Early studies suggested that the acute injections of nicotine to experimental animals increased both the population spike activity and burst firing of the DA neurons that project from the both the substantia nigra and VTA (Grenhoff et al. 1986). More recent studies have shown that the administration nicotine to experimental animals predominantly increases the number, duration, and frequency of phasic burst firing events evoked in the DA neurons of the VTA and substantia nigra (Zhang et al. 2009). These authors also found that there are fundamental differences in the frequency-dependent release of DA from terminals in the accumbal shell and dorsolateral striatum which favor DA overflow in the accumbal shell. As a result, the increase in phasic burst firing, evoked by an injection of nicotine, resulted in a preferential increase in DA release in the shell, results that are consistent with the results of earlier microdialysis studies (Benwell and Balfour 1997; Cadoni and Di Chiara 2000). This group also reported that nicotine injections substantially diminish DA release evoked by low-frequency tonic activity of the neurons. Thus, phasic DA activity and release is favored following an injection of nicotine and, as a result, nicotine injections enhance the “signal-to-noise relationship” within the terminal fields. A more recent study (Li et al. 2011) suggests that an acute nicotine injection also results in the development of synchronous firing of a subset of DA neurons within the VTA, a factor that may also contribute to the substantial increase of DA overflow into the extracellular space of the accumbal shell.

The administration of cocaine is also reported to elicit a preferential enhancement of phasic burst firing of the DA neurons that project to the accumbal shell and that this contributes to the increase in DA overflow evoked by the drug (Aragona et al. 2008). An earlier study from the same group showed that both non-contingently administered cocaine and contingent self-administration of the drug enhance phasic burst firing of the mesolimbic DA neurons that project to the nucleus accumbens (Stuber et al. 2005). Non-contingent cocaine administration to both cocaine-naïve rats and rats with previous experience of the drug evoked a substantial increase in the transient release of DA which was not time-locked to specific environmental stimuli. The contingent administration of the drug also evoked the changes in phasic release which were not time-locked to a stimulus. However, a subset of the phasic release events were time-locked to the lever-pressing responses, results which are consistent with the evidence that these transients relate the lever-pressing responses to conditioned stimuli that predict drug delivery (Phillips et al. 2003). Similar studies have yet to be performed with nicotine. However, the data support the working hypothesis that the administration of psychostimulant drugs of abuse elicits characteristic changes in the firing pattern of mesoaccumbens DA neurons. Furthermore, a significant proportion of the enhanced bursting activity of the neurons does not appear to be time-locked to the presentation of relevant conditioned stimuli and may, thus, subserve a different function putatively related specifically to dependence.

There is convincing evidence that the rewarding or reinforcing properties of nicotine, measured using a self-administration paradigm, depend upon the DA release from mesoaccumbens DA neurons. This conclusion is supported by the evidence that selective lesions of the DA projections to the accumbens result in a substantial reduction of intravenous nicotine self-administration in animals that have been trained in an operant chamber to press for nicotine (Corrigall et al. 1992). Furthermore, the local administration of nicotine receptor antagonists into the VTA evokes a similar attenuation of self-administration, data that support the view that the reinforcing properties of nicotine, measured using this paradigm, depend upon the stimulation of the DA neurons that project from the VTA (Corrigall et al. 1994). It is important to remember, however, that these observations may not be as compelling as they appear because lesioning procedures, similar to those adopted to attenuate nicotine self-administration, also attenuate the stimulatory effects of repeated nicotine on locomotor activity (Clarke et al. 1988; Louis and Clarke 1998). Moreover, the effects of intra-VTA nicotine on locomotion are inhibited by the prior administration of a nicotinic receptor antagonist (Reavill et al. 1990).

A most recent study by Cadoni et al. (2009) has shown that the self-administration of nicotine to inbred Lewis rats has a greater effect on DA overflow in both the nucleus accumbens shell and core than in the accumbens of inbred Fischer 344 rats. The study also showed that the Lewis rats were also more sensitive to the increase in locomotor activity, evoked by low doses of nicotine. A previous study suggested that, whereas Lewis rats can be trained to self-administer nicotine, Fischer 344 rats do not readily acquire this response (Brower et al. 2002). Furthermore, the Lewis rats that acquired nicotine self-administration responded preferentially on the active lever. The authors suggested that the data supported the conclusion that the Lewis strain may be genetically susceptible to the reinforcing properties of nicotine that underpin dependence. It is important to note, however, that Bower and colleagues used an extended unlimited access paradigm in which the animals were able to respond for nicotine for 23 h. By contrast, an earlier study by Shoaib et al. (1997), in which self-administration was measured over 1 h daily sessions, showed that neither Fischer nor Lewis rats readily acquired nicotine self-administration. Thus, the potential association between the genetic effects on DA overflow and reward, as measured using intravenous self-administration, should be treated with some caution.

The rewarding properties of nicotine can also be explored using a conditioned place preference paradigm in which one compartment of the apparatus is repeatedly paired with a nicotine injection. There is evidence that nicotine-induced conditioned place preference is attenuated if the DA projections to the nucleus accumbens are selectively lesioned (Di Chiara 2000). A more recent study showed that attenuation of nicotine-induced conditioned place preference could be evoked by selective lesions of the DA terminals in the accumbal shell, whereas lesions of the terminals in the accumbal core resulted in increased preference for the nicotine-paired compartment (Sellings et al. 2008). These authors concluded that the DA projections to the shell mediated the “rewarding” properties of the drug, whereas the DA projections to the accumbal core played a role in mediating the aversive properties of nicotine. However, as will be made clear later in this chapter, other roles have also been attributed to the DA neurons that project to the accumbal core.

Other researchers have employed more indirect approaches to explore the role of DA in the psychopharmacological responses to nicotine. For example, there is evidence that constituents of tobacco smoke cause inhibition of monoamine oxidase (MAO) activity in the brain and this effect is thought to enhance the addictive potential of nicotine when delivered in tobacco smoke (Brody 2006; Fowler et al. 2003). This hypothesis is supported by results reported by both Guillem et al. (2005) and Villegier et al. (2007) in which nicotine self-administration was shown to be enhanced by pretreating the animals with a drug that inhibits monoamine oxidase. A subsequent study (Guillem et al. 2006) demonstrated that this enhancement was particularly marked in animals pretreated with a selective MAO-A inhibitor but not in animals pretreated with an MAO-B inhibitor. In contrast to human brain, in which both isoforms of the enzyme are implicated in DA metabolism, in rat brain DA is preferentially metabolized by MAO-A (Saura et al. 1992). Thus, results with experimental animals are consistent with the possibility that the enhanced motivation to respond for nicotine is associated with the potentiation of DA. In other studies, Cohen et al. (2002) showed that pretreating rats with the cannabinoid CB1 receptor antagonist, rimonabant, attenuated both the effects of nicotine on DA overflow in the nucleus accumbens shell and nicotine-seeking behavior in a self-administration study. These data provide further support for the hypothesis that increased DA overflow in the accumbal shell plays a central role in nicotine-reinforced behavior.

In order to be able to interpret the results of studies with nicotine more clearly, it is instructive to consider how studies with other psychostimulant drugs of dependence have contributed to our understanding of the role of mesolimbic DA in addiction. Studies with cocaine have shown that rats can be trained to self-administer cocaine directly into the shell subdivision of the accumbens, whereas they cannot be trained to self-administer the drug directly into the accumbal core (Rodd-Henricks et al. 2002). Furthermore, this response was attenuated by the co-administration of the DA receptor antagonist, sulpiride, results which suggest that the reinforcing properties of cocaine delivered into the accumbal shell depends upon the stimulation of D2 receptors in this subdivision of the accumbens. Other studies have shown that the rewarding properties of amphetamine, measured using the place preference paradigm, are attenuated by selective lesions of the DA terminals in the accumbal shell (Sellings and Clarke 2003). Other anatomical loci have also been implicated in the reinforcing properties of psychostimulant drugs. Ikemoto (2003) noted that the DA neurons that project to the olfactory tubercle also seem to play a role in the reinforcing properties of cocaine. Furthermore, Sellings et al. (2006) extended these reported that the reinforcing properties of methylphenidate area associated with increased DA release in the medial olfactory tubercle. Thus, there is a need to be cautious when attributing the locomotor stimulant and reinforcing properties of nicotine solely to the events in the two principal subdivisions of the nucleus accumbens.

While the evidence that DA neurons play a central role in the reinforcing properties of psychostimulant drugs that underpin dependence is reasonably compelling, some studies suggest that the relationship is not simple. For example, Rocha et al. (1998) showed that transgenic mice lacking function neuronal DA transporters were hyperactive and could still learn to self-administer cocaine in manner that seemed similar to that seen for wild-type animals. The authors concluded that the reinforcing properties of cocaine cannot depend solely on its ability to inhibit the DA transporter and that other neural responses also play a key role in cocaine reinforcement. Studies with other drugs of abuse also suggest that DA may play a specific role in drug reinforcement. There is evidence that mesolimbic DA neurons may facilitate acquisition of opiate self-administration in rodents (Bozarth and Wise 1984; Singer and Wallace 1984). However, Pettit et al. (1984) demonstrated that, once the response had been acquired, lesions of the DA projections to the accumbens have no significant effects of heroin self-administration, whereas the lesions did attenuate established cocaine self-administration. Similar findings were reported by Gerrits and Van Ree (1996) who suggested that the results argued against a critical role for mesolimbic DA in the motivational mechanisms underpinning drug dependence. A subsequent study by Cannon and Palmiter (2003) showed that transgenic mice lacking tyrosine hydroxylase, and therefore the ability to synthesize DA, could still learn to respond for a sucrose reward. Thus, the data taken together support the possibility that increased DA release in the nucleus accumbens may facilitate the acquisition of responding for rewards or reinforcers but that it is not an absolute requirement.

Since a majority of drugs of dependence stimulate DA release and/or sustain DA overflow into the extracellular space, it is long been argued that this property of the drugs contributes significantly to neuropharmacological mechanisms which underpin the development of dependence (Di Chiara 1995; Wise 1987). Drug dependence is a chronic relapsing condition and it follows that the changes in the activity of mesolimbic DA neurons which occur as a consequence of chronic exposure to these drugs is likely to contribute to the mechanisms that underpin the transition to dependence. As already discussed, daily injections of nicotine result in sensitization of DA overflow in the core subdivision of the accumbens (Benwell and Balfour 1992; Cadoni and Di Chiara 2000; Iyaniwura et al. 2001). By contrast, the repetitive administration of nicotine, using the same protocol, does not elicit sensitization of DA overflow in the accumbal shell or dorsolateral striatum (Benwell and Balfour 1997; Cadoni and Di Chiara 2000; Iyaniwura et al. 2001). Indeed, some studies have shown that the effects of nicotine on DA overflow in the shell subdivision exhibit tolerance to nicotine if the drug is administered repeatedly (Cadoni and Di Chiara 2000; Tronci and Balfour 2011). If the animals are allowed to self-administer nicotine, a different pattern of responses is observed in the two principal subdivisions of the accumbens (Lecca et al. 2006). During the first week of nicotine self-administration, the effects of the drug on DA overflow in the nucleus accumbens shell are clear and significant. By contrast, the effects on DA overflow in the accumbens core are modest and do not achieve statistical significance. Thus, the effects of self-administered nicotine on DA overflow in the principal subdivisions of the accumbens resemble those seen in animals treated acutely with nicotine. During the third week of nicotine self-administration, there is a modest but statistically significant sensitization of the DA overflow in the accumbal core. However, in contrast to the effects of non-contingent nicotine, three weeks of self-administered nicotine result in sensitization of its effects on DA overflow in the accumbal shell. Similar sensitization of DA overflow in the accumbal shell is also observed in animals trained to self-administer cocaine or heroin (Lecca et al. 2007a, b). These observations support the view that preferential sensitization of the increase in DA overflow in the accumbal shell is a specific characteristic associated with the acquisition of contingent drug self-administration and play an important role in behaviors associated with the drug-taking behavior.

The putative behavioral significance of the changes in extracellular DA remains to be established. Grace (2000) has argued that the primary role of extracellular DA is to regulate phasic DA release through the DA autoreceptors and that the persistent increase in extracellular DA, evoked by chronic exposure to drugs of abuse, results in a sustained suppression of phasic responses. He posits that the craving to take drugs of abuse reflects a need to overcome this increased inhibitory effect and, thus, restore normal phasic DA release. Others have argued that increased extracellular DA, especially in the accumbal shell, plays a more direct role in drug-seeking behavior (Balfour 2009; Di Chiara et al. 2004). For nicotine, this hypothesis receives support from a number of studies which report that treatments which inhibit the increase in extracellular DA in the nucleus accumbens shell, evoked by the drug, also attenuate nicotine self-administration and conditioned place preference (Balfour 2009; Cohen et al. 2005, 2002; Di Chiara et al. 2004; Scherma et al. 2012, 2008; Tronci and Balfour 2011). Furthermore, in animals in which responding for the drug has been extinguished, the reinstatement of nicotine-seeking behavior, evoked by a non-contingent injection of nicotine, is also attenuated by a treatments that attenuate the increase in DA overflow in the accumbal shell evoked by nicotine (Mascia et al. 2011; Scherma et al. 2008). None of the studies have sought to determine whether the treatments act selectively or preferentially on phasic or tonic firing of the neurons.

The results presented above are consistent with the hypothesis that, like other psychostimulant drugs of abuse, increased DA overflow in the accumbal shell mediates the “rewarding” properties of nicotine. However, Salamone and colleagues (Salamone and Correa 2013; Salamone et al. 2012) have summarized a considerable body of evidence which suggests that responding for natural rewards, such as food, does not depend upon the stimulation of the DA projections to the nucleus accumbens. These pathways, however, do enhance behavioral activation, the motivational salience of the rewards, and effort-related choice. This hypothesis is consistent with an earlier study which demonstrated that transgenic mice, lacking a key enzyme (tyrosine hydroxylase) in the biosynthetic pathway for DA, still exhibit robust preference for sucrose over water although the transgenic animals consumed less sweetened solution than the wild-type controls (Cannon and Palmiter 2003). The authors concluded that the mice lacking DA exhibited a deficiency in goal-directed behavior rather than an impaired perception of the reward. Thus, there is a growing consensus that the DA projections to the accumbens influence the motivation to respond for a reinforcer, especially in an instrumental paradigm, rather than mediating their rewarding properties per se. It also seems reasonable to suggest, therefore, that compulsive drug-seeking and drug-taking behaviors reflect the effects of addictive drugs on these processes (Balfour 2009; Salamone and Correa 2012; Salamone et al. 2007). Salamone (Nunes et al. 2013; Salamone et al. 2012) and his colleagues have focused on the possibility that increased DA overflow into the extracellular space of the nucleus accumbens, including that evoked by drugs of dependence, enhances behavioral activation and effort-related choice behavior for rewards. By contrast, psychopathological conditions, such as depression, are posited to be associated with reduced DA release in this area of the brain and that this effect mediates the psychomotor slowing, anergia and apathy that characterize these conditions.

The increases in extracellular DA in the nucleus accumbens, evoked by the administration of nicotine and other drugs of dependence, are generally sustained for periods up to an hour or more. Thus, it seems reasonable to posit that they mediate the effects of sustained diffuse stimuli on drug-seeking or drug-taking behavior that are not time-locked to specific-conditioned stimuli (Balfour 2009). Studies in a number of laboratories have shown that nicotine self-administration is attenuated by pretreating the animals with an mGluR5 receptor antagonist (Palmatier et al. 2008; Paterson et al. 2003; Tessari et al. 2004). Tronci and colleagues (Tronci and Balfour 2011; Tronci et al. 2010) showed that this attenuation of nicotine self-administration is evoked at doses of antagonist that also attenuate the increase in DA overflow evoked by nicotine in the accumbens shell (Fig. 2). These data would appear to support the hypothesis that increased DA overflow in the accumbal shell mediates nicotine reinforcement in this instrumental paradigm and that the response to nicotine depends upon the co-stimulation of mGluR5 receptors. A parallel study by D’Souza and Markou (D’Souza and Markou 2011) showed that the microinfusion of an mGluR5 receptor antagonist directly into the VTA or accumbal shell attenuated nicotine self-administration. These results provide further support for a role for the DA projections to the accumbal shell in the reinforcing effects of nicotine and implicate mGluR5 receptors in these areas of the mesolimbic system in the response. However, the microinfusions into the VTA, but not the accumbal shell, also attenuated responding for a food reward. Systemic injections of moderate doses of MPEP, which attenuate nicotine self-administration, do not inhibit responding for a palatable food reward (Bespalov et al. 2005; Tronci and Balfour 2011) although it does attenuate the motivation to respond for food as determined using a progressive ratio paradigm (Paterson and Markou 2005). The effects of MPEP microinjections into the accumbal shell, therefore, most closely mimic the effects of systemic drug on nicotine self-administration, and it seems reasonable to conclude that the accumbal shell may be the primary site of the antagonists when they are administered systemically.

The reinforcing properties of nicotine that underpin dependence have been related to its ability to enhance brain reward function, as measured using an intracranial self-stimulation paradigm (O’Dell and Khroyan 2009) and to enhance the salience of other non-pharmacological reinforcers (Caggiula et al. 2002; Chaudhri et al. 2006; Donny et al. 2003; Palmatier et al. 2006). The reward-enhancing properties of nicotine are also observed in animals trained to self-administer the drug directly into the VTA, data which suggest that this property of the drug depends upon the stimulation of neurons, putatively DA neurons, that project from this area of the brain (Farquhar et al. 2012). Pretreatment with an mGluR5 receptor antagonist, however, is reported to have no effects on the reward-enhancing properties of nicotine (Kenny et al. 2003; Palmatier et al. 2008). Thus, although these facets of the nicotine psychopharmacology may be associated with stimulation of the DA projections from the VTA, it seems unlikely that they are dependent on the increase in extracellular DA evoked by the drug in the accumbal shell.

In experimental animals, both sensitization of the locomotor stimulant properties of nicotine and nicotine-seeking behavior in a self-administration paradigm can be conditioned to the environment in which the drug is administered (Bevins and Palmatier 2003; Diergaarde et al. 2008; Reid et al. 1998; Wing and Shoaib 2008). Furthermore, there is evidence that distal cues of this nature exert a significant influence on the craving to smoke tobacco (Le Foll and Goldberg 2005; Van Gucht et al. 2010). In the nicotine self-administration studies reported by Tronci and Balfour (2011), pretreatment with the mGluR5 negative allosteric modulator, MPEP, also suppressed responding on the inactive lever (Fig. 2). This observation implies that the drug does not act selectively on the reinforcing properties of nicotine. Moreover, as the dose of MPEP was increased, a higher proportion of the rats tested made no lever-pressing responses at all during the 1-h session (Table 1). This aspect of the response to MPEP, therefore, cannot be attributed to a neural interaction between nicotine and the mGluR5 antagonist. Moreover, studies on the effects of MPEP on locomotor activity indicated that the deficits in responding on the instrumental task did not reflect a general reduction in activity. MPEP pretreatment, however, selectively attenuated contextually conditioned hyperactivity in rats repetitively exposed to a maze following each daily injection of nicotine while having no significant effects on context-independent pharmacological sensitization of the locomotor response to the drug (Fig. 3) (Tronci et al. 2010). These observations seem most consistent with the possibility that a principal effect of MPEP is the attenuation of contextually conditioned behavioral responses to nicotine. Thus, MPEP seems to inhibit behavioral responses to nicotine in two ways. It attenuates the stimulation of DA overflow evoked in the nucleus accumbens by nicotine and, thereby, behaviors such as self-administration that depend upon this neural response. It also attenuates the effects of distal contextual cues that act, putatively through the hippocampus, to modulate the effects of nicotine on mesolimbic function and to promote nicotine-seeking behavior.

The effects of MPEP on the reward-enhancing properties of nicotine have also been explored using a paradigm similar to that described by Palmatier et al. (2007). MPEP pretreatment attenuated the enhanced responding for a non-pharmacological complex visual reinforcer seen in the animals given nicotine but also attenuated the moderate level of responding for the non-pharmacological reinforcer seen in animals trained with saline. As with the nicotine self-administration study, the effects of MPEP were not selective for the active lever. The data generated by this study, therefore, would appear consistent with the hypothesis that MPEP also attenuates contextually conditioned responding for this non-pharmacological reinforcer (Tronci et al. 2010). However, the data presented above contrast with those reported by Palmatier et al. (2008) who found no effects of MPEP on responding for the non-pharmacological reinforcer. The reason for the difference between the results of the two groups remains unclear although there are important differences in the experimental designs employed by the two groups which may explain why contextually conditioned responding contributed more significantly to the study performed by Tronci and Balfour (2011).

Studies using a place preference paradigm have shown that appetitive conditioning using a sucrose reward suggest that the neural circuitry that mediates the effects of conditioned spatial contextual cues on reward-seeking behavior differ from the effects of discrete conditioned stimuli (Ito et al. 2008). Significantly, these studies revealed that excitotoxic lesions of the accumbal shell attenuated the effects of the contextual cues, whereas lesions of accumbal core attenuated responding for discrete conditioned stimuli paired with presentation of the reward. The role of the accumbal shell depended upon the intact neural connections to the hippocampus. These results support the conclusion that limbic corticostriatal network plays a central role in spatial contextual conditioning. Moreover, studies with drugs of dependence suggest that the effects of spatial contextual stimuli on drug-seeking behavior are associated particularly with increased DA release in the accumbal shell (Bossert et al. 2007; Chaudhri et al. 2010; Crombag et al. 2008; Ito et al. 2000). DA overflow in the nucleus accumbens is increased by stimulation of glutamatergic projections from the hippocampus (Floresco 2007; Floresco et al. 2001; Legault and Wise 1999; Taepavarapruk et al. 2000). It has been proposed that these glutamatergic pathways play a pivotal role in the effects of distal contextual cues on behavior (Crombag et al. 2008). Crombag and colleagues focused on the role of glutamatergic projections from the dorsal hippocampus to the nucleus accumbens, whereas Grace and colleagues (Grace et al. 2007) have emphasized the role of the projections from the ventral hippocampus. The latter system is reported to enhance DA overflow in the nucleus accumbens shell via a circuit which projects through the ventral pallidum to the VTA by increasing the proportion of DA neurons that are tonically active. These observations imply that distal contextual cues may enhance the release of DA into the extracellular space of the shell of the accumbens by increasing the tonic activity of DA the neurons in the VTA. Stimulation of the glutamatergic afferents from the ventral subiculum to the nucleus accumbens increases both DA overflow and locomotor activity (Taepavarapruk et al. 2000). Studies to date have implicated both NMDA and non-NMDA glutamatergic receptors in this circuit (Floresco 2007; Floresco et al. 2001; Legault and Wise 1999; Taepavarapruk et al. 2000). There is a paucity of studies that have sought to explore the putative role of the hippocampus and its connections to the nucleus accumbens on nicotine-evoked contextual conditioning and, currently, there is no direct evidence that mGluR5 receptors are also implicated in the role of hippocampal afferents on DA release in the nucleus accumbens. However, the accumbal neurons that innervate the ventral pallidum are rich in mGluR5 receptor RNA, whereas only 50 % of the neurons that project directly to the VTA express these receptors (Lu et al. 1999), a finding that provides some indirect evidence for a role for mGluR5 receptor involvement in the circuit.

The repetitive non-contingent administration of drugs of nicotine results in a subregionally selective sensitization of its effects on DA overflow into the extracellular space of the accumbal core, an effect that nicotine shares with other drugs of dependence (Cadoni and Di Chiara 1999, 2000; Cadoni et al. 2000; Iyaniwura et al. 2001). Both the acquisition and expression of this sensitized DA response are attenuated by pretreatment with drugs that antagonize NMDA glutamatergic receptors, data which suggest that the sensitized response depends upon the co-stimulation of these receptors (Balfour et al. 1996; Shoaib et al. 1994). Other data support the conclusion that the sensitized DA response is caused by increased phasic burst firing the neurons that project to the accumbal core (Balfour et al. 1998; Schilstrom et al. 1998). This hypothesis is supported by a more recent study which demonstrated that increased phasic burst firing of the DA projections to the accumbal core depends upon the co-stimulation of nicotinic receptors composed of α6β2 subunits and NMDA receptors located on the DA neurons (Wickham et al. 2013). Data presented earlier in the chapter excluded the possibility that the increase in DA overflow, evoked by nicotine in the accumbal core, mediates the sensitized locomotor response seen in these animals when they are challenged with nicotine. These findings pointed to the likelihood that the sensitized DA responses mediate some other aspects of nicotine psychopharmacology, putatively associated with dependence (Balfour 2009; Balfour et al. 2000) although the nature of this role remains a matter of speculation (Di Chiara 2002; Di Chiara and Bassareo 2007). The administration of an NMDA receptor antagonist has, however, been shown to attenuate both nicotine self-administration and the increased brain reward function elicited by a nicotine injection (Kenny et al. 2009). Reduced nicotine self-administration and nicotine-facilitated brain reward function has also been observed in animals in which the antagonist was delivered locally into the VTA (Kenny et al. 2009). Thus, the reinforcing and reward-enhancing properties of nicotine can speculatively be associated with increased burst firing of mesolimbic DA neurons, but not necessarily those which project to the accumbal core. Indeed a subsequent study (D’Souza and Markou 2014) has shown that the responding for a nicotine-associated conditioned cue is enhanced by the local administration of an NMDA receptor antagonist into the accumbal core.

Discrete conditioned stimuli, repetitively paired with the self-administration of cocaine, substantially enhance self-administration of the drug and selectively activate neurons in the accumbal core (Hollander and Carelli 2007; Ranaldi and Roberts 1996). Selective excitotoxin-evoked lesions of the accumbal core have little effect on schedule-controlled cocaine self-administration but substantially inhibit drug-seeking behavior maintained by drug-associated conditioned cues (Ito et al. 2004). Other studies, reported by the same group, have shown that cocaine-seeking behavior, maintained by cocaine-paired conditioned stimuli, has no effects on DA overflow in the accumbal core or shell, but that non-contingent presentation of these stimuli results in a regionally selective increase in DA overflow in the core (Ito et al. 2000). In contrast, operant responding for cocaine-associated conditioned stimulus is associated with increased extracellular DA in the dorsal striatum, whereas the non-contingent presentation of the cue had no significant effects on extracellular DA in this region of the brain (Ito et al. 2002). These observations, the authors argued, suggest that increased extracellular DA in the accumbal core might be implicated in the reinstatement of drug-seeking behavior, evoked by exposure to drug-associated cues, whereas increased DA overflow in the dorsal striatum may be implicated in the maintenance of habitual cocaine-seeking behavior. These conclusions are consistent with recent results, employing an optogenetic approach, which show that cue-evoked reinstatement of cocaine-seeking behavior seems to be associated specifically with stimulation of the indirect pathway from the accumbal core to VTA that passages through the dorsoventral pallidum (Stefanik et al. 2013).