Dopamine and drug addiction: the nucleus accumbens shell connection
Introduction
Among brain neurotransmitters, dopamine (DA) is the one that has been more extensively implicated in the mechanism of drug addiction, not only as the substrate of psychostimulant reward but, more generally, as a substrate of drug-related learning and neuroadaptation. In dealing with the role of DA in drug addiction, a preliminary discussion of some basic aspects of the neurobiology of DA transmission relevant to its role in behavior is in order.
Section snippets
Basic aspects of dopamine transmission: large spatial domain, slow time constant
DA acts via G protein-coupled receptors in a typical neuromodulatory fashion (Missale et al., 1998). Neuromodulatory actions are characterized by large temporal and spatial dimensions (Di Chiara et al., 1994, Greengard, 2001). The spatial domain of DA actions eventually exceeds the immediate surroundings of the synapse to involve distant somatodendritic and presynaptic receptors following diffusion of the transmitter throughout the extracellular space (Venton et al., 2004, Gonon, 1997). DA
Dopamine affects responses to stimuli that follow those that triggered its release
It has been estimated that following electrical stimulation of DA neurons, a change in activity can be recorded extracellularly in striatal neurons only after a delay of about 300 ms (Gonon, 1997). On the other hand, it takes less than half of this time (about 100 ms) for a movement-triggering stimulus to disinhibit the thalamic or collicular targets of Basal Ganglia output (Hikosaka et al., 2000, Di Chiara, 2002b). In light of this, although burst firing of DA neurons takes place in response
In vivo monitoring of dopamine responsiveness to motivational stimuli
Microdialysis studies on the effect of feeding and food-related stimuli on extracellular DA, have shown that feeding releases DA in relation to taste rather than to post-consummatory effects (Hajnal et al., 2004). This response differs among different terminal DA areas in relation to the motivational valence (appetitive/aversive) and value (palatability), and the novelty and predictability of taste stimuli (Bassareo and Di Chiara, 1997, Bassareo and Di Chiara, 1999a, Bassareo et al., 2002).
Nucleus accumbens shell dopamine, memory consolidation and Pavlovian learning
The role of DA in Pavlovian stimulus-reward learning might be related to consolidation of memory traces of reward-associated stimuli. An example of this mechanism is provided by conditioned taste aversion (CTA) learning. Blockade of NAc shell DA D1 receptors or their stimulation after exposure to a novel palatable taste impairs and, respectively, facilitates learning of CTA (Fenu et al., 2001, Fenu and Di Chiara, 2003). In this paradigm, NAc shell DA, released by a novel pala table taste onto
Dopamine and incentive arousal
Mogenson viewed the ventral striatum as an interface between motivation and action (Mogenson and Yang, 1991). This view was later extended to DA, and generated a number of hypotheses centered on the role of DA as a substrate of the activational properties of motivational stimuli. Thus, DA has been viewed to play a complex sensory-motor role (Salamone, 1992), a switching role (Redgrave et al., 1999, Feldon and Weiner, 1992, van den Bos et al., 1991, Mehta et al., 2004), a gain-amplifying role (
Addictive drugs increase extracellular dopamine preferentially in the nucleus accumbens shell in a response-contingent manner
In the mid 1980s, a series of microdialysis studies from our laboratory showed that most, if not all, addictive drugs increase extracellular DA preferentially in the rat ventral striatum, namely in the NAc, as compared to the dorsal caudate-putamen (Imperato and Di Chiara, 1986, Imperato et al., 1986, Di Chiara and Imperato, 1988a, Di Chiara and Imperato, 1988b, Carboni et al., 1989). A preferential increase of extracellular DA in the NAc/ventro-medial striatum was also observed in the
Drug-reward vs. food-reward: differential role of dopamine
Although the ‘original’ as well as the ‘revised’ anhedonia hypotheses differ for the attribution of a role to DA in motivational arousal (Wise, 1982), both theories assume that DA mediates the hedonic properties of all rewards, no matter if conventional (food, water, sex, etc.), chemical (drugs of abuse) or physical (intracranial self-stimulation). After years of debate and experimental tests, the anhedonia hypotheses appear no longer tenable as such. The main reason for this is that food
Drug-conditioned taste aversion as an expression of drug hedonia
It has long been known that exposure to systemic drugs of abuse results in CTA towards saccharin taste on which it has been made contingent (Cappell and LeBlanc, 1971, Goudie, 1979, Hunt and Amit, 1987). This finding contrasts strikingly with the rewarding properties of these drugs in other paradigms and its straightforward interpretation (drugs of abuse are ambivalent as to their motivational properties) has never been fully satisfactory. Thus, various differences were observed between CTA
Differential roles of nucleus accumbens shell and core dopamine
DA might play different roles in the two subdivisions of the NAc.
The NAc shell is the site of DA-dependent pre-trial consolidation of taste traces to be associated with visceral malaise in CTA learning (Fenu et al., 2001, Fenu and Di Chiara, 2003) and of post-trial consolidation of CS-UCR association in a paradigm of Pavlovian approach (Phillips et al., 2003). The NAc shell is also a site of DA-dependent modulation of spatial working memory information, relayed from the ventral subiculum, in
Relative roles of NAc shell and core in place conditioning
Although the DA transmission of the NAc is commonly regarded as a critical substrate of the place preference conditioned (CPP) by drugs of abuse, the relative roles of its shell and core subdivisions have not been investigated until recently. Sellings and Clarke (2003), in 6OHDA lesioned rats, have correlated the distribution of the loss of DA terminals, as estimated by autoradiography of the DAT-ligand RTI-55, to changes in amphetamine-induced locomotion and acquisition of amphetamine and
A phosphorylation cascade affecting multiple time-related functions of DA in behavior
The double role of NAc DA in motivation and responding might occur through activation of a cascade of protein kinases and phosphorylation of a number of protein substrates with multiple delays from DA receptor activation, from few hundreds of ms (=>300 ms) to minutes and hours. For example, phosphorylation of voltage-dependent NMDA-channels via D1-dependent activation of adenylate cyclase and of PKA might be the substrate of the acute psychostimulant effects of DA receptor stimulation (Hyman et
Dysadaptive stimulation of accumbens DA as a basis for the motivational disturbance of drug addiction
Consistent with the role of NAc DA in motivation and with the property of addictive drugs to stimulate DA transmission in the NAc, is the idea that drug addiction is a condition of disturbed motivation related to drug-induced stimulation of NAc DA (Di Chiara, 1995). A theory that explicitly links the disturbance of motivation to the property of addictive drugs to stimulate DA transmission in the NAc, and in particular in the NAc shell, is the abnormal Pavlovian incentive learning hypothesis of
Acknowledgements
Funds for the studies of the author’s laboratory have been obtained from many sources including the Consiglio Nazionale delle Ricerche (CNR), Ministero dell’Universita e della Ricerca (MIUR), European Commission (EC), Regione Autonoma della Sardegna and Institute for Scientific Information on Coffee.
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