Dopamine Signaling in the Nucleus Accumbens of Animals Self-Administering Drugs of Abuse

1.2 Drug self-administration as an animal model for drug addiction

To better understand the neurobiology of drug abuse and addiction in humans, several animal models have been developed to investigate different aspects of drug addiction (Koob and Le Moal 2008). Among these models, paradigms that incorporate self-administration of drugs are thought to best capture the human condition because animals are allowed to voluntarily seek the drug and because drugs that are self-administered by animals correspond well with those that have high abuse potential in humans (Koob and Le Moal 2008). However, a great number of studies have examined the effects of drugs of abuse upon passive injection by the experimenter (non-contingent or response-independent administration). Therefore, in this chapter, we will review studies that have used contingent or response-dependent (self-administration), as well as non-contingent or response-independent drug injections.

1.3 Drug-self-administration and dopamine in the nucleus accumbens

Dopamine neurotransmission is highly implicated in the regulation of reinforcement in rodent drug self-administration paradigms. The dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc) has been identified as a critical substrate for the expression of drug reinforcement (Ritz et al. 1987; Wise and Bozarth 1987; Koob and Bloom 1988; Kalivas 2003). For example, direct dopamine receptor agonists are self-administered systemically as well as locally into the NAcc (Yokel and Wise 1978; Woolverton et al. 1984; Carlezon et al. 1995). Dopamine receptor antagonists administered systemically in low doses increase the rate of operant responding for cocaine in animals (DeWit and Wise 1977; Ettenberg et al. 1982; Roberts and Vickers 1984; Britton et al. 1991; Corrigall and Coen 1991; Caine and Koob 1994; Hemby et al. 1996), but decrease the motivation to carry out high work requirements to obtain an infusion of cocaine (Hubner and Moreton 1991; Richardson et al. 1993). Similarly, intra-cerebral administration of dopamine antagonists into the NAcc increases the rate of psychostimulant self-administration (Maldonado et al. 1993; Phillips et al. 1994), but decreases responding when work requirements for the drug infusion increase (McGregor and Roberts 1993). These effects have been interpreted as an attenuation of the reinforcing properties of the drug, such that more drug is taken to achieve the same level of reward and that less effort is invested into a drug infusion with decreased rewarding properties. In contrast, lesion or inactivation of the mesolimbic dopamine system in the VTA (Roberts and Koob 1982; Shoaib et al. 1998; Xi and Stein 1999) or the NAcc (Roberts et al. 1977, 1980; Lyness et al. 1979; Pettit et al. 1984; Corrigall et al. 1992; Shoaib et al. 1998) attenuate cocaine, amphetamine, heroin, and nicotine self-administration in rats. These findings further underline the critical importance of the mesolimbic dopamine system in drug taking. However, there are some conflicting reports on whether dopamine antagonists or lesions of the mesolimbic dopamine system affect responding for all drugs of abuse (Pettit et al. 1984; Hemby et al. 1996; Di Chiara 2000; Czachowski et al. 2001). Notably, the response of the NAcc dopamine system to drug administration (see below) differs significantly depending on whether the animal actively self-administers a drug of abuse or whether the animal receives it independent of a response (Hemby et al. 1995, 1997; Lecca et al. 2007).

1.4 Anatomy of the dopamine system and dopamine signal transduction: Phasic and tonic release

The VTA and the neighboring substantia nigra are the primary dopamine-producing nuclei in the brain (Swanson 1982). From these midbrain nuclei, relatively distinct dopamine cell groups innervate different functional domains of the striatum, i.e. sensorimotor, associative, and limbic circuits that are mainly defined by their differential cortical inputs (Carlsson et al. 1962; Dahlstrom and Fuxe 1964; Alexander and Crutcher 1990; Joel and Weiner 2000). The VTA predominantly projects to the limbic striatum including the NAcc. More than three quarters of this mesolimbic projection stems from dopaminergic neurons (Swanson 1982).

Dopamine acts on D1- or D2-type dopamine receptors upon release from dopaminergic fibers that densely innervate the striatum (Doucet et al. 1986; Ritz et al. 1987; Groves et al. 1994). Dopamine receptors are found at symmetric boutons formed by dopaminergic terminals on the neck or shaft of the spines of striatal projection neurons (Levey et al. 1993; Groves et al. 1994; Hersch et al. 1995; Caille et al. 1996). However, often dopamine receptors are also found on striatal dendrites outside such synapses, in the vicinity of asymmetric boutons on the head of dendritic spines that are contacted by glutamatergic terminals (Levey et al. 1993; Caille et al. 1996). Stimulation of dopamine receptors is terminated by reuptake of extracellular dopamine into the presynaptic terminals. Most dopamine reuptake sites are located on dopaminergic fibers outside synaptic contacts of dopaminergic terminals (Nirenberg et al. 1996; Hersch et al. 1997), similar to the dopamine receptors. Together, this distribution of receptors and reuptake sites allows for ‘volume transmission’; i.e., the activation of extrasynaptic dopamine receptors by dopamine that diffuses a few micrometers away from its release into the synaptic cleft (Garris et al. 1994; Garris and Rebec 2002; Rice and Cragg 2008). Therefore, the measurement of extracellular dopamine concentrations is a meaningful indicator of dopamine signaling.

Dopamine neurons are either hyperpolarized/quiescent or display different patterns of discharge activity: single-spike firing (2-10 Hz) or bursts of two to six action potentials (15-30 Hz) (Grace and Bunney 1984a, b; Freeman and Bunney 1987). Individual dopamine neurons can switch from one of these patterns to the other, as shown in freely-moving rats (Freeman and Bunney 1987; Hyland et al. 2002). Salient sensory stimuli can evoke a transient increase in firing rate and burst firing (Freeman and Bunney 1987; Mirenowicz and Schultz 1996). The ‘tonic’ extracellular concentration of dopamine, ranging from 5-20 nM depending on the target area, is thought to arise from basal dopamine neuron firing patterns, which predominantly consists of single-spike firing (Bunney et al. 1991; Grace 1991; Parsons and Justice 1992; Keefe et al. 1993; Floresco et al. 2003). Conversely, burst firing of dopamine neuron populations is thought to give rise to ‘phasic’ dopamine events which can reach as high as 1 μM (Gonon 1988; Chergui et al. 1994; Garris et al. 1997). In support of this assertion, it has been shown that electrical stimulations mimicking burst firing are much more potent in triggering dopamine overflow than single pulse stimulations (Wightman and Zimmerman 1990; Chergui et al. 1996; Gonon and Sundstrom 1996). In summary, the signaling modes that govern communication between dopamine neurons and their target cells are rapid and transient increases in dopamine concentrations (phasic dopamine) on top of a low, slowly changing dopaminergic tone (tonic dopamine).

2.1 In vivo microdialysis

Microdialysis is one of the most commonly used methods for the in vivo detection of dopamine and has excellent analyte selectivity and sensitivity. In microdialysis, extracellular dialysates of the brain are sampled through a membrane that is permeable to water and small solutes (Bito et al. 1966). The inside of the microdialysis probe inserted into the brain region of interest is continuously flushed with an isomolar solution that lacks the analyte of interest. The analyte of interest is sampled after diffusion from the extracellular space across the membrane into the microdialysis probe and thus changes in concentration can be detected. Another variant of this technique used for determining the absolute basal analyte concentrations is no-net flux microdialysis, which involves perfusion of known concentrations of the analyte of interest through the probe to establish when an equilibrium between the inside and the outside of the probe is reached (Parsons and Justice 1992). Despite the considerable size of the microdialysis probe (0.2-0.5 mm in diameter; 1-2 mm working length), several experimental studies indicate that the damage to the blood brain-barrier is minimal (e.g., Westerink and De Vries 1988; Tossman and Ungerstedt 1986).

Microdialysis is a sampling technique that is not directly coupled to any particular method of chemical analysis. The vast majority of studies uses high performance liquid chromatography in conjunction with electrochemical or fluorescence detection to analyze the very small amount of chemicals in the dialysate. Due to this small amount of dialysate, the sampling time-resolution is usually between 5 to 20 minutes. Even though there are now technical advances that will enable sample collection in intervals significantly shorter than a minute (Bowser and Kennedy 2001), most microdialysis experiments still operate on relatively low temporal resolution and are best suited for the quantitative analysis of basal and slowly changing tonic dopamine concentrations.

3.2 Drug effects on dopamine signaling measured over the course of minutes: Microdialysis studies

In the following sections, we will focus on studies investigating the effects of abused drugs on dopamine levels in the NAcc in the freely moving animal. Microdialysis studies in the behaving animal demonstrated that response-independent, systemic administration of cocaine, amphetamine, heroin, cannabinoids, nicotine, and ethanol increase dopamine levels in the NAcc (DiChiara 1986; Imperato and Di Chiara 1986; Imperato et al. 1986; Di Chiara and Imperato 1988; Kalivas and Duffy 1990; Kuczesnki et al. 1991; Yoshimoto et al. 1992; Pontieri et al. 1996; Tanda et al. 1997). The dose of the drug administered and the concentration of striatal dopamine following drug administration are positively correlated, as demonstrated for cocaine and ethanol (Nicolaysen et al. 1988; Bradberry 2002). Similar to response-independent drug administration, self-administered drugs of abuse, including cocaine, amphetamine, heroin and ethanol, induce increases in concentrations of dopamine in the NAcc (Hurd et al. 1989, 1990; Pettit and Justice 1989, 1991; Weiss et al. 1992, 1993; Di Ciano et al. 1995; Wise et al. 1995a, b). Conversely, drugs with low potential for abuse do not affect dopamine overflow (Di Chiara and Imperato 1988). These findings are in agreement with the dopamine hypothesis of addiction (see Sect. 3.1), since drugs of abuse increase tonic concentrations of extracellular dopamine in the NAcc.

During psychostimulant self-administration, animals learn to “load up” drug concentrations with an initial burst of operant responses before settling into a slower, more regular pattern of responding with inter-response rates varying between two and twenty minutes (Carelli and Deadwyler 1996). Response rates are inversely related to the infusion dose of cocaine or amphetamine, thus, the lower the dose the higher the number of responses (Pickens and Thompson 1968; Wilson et al. 1971; Yokel and Pickens 1973; Wise and Bozarth 1987; Di Ciano et al. 1995). However, the total intake of these drugs is elevated with higher doses. This intake pattern seems not to be due to aversive drug effects at high doses, since monkeys will choose infrequent high doses in preference to more frequent low doses (Iglauer et al. 1976) and rats show no reliable preference for one over the other (Di Ciano et al. 1995). Furthermore, animals will adjust their response rates to meet increased operant response demands (Roberts et al. 1989). Together, this suggests that animals titrate their drug intake to achieve a preferred level of intoxication.

Cocaine-induced increases in extracellular NAcc dopamine concentrations are thought to be the principal neurochemical event associated with the drug’s positive reinforcing action (see Sect. 1.3; Kuhar et al. 1991; Wise and Bozarth 1987; Roberts et al., 1977; Ritz et al., 1987). For example, psychostimulants are self-administered directly into the NAcc (Hoebel et al. 1983; MCkinzie et al. 1999), and morphine and ethanol into the VTA (e.g., Bozarth and Wise 1981; Gatto et al. 1994). With increased drug dose the dopamine “maintenance” concentration in the NAcc is also held at an increased level (Pettit and Justice 1991). Importantly, microdialysis studies have shown that animals will maintain the increased NAcc dopamine concentration during cocaine, amphetamine, and heroin self-administration sessions at a steady level over days, just like they maintain the drug concentrations at a steady level (Pettit and Justice 1989; Pettit et al. 1990; Wise et al. 1995a, b; Ranaldi et al. 1999). Furthermore, in a microdialysis study with advanced temporal resolution that sampled dopamine every minute, Wise and colleagues (1995b) demonstrated that the self-administration pattern of cocaine closely followed NAcc dopamine levels within sessions. This study demonstrated that cocaine dose-dependently increased dopamine concentrations after an infusion and that rats self-administered the next infusion as soon as the dopamine concentration diminished past a certain threshold. Consistent with this finding, it has been proposed that functional dopamine depletion in the NAcc represents a neurochemical correlate of drug craving (Dackis and Gold 1985; Koob et al. 1989). The findings presented above suggest that fluctuation in tonic dopamine concentration in the NAcc is a common denominator between different abused drugs that can regulate drug self-administration behavior.

3.3 Drug effects on dopamine signaling measured over the course of seconds to hours: Chronoamperometry studies

In vivo chronoamperometry studies in the behaving animal have demonstrated that experimenter-administered ethanol, cocaine, and amphetamine increase extracellular concentrations of dopamine over the course of minutes to hours (Kiyatkin 1994; Di Ciano et al. 1998b; Sabeti et al. 2003). Similarly, self-administration of heroin and psychostimulants caused an increase in dopamine concentrations in the NAcc on this time scale (Gratton 1996; Di Ciano et al. 2001, 2002). Thus, chronoamperometry studies with low time resolution confirmed microdialysis findings on the basic effects of abused drugs on extracellular concentration of dopamine in the NAcc.

To further investigate the temporal dynamics of dopamine signaling in animals self-administering drug, chronoamperometry with high time resolution was used to monitor dopamine on the order of seconds. NAcc dopamine concentrations were found to gradually increase preceding and to drop immediately following response-dependent (and – independent) intravenous injections of cocaine, before rising again around 4-6 min after infusion (Kiyatkin and Stein 1994, 1995). These post-response decreases in signal were dose-dependent, absent when the infusion was withheld, and the pre- response increases became increasingly bigger when the access to the lever was blocked (Kiyatkin et al. 1993; Kiyatkin and Gratton 1994; Gratton 1996). Furthermore, chronoamperometry studies reported similar response patterns during operant behavior maintained by other reinforcers such as heroin (Kiyatkin et al. 1993) and food (Kiyatkin and Gratton 1994), supporting the assumption that dopamine is the principal contributor to the reported biphasic signal fluctuations. In summary, the described high time resolution chronoamperometric data are in conflict with microdialysis findings which found that dopamine levels in the NAcc rise and fall in unison with oscillating blood/brain stimulant levels (Pettit and Justice 1989; Koob and Bloom 1988; Wise and Bozarth 1987; see Sect. 3.2).

The validity of chronoamperometry measurements has been challenged on basis of chemical sensitivity (Salamone 1996; Di Chiara 2002; Wightman and Robinson 2002). First, even though the electrodes are much less sensitive to DOPAC than to dopamine, the DOPAC concentration is several hundred times higher than dopamine and fluctuations in DOPAC concentration may contribute to the signal (Dayton et al. 1981; Gonon et al. 1984). Second, the voltage input step used to measure current changes that were assumed to be due to the oxidation/reduction of dopamine also measures changes in pH that often accompany dopamine signaling (Heien et al. 2004). The argument that chemical species other than dopamine are contributing to the chronoamperometry signal is supported by the fact that the detected task-related signaling changed dramatically during the development of self-administration behavior (Gratton 1996), an observation not reported for heroin or by microdialysis studies with cocaine. Furthermore, chronoamperometry studies report drug-induced elevations in dopamine concentrations last nearly twice as long as that measured with microdialysis (Di Ciano et al. 1995). Although these results were replicated and the reported electrochemical changes were shown to be task-related, one cannot be sure about the chemical specificity of the signal (Wightman and Robinson 2002), especially in light of evidence from a microdialysis study reporting the opposite finding (Wise et al. 1995b; see Sect. 3.2).

In summary, microdialysis and low time resolution chronoamperometry studies have convincingly demonstrated a link between tonic dopamine concentrations in the NAcc and the reinforcing effects of drugs of abuse. However, both techniques also raised questions. For example, what is the detailed temporal composition of dopamine signals? In contrast, chronoamperometry with high temporal resolution leaves the question of the chemical identity of observed phasic changes unanswered. These questions and some of the above described issues are not resolvable with these techniques, as the need for a combination of high temporal and chemical resolution is not satisfied by either of these techniques alone.

3.4 Drug effects on dopamine signaling measured on a subsecond time scale: FSCV studies

3.4.2 Changes in phasic dopamine signaling during cocaine self-administration: The role of operant behavior and conditioned stimuli

Pavlovian and operant conditioning paradigms using non-drug reinforcers have demonstrated that conditioned stimuli (CS) can elicit phasic dopamine release (Roitman et al. 2004; Day et al. 2007; Stuber et al. 2008; Owesson-White et al. 2008). In studies using drug reinforcers, it has been shown that repeated CS presentation with drug delivery subsequently can elicit an electrochemical response when the CS is presented alone (Kiyatkin et al. 1993; Kiyatkin and Gratton 1994; Di Ciano et al. 1998a). This response develops over time, as its development requires at least 10-50 pairings of the drug with the CS (Gratton 1996), and therefore indicates that these dopamine signals reflect a learning process. Studies that probed the contribution of CS to phasic dopamine in response to drug taking will be discussed below.

Contingent and non-contingent cocaine administration produce differential long-term effects on synaptic plasticity in VTA dopamine neurons (Chen et al. 2008). The effect of cocaine infusions on phasic dopamine release also depends on whether the drug administration is contingent upon an operant response or not, as shown with FSCV (Stuber et al. 2005a). For example, in rats pressing a lever for an intravenous infusion of cocaine, rapid changes in dopamine concentrations are time-locked to specific aspects of this behavior (Phillips et al. 2003; Stuber et al. 2005a, b; Fig. 1a), whereas no changes in dopamine levels are observed within 10 seconds of a response-independent cocaine administration to awake, but idle rats (Stuber et al. 2005a). In contrast, following these initial 10 seconds, the frequency of spontaneous dopamine transients increases dramatically independent of whether the administration of the drug was response-independent or –dependent (Stuber et al. 2005a). However, there is an ongoing debate as to what the exact latency of the pharmacological effects of cocaine is after intravenous infusion is (Espana et al. 2008; Wise et al. 2008). The considerable variance in the onset of these transients may be due to variability in the latency of drug delivery to the brain. Together, this suggests that a) early dopamine release events (first 10 seconds) in animals that self-administered cocaine may be related to learned associations, and b) the increase in spontaneous dopamine transients 10 seconds after the beginning of the infusion may be a consequence of the pharmacological effects of cocaine that is not related to learning. Consistent with this idea, these spontaneous transients are correlated with cocaine levels and the animal’s locomotion (Stuber et al. 2005a). In summary, cocaine self-administration is accompanied by early phasic dopamine release that is time-locked to the onset of drug infusion but cannot be attributed to the pharmacological effects of the drug.

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Figure 1

Phasic dopamine signaling in the NAcc associated with drug seeking and taking (a) Phasic dopamine signaling consists of multiple phasic events (triangles). The first event is elicited by the animal’s approach of the operant lever (pre-response signal; 1), whereas a bigger second event is associated with the onset of the audiovisual cue (dark gray bar) that is presented in response to the lever press (post-response signal; 2). A set of peaks (3) that is observed with an onset of approximately 10 seconds after the lever press and the beginning of the drug infusion (light gray bar), is thought to be a direct consequence of the pharmacological effect of the drug. The latency of this pharmacological effect relative to the operant response appears to be more variable than for the post-response signal. (b) During extinction, the audiovisual stimulus presented after the lever press is not accompanied by a drug infusion. As a consequence, the post-response dopamine signal becomes smaller with repeated non-reinforced responding. In contrast, the pre-response signal remains relatively stable during extinction. This suggests that the pre-response signal reflects the motivation to obtain drug, whereas the post-response encodes the expectation of the drug infusion.

Phillips et al. (2003) demonstrated that the largest change in dopamine concentration time-locked to cocaine self-administration behavior occurs immediately upon completion of the operant response (Fig. 1a). This effect was conditioned to an audiovisual stimulus (presented on the completion of the lever response) and was not due to the pharmacological actions of cocaine since it persisted during initial extinction trials where cocaine is replaced with saline (Stuber et al. 2005b; Fig. 1b). If the CS denoting the onset of the cocaine infusion was presented non-contingently during the period between operant responses, a similar dopamine signal could be evoked. Furthermore, this signal diminished gradually when the associative strength between the stimuli and cocaine is weakened during extinction (Stuber et al. 2005b; Fig. 1b). This phenomenon is identical to what has been observed with non-drug reinforcers, where cues that predict availability of these reinforcers are able to elicit phasic dopamine release on their own (Roitman et al. 2004, Owesson-White et al. 2008). Therefore, the change in extracellular dopamine that occurs at completion of the operant response (Fig. 1a) may encode the association of cue and drug delivery, and thus the expectation of cocaine delivery.

Phasic dopamine release has also been demonstrated just prior to the operant response for a self-administered infusion of cocaine (Phillips et al. 2003, Stuber et al. 2005a, b; Fig. 1a). These changes tended to be smaller than those following the operant response, but consistently preceded the animal’s approach to the response lever. In agreement with these antecedent neurochemical signals, dopamine neuron activation also occurs immediately before subsequent injections in rats trained to bar press for intravenous heroin (Kiyatkin and Rebec 2001). Furthermore, chronoamperometric studies detected a slow increase in dopamine-related signals (over the course of multiple seconds) in rats before they approached the lever for the next drug self-administration (Kiyatkin and Stein 1995). This temporal correlation with the drug seeking (lever approach) suggests that this component of the neurochemical signal might be causally linked to the behavior (Phillips et al. 2003, Stuber et al. 2005a, b). The temporal proximity of the signal precludes testing its role in drug seeking using conventional pharmacological approaches, since blockade of this signal will perturb other phasic dopamine signals or the tonic baseline level of dopamine. However, an electrically-evoked dopamine signal of similar brevity was sufficient to promote the lever approach (drug seeking), as such brief changes in dopamine, heavily influenced drug seeking by biasing the animal to initiate this behavior (Phillips et al. 2003). This may indicate a role for phasic dopamine in drug seeking or at least biasing the animal’s decision-making policies towards selecting actions leading to drug taking, rather than a direct role in drug reward. In contrast to the post-response signal, this pre-response signal does not appear to be a learned or conditioned process because it does not disappear during extinction trials, where the CS was presented contingent to the operant response but without drug infusion (Stuber et al. 2005b; Fig. 1b). Together, these findings indicate that the pre-response dopamine signal may be involved in initiating approach behavior.

In summary, these findings underline the multiple roles of phasic dopamine in operant responding for cocaine. Phasic dopamine release associated with operant behavior is comprised of signals in relation to approach, conditioned cues, and the pharmacological effects of the drug (Fig. 1a). Dopamine signaling is likely to play a role in motivation but probably also encodes other information about goal-directed behavior including learned association betweens cues and drug reward. The extinction-resistant pre-response signal seems to be related to drug seeking and therefore may have a motivational quality. In contrast, the post-response signal is linked to a learned association (lever-press and cue signaling the drug infusion) and therefore may be related to the expectation of drug delivery (see Sect. 3.4.2). Compared to natural reinforcers, such behavior-related dopamine release is enhanced due to the pharmacological properties of abused drugs. Therefore, the normal function of these signals is potentially corrupted, which may explain dysregulated goal-directed behavior in addiction (see Sect. 7.2).

4.1 Tonic dopamine during withdrawal

Microdialysis studies have demonstrated that the discontinuation of chronic treatment with ethanol (Rossetti et al. 1991, 1992a, b; Diana et al. 1993; Weiss et al. 1996), morphine (Acquas et al. 1991; Pothos et al. 1991; Acquas and Di Chiara 1992; Rossetti et al. 1992a, b; Crippens and Robinson 1994), nicotine (Rahman et al. 2004), amphetamine (Rossetti et al. 1992a), or cocaine (Parsons et al. 1991; Robertson et al. 1991; Imperato et al. 1992; Rossetti et al. 1992a, b; Segal and Kuczenski 1992; Weiss et al. 1992; Diana et al. 1993; Chefer and Shippenberg 2002; Zhang et al. 2003) decreases the basal extracellular concentration of dopamine in the NAcc.

However, there have been conflicting reports for withdrawal from psychostimulants. For example, several studies demonstrated a lack of change in basal concentrations of NAcc dopamine after withdrawal from amphetamine (Segal and Kuczenski 1992; Crippens et al. 1993; Crippens and Robinson 1994; Paulson and Robinson 1996). In the case of cocaine, some studies reported that withdrawal does not change tonic NAcc dopamine (Robinson et al. 1988; Kalivas and Duffy 1993; Hooks et al. 1994; Meil et al. 1995; Kuczenski et al. 1997), and yet others found an increase in basal dopamine levels (Imperato et al. 1992; Weiss et al. 1992; Johnson and Glick 1993; Heidbreder et al. 1996). While some studies reported changes in basal dopamine levels depending upon the time of cocaine withdrawal (Imperato et al. 1992; Heidbreder et al. 1996), these observed changes have not been consistent across studies. For example, some report that withdrawal after chronic cocaine exposure decreases basal dopamine levels in as early as a few hours (Zhang et al. 2003) to as long as 10 days (Parsons 1991), while others found increases in basal dopamine levels during 1 – 4 days of withdrawal (Imperato et al. 1992; Weiss et al. 1992; Heidbreder et al. 1996), and it was reported to have no effect on basal dopamine levels after 24 hours and 2 weeks withdrawal (Kalivas and Duffy 1993; Meil et al. 1995). Thus, at least for cocaine, no clear temporal effect of withdrawal on basal dopamine levels can be inferred from these studies. The studies described above utilized either conventional microdialysis or the more accurate method of determining exact basal dopamine levels, no-net flux microdialysis (Parsons and Justice 1992). The majority of studies employing no-net flux microdialysis did not observe changes in dopamine levels after withdrawal from cocaine treatment, strongly supporting no or minor effects of cocaine withdrawal on tonic dopamine concentration (Crippens et al. 1993; Kalivas and Duffy 1993; Heidbreder et al. 1996; Chefer and Shippenberg 2002).

Together, the effects of withdrawal from chronic drug treatment on NAcc dopamine levels depend on many factors, including the drug studied and the dose of the drug administered during the chronic treatment (Kalivas and Duffy 1993). In addition, it is known that tonic dopamine levels in the NAcc are affected by drug cues (see Sect. 5.1) and by contextual cues associated with aversive stimuli (Mark et al. 1991; Pezze et al. 1991; Saulskaya et al. 1995). Re-exposure to a drug-paired environment can either be rewarding or aversive depending on drug dose and time of drug-cue pairing after drug administration (Ettenberg 2004). Differences in these parameters may explain some of the discrepancies between studies presented here. In summary, according to microdialysis studies the NAcc dopamine system may undergo a depression after withdrawal from abused substances, however, this finding remains controversial regarding psychostimulants such as cocaine.

6.1 Motivation and addiction

The ‘incentive-sensitization’ theory of addiction proposed by Robinson and Berridge (1993) emphasizes the motivational function of NAcc dopamine. It states that hedonic processes (‘liking’) associated with drug intake are not mediated by the mesolimbic dopamine projection, which instead is involved in the attribution of incentive salience to stimuli associated with rewards (‘wanting’) (as described in Sect. 1.5.1). Thus, this theory postulates that NAcc dopamine mediates the motivation to pursue rewards. Addictive drugs are assumed to render these brain reward systems hypersensitive (i.e., ‘sensitized’) to drugs and drug-related stimuli, causing pathological wanting of drugs. According to this view, relapse to drug seeking and compulsive aspects of drug taking are mediated by the sensitized dopamine efflux in the NAcc in response to a drug-paired CS.

7.1 Dopamine signaling in the drug-naïve state (Fig. 2a)

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Figure 2

Drug-induced changes in phasic and tonic dopamine transmission in the NAcc (a) In the drug-naïve state, phasic (triangles) and tonic (solid horizontal line) dopamine signaling in the NAcc is normal. Few spontaneous phasic dopamine events (no cue) are observed. Salient stimuli (non-drug cues) can elicit phasic dopamine release and goal-directed behavior. (b) Drugs of abuse enhance tonic (dashed line) and phasic (triangles) dopamine signaling. Stimuli not associated with drug (non-drug cues) and drug-related cues both elicit phasic dopamine events, but the latter cause more robust release due to the temporal proximity to the drug administration. Furthermore, the number of spontaneous phasic dopamine events is increased. This may lead to aberrant learning of drug-cue associations and thus abnormal goal-directed behavior such as compulsive drug taking. (c) Effects of drug withdrawal on dopamine signaling are variable. For example, dampened tonic dopamine concentrations during withdrawal can be returned to and above basal concentrations by exposure to drug cues and drug context (left to right). Such drug cues may also elicit more phasic dopamine release (dashed triangle) compared to non-drug cues because 1) drugs represent a higher reward magnitude than natural reinforcers and/or 2) extended withdrawal results in incubation of drug craving. As a consequence, independent of tonic dopamine levels, seeking for drugs is more prevalent than seeking for natural reinforcers, which may promote relapse to drug taking.

In Figure 2, we summarize data reviewed in this chapter in a simplified manner and discuss it in light of the theoretical framework of NAcc dopamine function reviewed in sections 1.5 and 6. In a drug-naïve state (Fig. 2a), it is assumed that NAcc neurons receive physiological levels of receptor stimulation by tonic dopamine release providing normal motivational function of the organism. Phasic dopamine release and subsequent postsynaptic dopamine receptor stimulation may alter synaptic plasticity on striatal projection neurons (in concert with glutamate signals) in response to behaviorally-relevant novel stimuli and natural reinforcers. Together this allows for normal goal-directed behavior and reinforcement learning. In this drug-naïve state (Fig. 2a), stimuli that are specifically associated with drug intake, such as drug paraphernalia or cues predicting drug availability, will not affect dopamine neuron firing or release because the organism has not yet been exposed to the drug.

7.2 Immediate effects of drug exposure (Fig. 2b)

Thus far, we have reviewed data demonstrating that acute exposure to drugs of abuse increases phasic (see Sect. 3.4) and tonic dopamine concentrations (see Sect. 3.2 and 3.3) in the NAcc. What are the potential behavioral consequences of this enhanced dopamine signaling? During drug exposure, cues predicting reinforcer availability may elicit greater amounts of dopamine due to the drug-induced increase in the amplitude of phasic dopamine signals, similar to cocaine-induced increases in electrically stimulated release (Wu et al., 2001; Fig. 2a,b). Notably, exposure to cocaine and amphetamine also affects the processing of cues that are not related to drug intake (e.g., Puglisi-Allegra et al. 1994; Castellano et al. 1996; Cestari and Castellano 1996; Packard and White 1991). Additionally, the number of spontaneous phasic dopamine release events is increased dramatically due to the pharmacological effect of the drug which possibly leads to an association of an increased number of environmental stimuli with the drug experience (see Sect. 3.4). Together, this may explain how contextual cues not directly predicting drug administration become powerfully associated with the drug experience. In comparison to natural reinforcers and contextual cues, drug-associated cues are even more robustly ‘consolidated’ due to the high contiguity and contingency of drug administration and these cues (i.e., the drug-induced facilitation of dopamine signaling is strongest immediately after intake and drug cues are never experienced separately from drug administration) (Fig. 2b). Consistent with this idea, learning associations between cues and natural reinforcers transiently affects the synaptic properties of dopamine neurons, while drug experience promotes long-lasting changes to the intrinsic and synaptic properties of dopamine neurons (Chen et al. 2008; Stuber et al. 2008). Such facilitation in Pavlovian learning may then promote the development of abnormal levels of dopamine release by drug-conditioned stimuli upon re-exposure (Redish 2004; Di Chiara and Bassareo 2007).

With repeated training on a Pavlovian learning task using a natural reinforcer, the phasic dopamine signal shifts from reward delivery to the cue that predicts it (Day et al. 2007; Schultz et al. 1997). In contrast, dopamine signals in response to drug delivery in a drug self-administration task may not attenuate or may attenuate slower than with natural reinforcement because drugs directly activate the dopamine system. Therefore, this teaching signal may be constantly exhibited to both drug cues and the drug delivery itself. Thus, the brain continues to perceive drug delivery as a novel reward or positive prediction error despite repeated use (Redish 2004). Additionally, drug reward may be experienced as a reward of exaggerated magnitude and thus the positive prediction error may be extraordinarily large (Tobler et al. 2005). Together, this may lead to aberrant reinforcement learning and eventual fixation on pursuit of drugs and compulsive intake.

If dopamine acts to promote the repetition of actions that immediately precede rewarding events (Redgrave and Gurney 2006), drug exposure would immensely facilitate operant behavior that leads to drug administration. Alternatively, such drug-enhanced phasic dopamine signaling could also lead to the sensitized attribution of incentive salience to drug-related cues (Robinson and Berridge 1993). Thus, enhanced phasic signaling may promote abnormal responding to drug cues, whether due to aberrant learning and memory or motivation. Enhanced tonic dopamine concentrations may produce more exploratory activity and thus greater exposure of the organism to the drug environment including drug-related cues possibly promoting continued drug intake. This role for tonic dopamine fits well with the proposition that dopamine may have a function in overcoming the motivational costs required for completing tasks (Salamone and Correa 2002; Phillips et al. 2007). Tonically elevated dopamine concentrations may therefore keep the motivational cost for pursuing drug rewards minimal.

Together, we posit that the drug-induced enhancement of phasic dopamine signaling will increase phasic release in response to previously weak or neutral stimuli and specifically strengthen associations of drug cues and drug delivery, whereas increased tonic dopamine levels may maintain the organisms motivation to continue drug intake by promoting seeking of cues/environments associated with the drug (Fig. 2b).