Reward system and addiction: what dopamine does and doesn’t do

https://doi.org/10.1016/j.coph.2006.11.003Get rights and content

Addictive drugs share with palatable food the property of increasing extracellular dopamine (DA), preferentially in the nucleus accumbens shell rather than in the core. However, by acting directly on the brain, drugs bypass the adaptive mechanisms (habituation) that constrain the responsiveness of accumbens shell DA to food reward, abnormally facilitating Pavlovian incentive learning and promoting the acquisition of abnormal DA-releasing properties by drug conditioned stimuli. Thus, whereas Pavlovian food conditioned stimuli release core but not shell DA, drug conditioned stimuli do the opposite, releasing shell but not core DA. This process, which results in the acquisition of excessive incentive–motivational properties by drug conditioned stimuli, initiates the drug addiction process. Neuroadaptive processes related to the chronic influence of drugs on subcortical DA might secondarily impair the function of prefronto-striatal loops, resulting in impairments in impulse control and decision making that form the basis for the compulsive feature of drug seeking and its relapsing character.

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

References (69)

  • T.W. Robbins et al.

    Limbic-striatal interactions in reward-related processes

    Neurosci Biobehav Rev

    (1989)
  • G. Di Chiara

    A motivational learning hypothesis of the role of mesolimbic dopamine in compulsive drug use

    J Psychopharmacol

    (1998)
  • S. Fenu et al.

    Morphine-conditioned single-trial place preference: role of nucleus accumbens shell dopamine receptors in acquisition, but not expression

    Psychopharmacology (Berl)

    (2006)
  • B.J. Everitt et al.

    Neural systems of reinforcement for drug addiction: from actions to habits to compulsion

    Nat Neurosci

    (2005)
  • T.E. Robinson et al.

    The psychology and neurobiology of addiction: an incentive-sensitization view

    Addiction

    (2000)
  • R.A. Yokel et al.

    Increased lever pressing for amphetamine after pimozide in rats: implications for a dopamine theory of reward

    Science

    (1975)
  • R.A. Wise

    Neuroleptics and operant behavior: the anhedonia hypothesis

    Behav Brain Sci

    (1982)
  • H.C. Fibiger et al.

    Decreased intracranial self-stimulation after neuroleptics or 6-hydroxydopamine: evidence for mediation by motor deficits rather than by reduced reward

    Psychopharmacology (Berl)

    (1976)
  • D.L. Robinson et al.

    Detecting subsecond dopamine release with fast-scan cyclic voltammetry in vivo

    Clin Chem

    (2003)
  • N.D. Volkow et al.

    Positron emission tomography and single-photon emission computed tomography in substance abuse research

    Semin Nucl Med

    (2003)
  • A.A. Grace

    The tonic/phasic model of dopamine system regulation and its implications for understanding alcohol and psychostimulant craving

    Addiction

    (2000)
  • A. Lavin et al.

    Mesocortical dopamine neurons operate in distinct temporal domains using multimodal signaling

    J Neurosci

    (2005)
  • S.R. Sesack et al.

    Anatomical substrates for glutamate-dopamine interactions:evidence for specificity of connections and extrasynaptic actions

    Ann N Y Acad Sci

    (2003)
  • P. Greengard

    The neurobiology of slow synaptic transmission

    Science

    (2001)
  • B.J. Venton et al.

    Real-time decoding of dopamine concentration changes in the caudate-putamen during tonic and phasic firing

    J Neurochem

    (2004)
  • P. O’Donnell

    Dopamine gating of forebrain neural ensembles

    Eur J Neurosci

    (2003)
  • F. Gonon

    Prolonged and extrasynaptic excitatory action of dopamine mediated by D1 receptors in the rat striatum in vivo

    J Neurosci

    (1997)
  • M.F. Roitman et al.

    Dopamine operates as a subsecond modulator of food seeking

    J Neurosci

    (2004)
  • P.E. Phillips et al.

    Subsecond dopamine release promotes cocaine seeking

    Nature

    (2003)
  • G. Di Chiara

    Nucleus accumbens shell and core dopamine: differential role in behavior and addiction

    Behav Brain Res

    (2002)
  • V. Bassareo et al.

    Differential influence of associative and nonassociative learning mechanisms on the responsiveness of prefrontal and accumbal dopamine transmission to food stimuli in rats fed ad libitum

    J Neurosci

    (1997)
  • A. Hajnal et al.

    Oral sucrose stimulation increases accumbens dopamine in the rat

    Am J Physiol Regul Integr Comp Physiol

    (2004)
  • V. Bassareo et al.

    Differential responsiveness of dopamine transmission to food-stimuli in nucleus accumbens shell/core compartments

    Neuroscience

    (1999)
  • C. Gambarana et al.

    Acquisition of a palatable-food-sustained appetitive behavior in satiated rats is dependent on the dopaminergic response to this food in limbic areas

    Neuroscience

    (2003)
  • Cited by (417)

    View all citing articles on Scopus
    View full text