Intra-Accumbens Amphetamine Increases the Conditioned Incentive Salience of Sucrose Reward: Enhancement of Reward “Wanting” without Enhanced “Liking” or Response Reinforcement

“inson (Robinson and Berridge, 1993; Berridge and Robinson, 1998).”

“There were also significant effects on lever pressing for the drug dose factor (F(3,270) 5 3.164; p , 0.05) and the Pavlovian cue presence (F(1,270) 5 30.651; p , 0.001), and there was a significant interaction between cue 3 group (F(1,270) 5 5.671; p , 0.05).”

“First, by making the cue light located on the sucrose lever more attractive, the cue would become a more potent elicitor of approach responses (in a manner similar to autoshaping) ( Brown and Jenkins, 1968; Beagley and Holley, 1977; Rescorla and Cunningham, 1979; Davey et al., 1984; Toates, 1986, 1994; Oscos et al., 1…”

“…processes such as incentive salience, because it measures the ability of a cue to trigger motivation for rewards in the absence of both primary and secondary reinforcement (Rescorla and Solomon, 1967; Toates, 1986; Dickinson and Dawson, 1987; Balleine, 1994; Dickinson and Balleine, 1994).”

“Using the taste reactivity measure of hedonic impact, it was shown that intra-accumbens amphetamine failed to increase positive hedonic reaction patterns elicited by sucrose (i.e., sucrose “liking”) at doses that effectively increase sucrose “wanting.””

“Dopaminergic projections from the ventral tegmental area to the nucleus accumbens (part of the mesolimbic dopamine system) are the most crucial component of the implicit or unconscious wanting system [17,52,107] (Fig.”

“Previous animal research has shown that midbrain dopamine projections into areas including the accumbens are key to the appetitive and desire aspects of reward behavior.(70-73) Few neuroimaging studies have evaluated functional or morphometric changes in the accumbens area in subjects with mood disorders, despite the…”

“2003), or in rats following amphetamine or drug sensitization-induced elevation of dopamine release (Wyvell and Berridge 2000; Tindell et al. 2005).”

“…reward-associated cues (Blackburn et al., 1992; Di Ciano et al., 2001; Wakabayashi et al., 2004), whereas augmenting NAc dopamine transmission increases operant responding elicited or maintained by reward-associated cues (Taylor and Robbins, 1986; Wolterink et al., 1993; Wyvell and Berridge, 2000).”

“Moreover, dopamine concentrations in nucleus accumbens selectively affect the amount of effort an animal will exert to obtain a reward (Wyvell & Berridge, 2000).”

“…use disorders is that the dopamine response to drug-paired cues is potentiated, such that these cues trigger craving for drug and drug seeking (Bossert et al., 2005; Everitt et al., 2003; Parkinson et al., 2001, 1999; Shaham et al., 2003; Taylor and Robbins, 1986; Wyvell and Berridge, 2000).”

“…also showed that this effect was dependent on DA in the core of the accumbens, and therefore, this was presumably due to the general form of PIT, which requires dopamine, as the specific form is not dopaminedependent (Dickinson et al., 2000; Ostlund and Maidment, 2012; Wyvell and Berridge, 2000).”

“…these different motivational conditions Previous studies examining the role of the VTA or dopaminergic activity in PIT (Dickinson et al., 2000; Wyvell & Berridge, 2000; Murschall & Hauber, 2006) have demonstrated an important role for these systems; however, these studies have used designs…”

“It is an open question whether abstract rewards such as money are treated in the same way as fundamental rewards, but there is emerging evidence to suggest that there are important differences in the underlying brain processing (Sescousse et al., 2013a,b).”

“, 2001) after nucleus accumbens lesions in rats, and as increased lever pressing in response to a reward predicting cue in rats after amphetamine injection into the nucleus accumbens (Wyvell and Berridge, 2000).”

“Beyond the amygdala, incentive salience is mediated by larger mesocorticolimbic reward circuits, including nucleus accumbens dopamine, ventral pallidum, and other structures (Wyvell and Berridge, 2000; Zhang et al., 2003; Tindell et al., 2005; Day et al., 2007; Volkow et al., 2007; Di Ciano, 2008).”

“The latter effect is termed Pavlovian–instrumental transfer — or sometimes ‘wanting’ [21,22], although this term could equally refer to the instrumental incentive value underpinning true goal-directed action.”

“…the Pavlovian ‘critic’ and the instrumental ‘actor’ might be further subdivided in model-based and model-free components [7], this arrangement allows for multiple ways in which dopamine could affect model-based, goal-direct behavior via altering model-free Pavlovian control [2 (cid:2)(cid:2) ,62].”

“In the nineties, Berridge and co-workers challenged this hedonic perspective of incentive motivational theories through a corpus of experiments conducted on rodents (Berridge and Robinson, 1998; Mahler and Berridge, 2012; Pecina et al., 2003; Wyvell and Berridge, 2000, 2001).”

“Berridge et al., 1989; Berridge & Valenstein, 1991; Wyvell & Berridge, 2000 ).”

“…circuits, and so magnify incentive salience or phasic UCS ‘wanting’ peaks triggered by a CS+. Mesolimbic amplification of incentive salience may explain why a particular cue encounter can become irresistibly tempting, even when previous encounters were successfully resisted before.”

“Whereas the “liking” component is associated with striatal opioids (Peciña and Berridge, 2000), “wanting” seems to be related to dopaminergic neurotransmission in the ventral striatum (Wyvell and Berridge, 2000).”

“…shell microinfusions of amphetamine strongly potentiates the motivational vigor of lever pressing in the presence of a cue during pavlovian-to-instrumental transfer (PIT), as does chronic pretransfer experience with cocaine (Wyvell and Berridge, 2000; Saddoris et al., 2011; LeBlanc et al., 2013).”

“Whether CRF acts directly on nucleus accumbens circuits in ways comparable to dopamine, or interacts with dopamine release in nucleus accumbens, CRF release in nucleus accumbens might facilitate incentive salience mechanisms [27-31].”

“…Hall et al. 2001), and injection of amphetamine (a drug that increases extracellular dopamine) into the NAc enhances the CS-induced potentiation of responding (Wyvell and Berridge 2000, 2001), suggesting a critical role for NAc neurons in promoting behavior in response to goal-associated cues.”

“It has been demonstrated that presentation of a drugassociated CS to animals can induce large conditioned increases in nucleus accumbens DA (Di Ciano et al, 1998; Ito et al, 2000), suggesting that DA in the nucleus accumbens may be involved in cue-controlled drug-seeking (Wyvell and Berridge, 2000) through interaction…”

“Assessing liking in animal models mostly relies on facial expression studies, for example in mice, where it was demonstrated that DA, while reinforcing behavior, does not induce liking (Wyvell and Berridge, 2000; Leyton et al., 2002; Berridge and Robinson, 2003).”

“…of DA receptors (Dickinson et al. 2000) as well as transient inactivation (Murschall and Hauber 2006; Corbit et al. 2007) or DA depletion (El-Amamy and Holland 2007) of the VTA abolished, while stimulation of mesoaccumbens DA neurotransmission increased general PIT (Wyvell and Berridge 2000).”

“1997) and the ability of a CS+ to invigorate responding (known as Pavlovian to Instrumental Transfer: PIT) appears to be modulated by ventral striatal dopamine (Wyvell and Berridge 2000).”

“Drugs that facilitate DA transmission within the mesolimbic pathway enhance the processes by which otherwise neutral stimuli acquire incentive salience and motivate further drug-seeking behavior (Berridge and Robinson, 1998; Wyvell and Berridge, 2000).”

“Infusion of the psychostimulant and indirect dopamine agonist amphetamine into the NAcc shell increases operant responding to a reward-associated cue (Wyvell and Berridge, 2000) and increases breakpoint in a progressive ratio task (Zhang et al., 2003).”

“Frontiers in Behavioral Neuroscience www.frontiersin.org August 2012 | Volume 6 | Article 50 | 8 One example of such effects is the finding that increasing VS core dopamine levels by local amphetamine injection potentiates PIT for food rewards (Wyvell and Berridge, 2000).”

“Sucrose pellets, rather than liquid sucrose were used for comparison of these findings with previous PIT studies in our lab (Wyvell and Berridge 2000, 2001).”

“It has also been demonstrated that manipulation of NAC DA function by intra-NAC infusions of D1 or D2 receptor agents modulate the rate or vigor of responding with conditioned reinforcement or to rewardpredictive cues (Taylor and Robbins, 1986; Wolterink et al, 1993; Nicola et al, 2005), sometimes interpreted as ‘ince…”

“The composite score was calculated by summing all of the resulting measures 68,69 .”

“Specific infusions of dopamine D1 or D2 receptor antagonists into the core or shell also attenuate G-PIT (Lex & Hauber, 2008) whereas infusions of amphetamine into the NAc to stimulate dopamine transmission enhance the G-PIT effect (Wyvell & Berridge, 2000).”

“Indeed, low doses of AMPH preserve and improve learning and behavioral performance (Mayorga et al., 2000; Wyvell and Berridge, 2000; Taylor and Jentsch, 2001; Zhang et al., 2003; Knutson et al., 2004).”

“…signaling is also necessary for pavlovian food cues to produce conditioned motivation, as measured with PIT procedures (Dickinson et al., 2000; Wyvell and Berridge, 2000, 2001; Lex and Hauber, 2008; Aragona et al., 2009; Saddoris et al., 2011; Wassum et al., 2011, 2013; Ostlund and Maidment,…”

“Whereas, the mesolimbic dopamine system is crucial for food “wanting” (e.g. Pecina, Cagniard, Berridge, Aldridge, & Zhuang, 2003; Tindell, Berridge, Zhang, Pecina, & Aldridge, 2005; Wyvell & Berridge, 2000; for a review see Castro & Berridge, 2014).”

“discovered that increasing DA signalling in the NAc shell (and to a lesser extent the NAc core (but see [27]) via direct amphetamine administration increases the willingness to work for sugar pellets on a PR schedule of reinforcement [371] whereas others found that it actually inhibits free-feeding intake [191,192] an…”

“Dopamine fails to alter taste reactions By contrast to hedonic neurochemicalmanipulations, NAc dopamine stimulation by amphetaminemicroinjectionswithin or outside the shell hotspot [106,129], by genetic elevation of dopamine in the synapse (via knockdown of dopamine transporter in presynaptic dopamineneurons) [87], or…”

“Of particular relevance are recent developments in behavioral procedures that can be used to measure impairments in the ability to pursue and learn about reward.”

“…nucleus accumbens (Acb), has a key role in drug selfadministration by mediating pavlovian influences on instrumental seeking behavior (Cardinal et al, 2002; Wyvell and Berridge, 2000) as well as mediating the reinforcing effects of stimulant drugs through its dopaminergic innervation (Wise, 2004).”

“In some rats, intraoral fistulas for delivery of taste stimuli directly into the oral cavity (25) were fitted as described earlier, with the external port joining the head piece.”

“We then performed a small volume correction on the striatal activations in the putamen using an anatomical region of interest defined according to the Talairach Daemon atlas (Lancaster et al., 1997) using the SPM WFU PickAtlas tool (Maldjian et al., 2003).”

“In addition, cocaine-induced locomotor activity was used as a general ‘read out’ of mesolimbic function, as enhanced responsivity of mesolimbic circuits increases the motivational impact of food cues (Wyvell and Berridge, 2000, 2001).”

“…striatum is altered in addiction, and that changes there could contribute to the compulsivity of drug-seeking in addiction (Belin and Everitt, 2008; Everitt and Robbins, 2005; Robinson and Berridge, 1993; Volkow et al., 1999; Volkow et al., 1997; Volkow et al., 2006; Wyvell and Berridge, 2000).”

“…of the two measures observed here might be interesting in the context of their association with dissociable underlying corticostriatal circuitries (Taylor and Robbins, 1986; Jentsch and Taylor, 1999; Wyvell and Berridge, 2000; Eagle and Robbins, 2003a, b; Aron et al , 2003; Robbins, 2000).”

“Dopaminergic or electrical stimulation in this region enhances wanting and motivational responding with increased food consumption but with no enhancement of liking reactions (25, 26).”

“Lesions of the NAcc have also been shown to disrupt Pavlovian-toinstrumental transfer (de Borchgrave et al., 2002), whereas Pavlovian-to-instrumental transfer was enhanced by intraaccumbens administration of D-amphetamine ( Wyvell and Berridge, 2000 ).”

“We have observed a number of other similar brain manipulations that caused increases in motivational 'wanting', but failed to increase pleasure ('liking') for the same reward (Reynolds & Berridge, 2002; Robinson & Berridge, 2003; Wyvell & Berridge, 2000; Wyvell & Berridge, 2001).”

“This reward-induced dopaminergic activity promotes motivated behaviors and links those behaviors to cues associated with the reward (Wyvell and Berridge, 2000; Sotak et al., 2005; Hamid et al., 2016).”

“Thus, a more specific way to measure ‘wanting’ or the incentive salience of reward cues is the pure conditioned incentive Pavlovian-instrumental transfer procedure (PIT) [18,68,69].”

“Enhanced dopamine increases appetitive PIT (Wyvell and Berridge, 2000), while appetitive PIT is lowered when striatal dopamine is reduced (Dickinson et al., 2000; Hebart and Gläscher, 2015; Lex and Hauber, 2008).”

“p. 1485] – might be better suited than ‘wanting’ to describe the compulsive nature of drug taking at a stage that is characterized by considerable control of drug-associated stimuli over the individual’s behavior (see also the section on habit formation below).However, to paraphrase Berridge and Robinson, the most com…”

“First, manipulations that increase incentive motivation, such as food restriction and amphetamine treatment (Berridge, 1996; Wyvell & Berridge, 2000), produce a similar pattern of behavioral effects on the DRL-30-s and delay discounting tasks as we report here for STN lesions [i.e. increase…”

“Dopaminergic projections from the ventral tegmental area to the nucleus accumbens and prefrontal cortex are the most important component of the implicit or unconscious “wanting” system (FIGURE 4) (24, 41, 89).”

“Micro-injection of amphetamine into the NAc shell immediately prior to test likewise facilitated the acquisition of second-order conditioning for food pellets (Wyvell and Berridge, 2000).”

“2000) and that intra-accumbens d-amphetamine potentiates PIT ( Wyvell and Berridge 2000 ).”

“The ‘wanting’ (or desire) component is the positive value resulting from the relevance of the behavior for the needs of the individual [30, 32, 33], while the ‘liking’ component is the positive value resulting from the hedonic pleasure associated with the performance of the behavior [29].”

“However, wanting can also be dissociated from liking as demonstrated by sodium-depleted rats ‘wanting’ hypertonic saline, a taste they had never ‘liked’ before and also by drug addicts that do no longer ‘like’ to inject themselves [10,11].”

“Moreover, NAc injection of a dopamine reuptake blocker, a D1 or D2 receptor agonist, or the dopamine releaser amphetamine increases the probability of cued approach (Wyvell and Berridge, 2000; Nicola et al., 2005; du Hoffmann and Nicola, 2013).”

“Likewise, Wyvell and Berridge [66] found that intraaccumbens injections of amphetamine enhanced Pavlovian to instrumental transfer, but left orofacial responses to food itself unaffected.”

“This theory has given impetus to groundbreaking research with non-human (e.g., Wyvell & Berridge, 2000) and human (e.g., Wiers & Stacy, 2006) subjects, on behavioral and neuropsychological levels (e.g., Evans et al., 2006), and has impacted a wide range of impulse control disorders (e.g., Noël,…”

“For example, increases in nAc dopamine potentiate responding maintained by conditioned stimuli (Taylor and Robbins 1984; Wyvell and Berridge 2000), effects that can be blocked by lesions of the nAc (Taylor and Robbins 1986), or infusions of dopamine receptor antagonists (Wolterink et al. 1993).”

“However, pharmacological enhancement of dopamine transmission in the shell improves the ability of conditioned stimuli to increase reward seeking (Wyvell & Berridge, 2000).”

“…circuit (BA 25, agranular insula and ventral striatum) suggest a potential role in gauging inner emotional states through attention to inner physiology (Damasio, 1996; Craig, 2002; Phan et al., 2002; Critchley et al., 2004) and motivation (Wyvell and Berridge, 2000; Liljeholm and O’Doherty, 2012).”

“Drug doses and infusion intervals were selected based both on our own pilot experiments and a previous study demonstrating selective behavioral effects of manipulating the NAc subregions (Wyvell and Berridge, 2000).”

“Notably, lesions of NAc fail to disrupt the simple conditioning aspects of either Pavlovian or instrumental performance alone, but selectively impair the “transfer” ability of the cue to modulate operant activity (71, 86, 103), while DAenhancing infusions of amphetamine into the NAc shell enhance this effect (104).”

“Soon, however, we also found positive evidence that stimulation of mesolimbic dopamine systems in rats increased their motivational “wanting” to pursue or consume food rewards yet failed to enhance their “liking” of those same rewards (Berridge & Valenstein 1991, Wyvell & Berridge 2000).”

“Taken together, the present and previous results offer strong support to the idea that development of drug-induced CPP does not require the development of sensitization to the incentive effects of drugs of abuse (Cardinal et al. 2002; Wyvell and Berridge 2000).”

“…drugs enhances the influence of salient, reward-, or punishmentassociated cues on behavior (Robbins et al. 1983; Killcross et al. 1997; Wyvell and Berridge 2000) and can also enhance reward- and punishment-driven learning processes (Carr and White 1984; Hitchcott et al. 1997; Phillips…”

“It may be noteworthy that dopamine in NAc, like glutamate AMPA disruption, fails to enhance ‘liking’ reactions to sensory pleasure even when it elevates ‘wanting’, suggesting a functional similarity between ionotropic glutamate and dopamine actions in NAc [54,55].”