavlovian and instrumental learning mechanisms that strengthen or consolidate drug-taking and -seeking behaviour [22], [100]. According to this view the transition to addiction evolves from initial memory representations
Pre-disposition to addiction
A major challenge in drug addiction research is to understand why many people can apparently maintain prolonged recreational drug use without ever progressing to compulsive drug use, as defined in DSM-IV by increasing drug use with almost complete disregard for its harmful consequences. It has been estimated, for example, that as few as 20% of people who use cocaine actually become addicted to the drug [112]. Increasing evidence also suggests that certain personality traits, including the
Conclusions and future perspectives
DA has long been recognised to play a critical role in cognition and emotion and in synaptic plasticity and memory processes [19], [81]. The review considers addiction as a pathological disorder of the brain's learning and memory systems established and maintained by genetic pre-dispositions and drug-induced neuroadaptations in the brain's reinforcement systems [72], [73]. The notion that drug addiction evolves as a series of learning-related transitions from voluntary drug use to habitual and
Acknowledgments
The research reviewed in this article was conducted within the Cambridge University Behavioural and Clinical Neuroscience Institute and was funded by MRC grants to J.W.D. (G0401068, G0701500) and B.J.E. (G9536855), a Wellcome Trust Programme grant to T.W. Robbins, B.J.E., A.C. Roberts and B.J. Sahakian (076274/z/04/z) and a consortium joint award from the MRC and Wellcome Trust (G0001354).
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