Reward system and addiction: what dopamine does and doesn’t do
Introduction
In November 2006, a PubMed search for ‘dopamine and addiction’ gave 1220 citations against 503 for ‘ventral striatum and addiction’, 416 for ‘cortex and addiction’, 336 for ‘serotonin and addiction’, 213 for ‘glutamate and addiction’, 208 for ‘GABA and addiction’ and 163 for ‘amygdala and addiction’. This simple search indicates that studies in the addiction field have privileged dopamine (DA) over all other topics.
Knowledge of the involvement of DA in the action of addictive drugs came almost 20 years [1] after its discovery as the transmitter of the motor striatum in the late 1950s. Moreover, this involvement was originally utilized to support a role for DA in reward, rather than in drug addiction [1]. This evidence was initially obtained by lesioning of DA neurons and by pharmacological manipulation of DA transmission [2]. Although this experimental approach greatly contributed to the foundations of our present view of the function of DA, it also generated significant debate owing to the difficulty of excluding a contribution by non-specific motor effects to the behavioral impairments induced by experimental manipulation of DA transmission [2, 3, 4]. In the past 25 years, several methods have become available that enable the function of the DA system, and its correlation with behaviour, to be monitored.
DA function can be monitored by extracellular recording of the firing activity of DA neurons [5] and by estimating the extracellular concentrations of DA by microdialysis [6, 7••], voltammetry [8] and brain imaging (i.e. positron emission tomography [PET]) [9, 10••]. Each of these methods has different time frames: milliseconds for extracellular recordings, seconds for voltammetry, and minutes for microdialysis and PET. These different methods do not necessarily estimate the same aspect of the function of DA. It has been proposed that DA operates in different modalities depending upon the time-scale of its action [11, 12••]. Thus, a phasic modality, operating in a time-frame of hundreds of milliseconds and related to release of DA by a burst of spikes onto low affinity DA receptors, has been distinguished from a tonic modality, operating in a circadian time-frame and related to the basal steady-state concentration of DA in the extracellular compartment arising from the dilution and diffusion of released DA. The phasic modality corresponds to DA transients estimated by voltammetry, the tonic modality to basal DA concentrations estimated by microdialysis [11]. This dicotomous categorization, however, is insufficient to describe the changes in the minute time-frame observed by microdialysis and PET in response to reward-related stimuli. Therefore, a more comprehensive model envisions the existence of multiple time-related modalities of DA transmission that depend upon the number of bursts fired by specific pools of DA neurons [13].
Here we examine the current views on the role of DA in drug reward and motivation; specific emphasis has been placed on the differential responsiveness of DA transmission at different terminal areas to drug and food reinforcers, as well as to drug- and food-conditioned stimuli, and on the role that these differences might play in the mechanism of drug addiction.
Section snippets
Basic aspects of dopamine transmission relevant for behavior
DA acts via G-protein-coupled receptors in a typical neuromodulatory fashion [14]. DA release sites are placed immediately outside the synaptic cleft [13]. Once released, DA diffuses in the extracellular fluid, from which it is slowly cleared as a result of reuptake and metabolism [15]. DA does not directly affect the conductance of receptive membranes but modifies their response to afferent input [16]. These three aspects (extrasynaptic release, G-protein-coupled receptor signal transduction
In vivo monitoring of dopamine responsiveness to taste stimuli
Microdialysis studies in the rat have shown that appetitive taste stimuli release DA in the NAc shell and core, as well as in the prefrontal cortex (PFC) [21, 22]. NAc shell DA responsiveness shows some differences to that of the NAc core and PFC, as it is dependent upon the hedonic valence (appetitive or aversive) [23] and relative novelty of taste stimuli [21, 23, 24]. Thus, NAc shell DA release is stimulated by unfamiliar appetitive tastes, but is unaffected or even decreased by aversive
Extracellular recording of dopamine neurons
Recordings from electrophysiologically identified DA neurons of the monkey substantia nigra show that they respond specifically to the unpredicted occurrence or non-occurrence of reward-conditioned stimuli [5]. These observations suggest that DA neurons respond to stimuli according to an error in the ‘prediction of reward’ occurrence. Because a reward-prediction error forms the basis of Pavlovian learning theories, it has been postulated that DA neurons provide an error signal for the learning
Monitoring of extracellular dopamine after addictive drugs: focus on the accumbens shell
Microdialysis and PET studies show that addictive drugs increase extracellular DA preferentially in the ventral striatum (namely in the NAc) in rats, non-human primates and humans [20]. Furthermore, addictive drugs preferentially increase dialysate DA in the NAc shell, rather than the core, after response non-contingent [32, 33, 34] and response-contingent [35••, 36••, 37••] administration in the rat. Caffeine, a non-addictive drug, fails to stimulate DA transmission in the NAc shell [38, 39].
Drug-reward versus food-reward: differential role of dopamine
Historically, evidence that drug (psychostimulant)-induced stimulation of DA transmission was rewarding proved highly influential in the formulation of a general anhedonia hypothesis that extended the role of DA to all rewards [1, 2]. However, after years of debate, the anhedonia hypothesis appears no longer tenable. The main reason for this is that food reward is, to a large extent, independent of DA [4, 41]. On this basis, activational and incentive-motivational theories have extended to all
Dopamine and incentive arousal
Mogenson and Yang [47] viewed the ventral striatum as an interface between motivation and action. Indeed, DA neurons respond to motivationally significant stimuli with a burst of spikes and a phasic release of DA in terminal areas [5, 20]. However, as mentioned above, it is unlikely that DA is ‘in series’ between a stimulus and a response and that it mediates stimulus-response coupling. Rather, DA release by Pavlovian stimuli might modulate stimulus–response coupling, thus being in parallel
Dopamine release by drug and food conditioned stimuli
Past and current hypotheses of DA function in behavior attribute an important role to the ability of conditioned stimuli to release DA. Clear differences between drug and non-drug Pavlovian conditioned stimuli have been shown in microdialysis studies. Thus, Pavlovian stimuli conditioned to palatable food acquired incentive properties and released DA in the PFC and in the NAc core, but consistently failed to release DA in the NAc shell [21, 23, 24]. The same stimuli conditioned to morphine or
Dopamine-dependent learning and drug addiction
DA has been implicated in virtually all stages of drug addiction, from induction to maintenance and then to relapse after a period of abstinence. Current theories of drug addiction attribute an important role to DA in mediating changes in synaptic efficiency resulting from repeated exposure to addictive drugs. Differences among theories relate to the mechanism by which these processes take place. Schematically, one can distinguish between associative learning and non-associative (neuroadaptive)
Dopamine-dependent sensitization and drug addiction
Robinson and Berridge [58], largely on the basis of studies with psychostimulants, have proposed an incentive-sensitization theory of drug addiction. This theory posits that repeated drug exposure induces a state of sensitization of mesocorticolimbic DA neurons; as a result of this adaptive non-associative change, drug-related stimuli would become more effective at stimulating DA transmission in mesocorticolimbic areas and in triggering craving, regarded as an abnormal incentive state (abnormal
Dopamine, relapse and vulnerability to drug addiction
A reduction of tonic DA transmission in striatal areas has been implicated in the motivational disturbances (anhedonia) of abstinence in dependent subjects, as well as in the individual vulnerability to drug addiction [62•]. Withdrawal from cocaine, nicotine and ethanol in dependent subjects results in a reduction of the excitability of the reward system, as indicated by an increase in the threshold for brain stimulation reward [63]. These changes are thought to maintain drug
Conclusions
Addictive drugs of different classes preferentially stimulate DA transmission in the NAc shell and extended amygdala complex, thus inducing a state of incentive arousal. This DA-dependent state has hedonic properties (e.g. state-hedonia, euphoria) and is accordingly self-referred to as ‘liking’, but should not be distinguished from DA-independent sensory stimulus-bound hedonia elicited by conventional non-drug rewards (e.g. taste, sex). Incentive arousal exerts profound effects on behavior,
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
The studies from the authors’ laboratory have been funded by grants from Ministero dell’Università e della Ricerca (PRIN 2005 and FIRB), the European Commission (NIDE project), Centro di Eccellenza per lo Studio delle Dipendenze, Fondazione Banco di Sardegna and the association Physiological Effects of Coffee (PEC, Paris).
Glossary
- Anhedonia
- inability to experience pleasure.
- Habituation
- reduction or cessation of response to a stimulus after repeated exposure. Habituation, in contrast to tolerance, is not reversed by increasing stimulus strength.
- Hedonia
- the interoceptive sensation of pleasure. ‘State hedonia’, related to a drug-induced ‘high’ or ‘rush’, is distinguished from ‘sensory hedonia’, which is related to hedonic stimuli arising from rewards (e.g. taste stimuli, sexual stimuli).
- Incentive
- a stimulus that promotes
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